Crohn Disease

Complex MONDO:0005011 Pathograph 31 Show in embeddings browser Inflammatory Bowel Disease Autoimmune Disease

A chronic inflammatory bowel disease that affects the lining of the digestive tract, causing a wide range of gastrointestinal and systemic symptoms.

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Classifications

Harrison's Part

👪

Inheritance

Multifactorial

Crohn's disease follows a complex, multifactorial inheritance pattern with contributions from multiple genetic risk loci (NOD2, ATG16L1, IL23R, and over 200 additional GWAS loci) interacting with environmental factors.

Show evidence (1 reference)

PMID:32242028 SUPPORT

"Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown."

Confirms multifactorial etiology involving genetic susceptibility and environmental factors.

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Subtypes

Ileal Crohn's Disease

Involves inflammation of the ileum, the latter part of the small intestine.

Show evidence (3 references)

PMID:37377591 SUPPORT

"In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type."

This reference supports the statement that Crohn's disease involves inflammation of the ileum, and specifies this subtype as Ileal Crohn's Disease.

PMID:30882291 SUPPORT

"Gastroscopy revealed severe aphthous pangastritis with biopsies showing a focal active and chronic gastritis with presence of granulomas... coloscopy showing an aphthous terminal ileum... concordant with a slightly active, mildly chronic terminal ileitis typical for Crohn's disease."

This reference supports the claim that Crohn's disease can involve the ileum, characterizing it distinctly as terminal ileitis which is a known feature of Ileal Crohn's Disease.

PMID:31960900 SUPPORT

"Crohn's disease patients with unequivocal imaging findings of ileal inflammation at enterography despite negative ileoscopy and biopsy are likely to have active inflammatory Crohn's disease."

This reference highlights that Crohn's disease can manifest as inflammation of the ileum, aligning with the subtype of Ileal Crohn's Disease.

Colonic Crohn's Disease

Affects the colon (large intestine) with skip lesions.

Show evidence (5 references)

PMID:38437854 SUPPORT

"Commonly affecting the terminal ileum and proximal colon, Crohn's disease inflammation is often discontinuous and patchy, segmental, and transmural."

The literature indicates that Crohn's disease can affect the colon and often presents with discontinuous, patchy inflammation. However, it is typically not limited to the colon and often involves the terminal ileum.

PMID:11271896 SUPPORT

"The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient. Typical small intestinal CD occurred in four of seven patients with marked aphthous lesions of the small intestine, whereas colonic CD occurred in two of eight..."

This study shows that Crohn's disease can indeed affect the colon specifically, supporting the subtype known as Colonic Crohn's Disease.

PMID:26906301 SUPPORT

"Although ileitis can be seen in HSP, terminal ileitis is virtually pathognomonic for Crohn disease."

The focus is on terminal ileitis, commonly seen in Crohn’s disease. It suggests that Crohn's disease frequently involves the ileum, but does not refute that the colon can also be involved.

+ 2 more references

Ileocolonic Crohn's Disease

Involves both the small intestine (ileum) and the colon.

Show evidence (3 references)

PMID:33712743 SUPPORT

"Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment."

Although the literature acknowledges different manifestations of Crohn's disease involving the ileum and colon, it primarily discusses the broader differentiation between small-intestinal and colonic Crohn's Disease without naming or detailing specific subtypes such as Ileocolonic Crohn's Disease.

PMID:11271896 SUPPORT

"The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient."

This provides clinical evidence of Crohn's Disease affecting both the ileum and colon in patients but does not explicitly label it as Ileocolonic Crohn's Disease.

PMID:38294885 SUPPORT

"The terminal ileum and small bowel (SB) are involved in 30-45% of patients with Crohn's disease, while 20% have both small and large bowel involvement."

This literature reference supports the statement by noting that 20% of Crohn's disease cases involve both the small and large intestines, which corresponds to the description of Ileocolonic Crohn's Disease.

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Mechanistic Hypotheses

Amplification of polygenic Crohn disease risk in adverse contexts via shared intestinal-inflammation convergence

pgs_context_amplification EMERGING

Evidence balance 2 support

Polygenic-score-by-context (PGS×C) interactions reported for inflammatory bowel disease in the UK Biobank appear to reflect amplification rather than context-specific causal variants: the same susceptibility loci (e.g. NOD2, ATG16L1, IL23R) exert systematically larger effects in disease-promoting contexts. This entry proposes that the amplification arises because polygenic liability and adverse exposures — notably tobacco smoking (a risk factor in Crohn disease, in contrast to its protective association in ulcerative colitis) and diet — converge on the shared Intestinal Inflammation and Epithelial Injury node, so their joint effect on the liability-threshold scale is super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026, PMID:42443528) report pervasive PGS×context interactions for prevalent IBD.

EMERGING hypothesis motivated by population-scale PGS×context analyses (primary source PMID:42443528; general amplification mechanism corroborated by PMID:37228747). The convergence claim (polygenic liability + smoking/diet → Intestinal Inflammation and Epithelial Injury) is a mechanistic interpretation and is not itself established as causal — see the reverse-causation knowledge gap under discussions.

Show evidence (2 references)

PMID:42443528 SUPPORT Computational

"The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health"

Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and 75 contexts, amplification of genetic effects in adverse contexts is identified as the predominant mechanism of PGS×context interaction — the mechanism applied in this hypothesis.

PMID:37228747 SUPPORT Computational

"GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects"

Corroborates amplification — systematic differences in the magnitude of polygenic effects rather than in the identity of causal variants — as the primary mode of gene-by-context interaction.

Canonical NOD2 / Autophagy / Th17 Mucosal Dysregulation Model

canonical_nod2_autophagy_th17_mucosal_dysregulation_model CANONICAL

Evidence balance 1 support

Crohn's disease arises from a polygenic susceptibility to impaired mucosal innate immunity (NOD2, ATG16L1, IRGM, and other autophagy genes) combined with environmental triggers (smoking, diet, microbiota perturbation) that produce defective bacterial sensing and clearance by Paneth cells, macrophages, and intestinal epithelial cells. The resulting chronic exposure of lamina propria APCs to commensal antigens drives IL-23-dependent Th17/Th1 polarization, granuloma formation, and transmural inflammation. Anti-TNF (infliximab, adalimumab), anti-IL-12/23 (ustekinumab), anti-α4β7 (vedolizumab), and JAK inhibitors all corroborate this immune-dysregulation model by interrupting specific cytokine and trafficking axes downstream of the underlying innate-immunity defect.

Retained as CANONICAL but with a partially-supported qualification. The 2026 falcon hypothesis-search report (kb/hypotheses/Crohn_Disease/canonical_nod2_autophagy_th17_mucosal_dysregulation_model; openscientist timed out at 3600s) finds direct human and mechanistic evidence continues to strongly support that autophagy/innate-microbial-handling risk variants produce cell-type-specific defects in antigen handling and Paneth-cell homeostasis, with IL-23-driven innate cytokine programs detectable in macroscopically healthy mucosa. Three critical qualifications mark the model as best treated as a modular, context-dependent framework rather than a universal mechanism: (1) some canonical risk alleles show no functional effect in specific assays/cell types — e.g., NOD2 R702W in DC autophagy flux; NDP52 Val248Ala in epithelial AIEC xenophagy assays; (2) the IL-23 → IL-17 step is not consistently observed in early human disease, despite IL-23 detection in pre-clinical mucosa; (3) parallel upstream mechanisms — macrophage LRRK2 hyperactivity (especially with smoking), virome sensing deficits, and microbiome virulence programs such as type III secretion systems — can produce Crohn-like inflammatory trajectories WITHOUT requiring an epithelial-intrinsic NOD2/autophagy defect as the initiating event. The canonical model remains a strong scaffold for a subset of Crohn biology but does not capture all etiologic paths.

Deep research

Falcon citations 51 citations 2026-05-23T23:27:27.417947

Show evidence (1 reference)

PMID:32242028 SUPPORT Human Clinical

"Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors"

Canonical mechanism reference used as the seed for the hypothesis-search deep-research run.

Discussions and Knowledge Gaps

Are the IBD PGS×context interactions driven by adverse exposures causally amplifying genetic risk, or are some "contexts" (e.g. CRP, fecal calprotectin, diet change) actually downstream readouts/responses of active disease (reverse causation)?

KNOWLEDGE GAP OPEN crohn_pgsxc_reverse_causation

Attached to

pathophysiology#Intestinal Inflammation and Epithelial Injury biochemical#C-Reactive Protein (CRP) biochemical#Fecal Calprotectin environmental#Diet

Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. For Crohn disease the biochemical "contexts" C-reactive protein and fecal calprotectin are disease-activity readouts (consequences of active inflammation), and dietary change is a classic response to gastrointestinal symptoms rather than a pure upstream driver, making both prime reverse-causation suspects. Distinguishing genuine amplification of genetic effects from reverse causation determines whether the modelled interventions (smoking cessation, dietary modification) would actually reduce risk.

Proposed experiments

Mendelian randomization of exposure-to-Crohn direction across PGS strata

crohn_pgsxc_mr_direction

Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (smoking, diet, inflammatory biomarkers) causally affects Crohn disease versus being a consequence of active disease, and whether the causal effect estimate scales with polygenic liability as the amplification model predicts.

Decision criterion

A context is retained as a causal amplifier if MR supports exposure-to-disease directionality and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.

Prospective incident-Crohn analysis restricted to pre-diagnosis exposure windows

crohn_pgsxc_prospective_temporal

Restrict exposures to measurements taken well before diagnosis and repeat the PGS×context liability-threshold modelling on incident cases only, to reduce the chance that exposure and biomarker values reflect established disease rather than antecedent risk.

Decision criterion

Amplification is supported if the PGS×context deviation from additivity persists when only pre-diagnosis exposure windows and incident cases are used.

Are creeping fat-derived CTHRC1-positive mechanosensitive fibroblasts a necessary and targetable driver of Crohn strictures, or are they a downstream marker of bowel-wall inflammation and established fibrosis?

KNOWLEDGE GAP OPEN gap_crohn_creeping_fat_stricture_causality

Attached to

pathophysiology#Fibrosis and Stricture Formation pathophysiology#Intestinal Inflammation and Epithelial Injury pathophysiology#Myeloid-Stromal Cell Crosstalk

The Crohn entry captures inflammation-driven fibrosis, but recent single-cell and animal-model work suggests that mesenteric creeping fat may supply a mechanosensitive fibroblast population at the fat-bowel interface. Testing necessity and reversibility would determine whether future anti-fibrotic experiments should target bowel inflammation alone or the mesenteric-fat interface as a separate disease mechanism.

Proposed experiments

Patient-derived creeping-fat bowel-interface fibrosis-on-chip assay

patient-derived organ-on-chip fibrosis perturbation experiment

exp_crohn_creeping_fat_bowel_interface_yap_taz_rescue

Construct a patient-derived Crohn bowel-wall organoid or organ-on-chip that juxtaposes intestinal epithelial organoids, bowel-wall stromal cells, mesenteric adipose stromal cells, and myeloid cells on tunable-stiffness matrix; then deplete or inhibit CTHRC1-positive/YAP-TAZ-high fibroblasts to test whether extracellular-matrix deposition and stricture-like tissue contraction are prevented or reversed.

Model systems

Crohn creeping-fat bowel-interface organ-on-chip

Microphysiological model of the fibrotic Crohn fat-bowel interface combining intestinal epithelium, lamina propria stromal cells, mesenteric adipose stromal cells, fibroblasts, and myeloid cells under tunable mechanical stiffness.

ORGAN ON CHIP namo:OrganOnChip link

human NCBITaxon:9606

ileum UBERON:0002116

intestinal epithelial cell CL:0002563 fibroblast CL:0000057 adipocyte CL:0000136 macrophage CL:0000235

Perturbations

CTHRC1-positive fibroblast depletion

pathophysiology#Fibrosis and Stricture Formation

Genetic, antibody-based, or sorting-based removal of CTHRC1-positive/YAP-TAZ-high fibroblasts from the creeping-fat compartment to test necessity for fibrotic remodeling.

CTHRC1

YAP/TAZ mechanotransduction inhibition

pathophysiology#Fibrosis and Stricture Formation

Pharmacologic or genetic blockade of YAP/TAZ activity under high-stiffness matrix conditions to test whether mechanosensitive signaling maintains extracellular-matrix deposition.

YAP1 WWTR1

regulation of transcription by RNA polymerase II GO:0006357

Myeloid-stromal inflammatory challenge

pathophysiology#Myeloid-Stromal Cell Crosstalk

Myeloid-cell cytokine challenge used to test whether creeping-fat fibroblasts require inflammatory crosstalk to invade the bowel-wall compartment.

inflammatory response GO:0006954

Readouts

Extracellular-matrix deposition and contraction

pathophysiology#Fibrosis and Stricture Formation

Collagen deposition, matrix stiffness, gel contraction, and luminal narrowing analogs.

extracellular matrix organization GO:0030198

extracellular matrix immunostaining traction force microscopy

Direction: POSITIVE

CTHRC1-positive/YAP-TAZ fibroblast state

pathophysiology#Fibrosis and Stricture Formation

Single-cell and spatial profiling of CTHRC1-positive fibroblasts, YAP/TAZ target-gene signatures, and fat-bowel interface localization.

single-cell transcriptomic profiling spatial transcriptomic profiling

Direction: POSITIVE

Epithelial barrier injury under fibrotic stiffness

pathophysiology#Intestinal Inflammation and Epithelial Injury

Barrier permeability and epithelial injury-state readouts coupled to stromal stiffness.

permeability assay epithelial inflammatory profiling

Direction: POSITIVE

Controls

Bowel-wall organoid without creeping-fat compartment

Patient-derived intestinal organoid and stromal culture lacking mesenteric adipose cells.

Non-stricturing Crohn comparator culture

Patient-derived culture from inflammatory, non-stricturing Crohn tissue.

Low-stiffness matrix control

Mechanical control testing whether fibroblast activation depends on fibrotic stiffness.

Decision criterion

Creeping-fat fibroblasts are supported as causal if their presence increases CTHRC1/YAP-TAZ state, extracellular-matrix deposition, matrix contraction, and epithelial injury, and if depletion or YAP/TAZ blockade prevents or reverses these readouts despite inflammatory challenge.

Would support

pathophysiology#Fibrosis and Stricture Formation pathophysiology#Myeloid-Stromal Cell Crosstalk

Would refute

pathophysiology#Fibrosis and Stricture Formation

Show evidence (3 references)

PMID:40967215 SUPPORT Human Clinical

"we identified CF-derived, CTHRC1+ fibroblasts enriched for Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signatures and localized to a fibrotic CF-bowel wall interface within the stricture."

Supports the proposed target population and its localization at the creeping-fat bowel interface in human Crohn strictures.

PMID:40967215 SUPPORT Model Organism

"analogous Cthrc1+ mouse fibroblasts derive from mesenteric adipose tissue stromal cells, infiltrate fibrotic bowel, and deposit extracellular matrix in a YAP/TAZ-dependent manner"

Provides causal animal-model support for testing YAP/TAZ-dependent extracellular-matrix deposition in a humanized ex vivo platform.

+ 1 more reference

Is there any Crohn-specific evidence that copper-dependent cell death occurs in ileal or colonic lesions, or does the CD literature consist entirely of transcriptomic cuproptosis-gene signatures that measure different members of the cuproptosis gene set and are not directly comparable, so that copper dysregulation belongs on this entry only as a susceptibility or metabolic-stress marker?

KNOWLEDGE GAP OPEN gap_crohn_cuproptosis_evidence_hierarchy

Attached to

pathophysiology#Intestinal Barrier Dysfunction pathophysiology#Dysregulated Immune Response

Crohn disease is named in the cuproptosis-in-autoimmunity literature only inside an undiscriminated "inflammatory bowel disease" grouping, and the CD-specific literature that does exist stops at bioinformatic inference, the lowest tier of the source review's own evidence hierarchy. Two studies interrogate CD directly, and they are not directly comparable because they measure disjoint members of the cuproptosis gene set: a 2022 GEO analysis of 437 CD samples found most differentially expressed cuproptosis genes - the canonical hub genes - expressed at lower levels in CD and negatively related to immune cell infiltration, while a 2025 bulk plus single-cell study found four different markers (CD274, PDK1, CP, SLC31A2) upregulated in CD. No gene is shared between the two result sets, so the two findings are simultaneously coherent rather than contradictory, and a dedicated IBD review reports the core regulators as downregulated in IBD, consistent with the 2022 direction. Neither measured copper, lipoylated-protein aggregation, Fe-S cluster loss, or attempted rescue, and the 2025 study says outright that experimental validation is still required. The functional colitis work that does clear part of the canonical bar - tetrathiomolybdate and penicillamine rescue of barrier damage - was done in DSS and TNBS models, which are colitis models and speak to the parallel gap on Ulcerative_Colitis, not to transmural ileal Crohn disease. No cuproptosis pathophysiology node is therefore added here. The gap is attached to intestinal barrier dysfunction, which is what the rodent copper work perturbs and what a CD cuproptosis mechanism would have to act on, and to the dysregulated immune response node, because the only CD-specific claim in the literature is a correlation between the cuproptosis gene signature and immune cell infiltration. Recording it keeps the question findable and stops a future transcriptomic association being mistaken for a resolved mechanism.

Proposed experiments

Canonical-cuproptosis criteria in Crohn ileal tissue, measured across the whole gene set

mechanism validation study in human surgical tissue and patient-derived organoids

exp_crohn_canonical_cuproptosis_criteria_in_ileal_tissue

Do not start from another GEO reanalysis. Take paired inflamed and uninflamed full-thickness ileal and colonic tissue from Crohn resection specimens, plus non-IBD surgical controls, and apply the five canonical criteria to the tissue: quantify mucosal and transmural copper, assay FDX1 and LIAS protein with lipoylated DLAT/DLST aggregation, and measure Fe-S cluster protein destabilization. Supply the rescue arm with patient-derived ileal organoids treated with tetrathiomolybdate. In the same specimens, measure the four markers reported as upregulated (CD274, PDK1, CP, SLC31A2) and the hub genes reported as downregulated at protein level, stratified by inflamed versus uninflamed and by Montreal behaviour. The point of measuring both sets in the same specimens is that the two published studies never did: they report disjoint genes, so whether the cuproptosis gene set moves coherently in CD is untested rather than disputed. Because the only CD-specific claim in the literature ties the signature to immune infiltration, deconvolve or sort the immune compartment so an apparent epithelial copper phenotype is not an infiltrate composition artefact.

Assays

tissue copper quantification FDX1 and LIAS immunoblot and in situ protein detection lipoylated protein aggregation assay Fe-S cluster protein stability assay immune cell deconvolution and flow cytometric sorting

Readouts

Copper-dependent epithelial death in Crohn lesions

pathophysiology#Intestinal Barrier Dysfunction

Copper content, DLAT/DLST aggregation and Fe-S cluster protein loss in inflamed versus uninflamed Crohn ileum, with barrier integrity assayed in matched organoids under copper chelation.

Direction: ALTERED

Interpretation: Satisfaction of the canonical criteria in inflamed tissue with chelation rescue in organoids would justify a cuproptosis node upstream of barrier dysfunction; failure would confine copper dysregulation to a metabolic-stress marker.

Cuproptosis signature versus immune infiltrate composition

pathophysiology#Dysregulated Immune Response

Cuproptosis gene and protein signature measured before and after adjustment for immune cell composition, stratified by inflammatory activity.

Direction: ALTERED

Interpretation: A signature that disappears after adjusting for infiltrate composition would close the question without a new node; one that persists would localise a genuine copper phenotype to a defined cell population.

Controls

Uninflamed margin from the same resection

Within-patient control separating a copper phenotype specific to Crohn lesions from one attributable to the patient or to surgery.

Non-IBD inflamed intestine

Infectious or ischaemic enteritis, to test whether any copper phenotype is specific to Crohn disease rather than to intestinal inflammation.

Decision criterion

Add a cuproptosis pathophysiology node to this entry only if all five canonical criteria - copper dependence, FDX1-lipoylation axis involvement, lipoylated-protein aggregation, Fe-S cluster destabilization, and functional rescue - are demonstrated in Crohn tissue or patient-derived Crohn organoids, and only if the signal survives adjustment for immune infiltrate composition. Transcriptomic signatures, however well validated as classifiers, do not meet the bar, and colitis-model results do not transfer to this entry.

Would support

pathophysiology#Intestinal Barrier Dysfunction pathophysiology#Dysregulated Immune Response

Posed by automated curation scanner (high_effort) Posed 2026-08-25T00:00:00Z

Filed from monarch-initiative/dismech#8397, which asked whether the cuproptosis evidence-hierarchy gap recorded on Systemic_Lupus_Erythematosus, Rheumatoid_Arthritis and Ankylosing_Spondylitis in #8326 should also be carried by the two dismech entries that IBD splits into. It should, and against CD- and UC-specific sources rather than the umbrella review's undiscriminated "inflammatory bowel disease" sentence. The parallel gap on Ulcerative_Colitis is kind HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP, because chelator rescue of the colitis phenotype has been shown in rodents; no equivalent functional result exists for Crohn disease in any species.

Show evidence (8 references)

PMID:42435071 SUPPORT Other

"canonical cuproptosis can only be confirmed when copper dependence, involvement of the Ferredoxin 1 (FDX1)-lipoylation axis, aggregation of lipoylated proteins, destabilization of Fe-S clusters, and functional rescue are demonstrated"

Gives the explicit five-part confirmation bar that this discussion's decision criterion is written against, shared verbatim with the parallel gaps on Ulcerative_Colitis, Systemic_Lupus_Erythematosus, Rheumatoid_Arthritis and Ankylosing_Spondylitis.

PMID:42435071 SUPPORT Other

"systemic AIDs (e.g., systemic lupus erythematosus, rheumatoid arthritis) and organ-specific AIDs (e.g., inflammatory bowel disease, ankylosing spondylitis) were summarized. Findings mostly reflected copper-associated metabolic stress or susceptibility markers rather than definitive functional activation."

The sentence that names inflammatory bowel disease without discriminating Crohn disease from ulcerative colitis - the reason this gap was originally left off both IBD entries, and the reason it is now curated against CD-specific sources instead.

PMID:42495776 SUPPORT Other

"the precise function of genes linked to cuproptosis in ulcerative colitis (UC) (14) and Crohn's disease (CD) remains unclear"

A dedicated IBD-cuproptosis review that does discriminate CD from UC, and states for CD specifically that the function of cuproptosis-linked genes is unresolved.

+ 5 more references

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Pathophysiology

Dysregulated Immune Response

The immune system attacks the gastrointestinal tract, leading to chronic inflammation.

Experimental models

PSC-derived intestinal organoid-macrophage coculture model IPSC DERIVED MODEL Captures macrophage cytokine responses to proinflammatory signals within a human intestinal tissue context.

Downstream

Intestinal Inflammation and Epithelial Injury Persistent immune activation sustains bowel-wall inflammation with epithelial and stromal injury in affected segments.

IL-23/Th17 Axis Dysregulation Chronic mucosal immune activation promotes sustained IL-23-driven Th17 polarization.

Show evidence (3 references)

PMID:32242028 SUPPORT

The statement is supported as one of the major factors causing Crohn's Disease is the dysregulated immune system attacking the gastrointestinal tract.

PMID:36720220 SUPPORT

"Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors... we mapped markers of disease-associated myofibroblast activation and identified CHMP1A,..."

This study supports the mechanism involving the immune system leading to inflammation and chronic disease in the gastrointestinal tract.

PMID:21543977 SUPPORT

"The lymphatic system is re-emerging as a critical player in inflammatory and immune processes... Recent studies reporting lymphangitis, lymphangiogenesis, bacterial infiltration and lymph node infection, immune cell trafficking, and fat-wrapping in Crohn's disease suggest altered lymph drainage..."

The literature acknowledges the immune system's involvement in Crohn's Disease through various mechanisms, including lymphatic system dysfunction.

Microbiome Imbalance

Alterations in gut microbiota contribute to the disease mechanisms.

Experimental models

Primary human small-intestinal monolayer barrier model PRIMARY CELL CULTURE Supports controlled host-microbiota interface experiments relevant to dysbiosis-linked epithelial dysfunction in Crohn disease.

Downstream

Intestinal Barrier Dysfunction Dysbiosis challenges epithelial barrier integrity and promotes abnormal host-microbiota interactions.

Dysregulated Immune Response Altered gut microbial communities shape a pathological mucosal immune response.

Show evidence (3 references)

PMID:34313550 SUPPORT

"Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier..."

This study details changes in microbial composition and reduction in species diversity as key factors in the dynamics of Crohn's Disease, thereby supporting the statement.

PMID:18810765 SUPPORT

"This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta-defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation."

This study indicates that defects in innate defense mechanisms allow microbial invasion, which triggers inflammation, supporting the involvement of microbiota alterations in Crohn's Disease.

PMID:23971750 SUPPORT

"Inflammatory bowel disease includes ulcerative colitis and Crohn's disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental..."

This article mentions the role of gut microbiota as an environmental factor in the etiology of Crohn's Disease, supporting the contribution of microbiome imbalance to disease mechanisms.

Paneth Cell Autophagy Impairment

Defective autophagy in Paneth cells due to mutations in autophagy genes (ATG16L1, ATG5) causes abnormal granule formation and impaired antimicrobial peptide secretion.

Paneth cell CL:0000510

ATG16L1 hgnc:21498

Autophagy GO:0006914

Terminal ileum UBERON:0002116

Downstream

Antimicrobial Defense Deficiency Loss of Paneth cell granule secretion reduces antimicrobial peptide levels in intestinal lumen.

Show evidence (1 reference)

PMID:18849966 SUPPORT Model Organism

"ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway"

This study demonstrates that autophagy proteins ATG16L1 and ATG5 are essential for Paneth cell function and that defects cause granule abnormalities linked to Crohn's disease.

Antimicrobial Defense Deficiency

Reduced secretion of antimicrobial peptides (defensins, lysozyme) allows increased bacterial translocation across the intestinal epithelium.

NOD2 hgnc:5331 CARD9 hgnc:16391

Antimicrobial humoral response GO:0019730

Terminal ileum UBERON:0002116

Downstream

Intestinal Barrier Dysfunction Loss of antimicrobial peptide defense permits microbial encroachment at the epithelial surface and increased translocation.

Intestinal Barrier Dysfunction

Disrupted epithelial integrity and increased permeability permit microbial translocation and amplify mucosal immune activation.

intestinal epithelial cell CL:0002563

Terminal ileum UBERON:0002116

Experimental models

Primary human small-intestinal monolayer barrier model PRIMARY CELL CULTURE Supports permeability and barrier-integrity readouts relevant to epithelial dysfunction in Crohn disease.

Enteroendocrine-deficient intestinal enteroid barrier model IPSC DERIVED MODEL Directly measures transepithelial resistance and paracellular permeability in cytokine-sensitive intestinal epithelial monolayers.

Downstream

Dysregulated Immune Response Increased microbial and luminal antigen exposure drives chronic mucosal immune activation.

Show evidence (1 reference)

PMID:34313550 SUPPORT

Supports epithelial barrier dysfunction as a mechanistic bridge between dysbiosis and pathological immune activation in Crohn disease.

Intestinal Inflammation and Epithelial Injury

Active intestinal inflammation produces epithelial and stromal injury that disrupts mucosal function in Crohn disease.

intestinal epithelial cell CL:0002563

Terminal ileum UBERON:0002116

Experimental models

Enteroendocrine-deficient intestinal enteroid barrier model IPSC DERIVED MODEL Models inflammatory-cytokine-associated epithelial barrier injury in a Crohn-relevant gut epithelium context.

Downstream

Diarrhea Inflamed intestinal mucosa and epithelial injury perturb absorptive and secretory function, contributing to diarrheal symptoms.

Abdominal Pain Active intestinal inflammation causes abdominal pain during Crohn flares.

Fibrosis and Stricture Formation Persistent inflammatory injury promotes fibroblast activation and progressive tissue remodeling.

Show evidence (2 references)

PMID:34313550 SUPPORT

Supports active intestinal inflammation as a proximal tissue-level step linking barrier and immune dysregulation to Crohn manifestations.

PMID:36720220 SUPPORT

"Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells."

Supports epithelial and stromal injury as a defining feature of active Crohn inflammation in affected intestinal tissue.

Macrophage Autophagy Dysfunction

Impaired autophagy in lamina propria macrophages (particularly with hyperactive LRRK2 variants such as G2019S, N2081D) leads to defective clearance of intracellular bacteria and pro-inflammatory cytokine release that impairs Paneth cell homeostasis.

Macrophage CL:0000235

LRRK2 hgnc:18618

Autophagy GO:0006914

Intestinal lamina propria UBERON:0001238

Downstream

Paneth Cell Autophagy Impairment LRRK2-hyperactive macrophages release pro-inflammatory cytokines that disrupt Paneth cell autophagy and antimicrobial function.

Dysregulated Immune Response Defective bacterial clearance and cytokine release amplify chronic intestinal inflammation.

Show evidence (2 references)

PMID:39514635 SUPPORT Model Organism

"LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy"

Sun et al. (Sci Immunol 2024) demonstrate that LRRK2 hyperactivity in lamina propria macrophages suppresses autophagy and releases cytokines that impair Paneth cell function, directly supporting macrophage autophagy dysfunction as a CD mechanism upstream of Paneth cell impairment.

PMID:39514635 SUPPORT Human Clinical

"patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction"

Confirms that the macrophage-LRRK2-autophagy mechanism is observed in CD patients, not only in mouse models.

IL-23/Th17 Axis Dysregulation

Overactive IL-23 signaling drives pathogenic Th17 cell differentiation and chronic intestinal inflammation.

Th17 cell CL:0000899 Dendritic cell CL:0000451

IL23R hgnc:19100 STAT3 hgnc:11364

Th17 cell differentiation GO:0072538 IL-23 signaling GO:0038155

Intestinal mucosa UBERON:0002116

Show evidence (1 reference)

PMID:38319717 SUPPORT Human Clinical

"high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation"

Angriman et al. (Dis Colon Rectum 2024) demonstrate that IL-23 is elevated in the healthy ileal mucosa of newly diagnosed CD patients, supporting the role of IL-23 axis dysregulation as an early driver of Crohn's disease inflammation.

Fibrosis and Stricture Formation

Chronic inflammation leads to fibroblast activation, extracellular matrix deposition, and intestinal strictures.

Fibroblast CL:0000057 Myofibroblast CL:0000186

Extracellular matrix organization GO:0030198 Tissue remodeling GO:0048771

Intestinal wall UBERON:0001262 Mesenteric adipose tissue UBERON:0015143

Downstream

Intestinal Obstruction Progressive stricture formation narrows the bowel lumen and produces obstructive symptoms.

TL1A-Mediated T Cell Activation

Tumor necrosis factor-like ligand 1A (TL1A) activates T cells through death receptor 3 (DR3), promoting inflammatory cytokine production and recruitment of myeloid cells to sites of tissue damage.

T cell CL:0000084

TNFSF15 hgnc:11931

T cell activation GO:0042110

Rectal mucosa UBERON:0003346

Downstream

Dysregulated Immune Response TL1A-DR3 signaling amplifies pathogenic T-cell cytokine programs within the broader Crohn inflammatory network.

Myeloid Cell Recruitment to Perianal Tissue Activated T cells produce chemokines that recruit macrophages to perianal inflammatory sites.

Myeloid Cell Recruitment to Perianal Tissue

Chemokine-driven infiltration of macrophages and other myeloid cells into perianal tissues, establishing chronic inflammation.

Macrophage CL:0000235

Leukocyte migration GO:0050900

Perianal region UBERON:0012336

Downstream

Myeloid-Stromal Cell Crosstalk Recruited macrophages interact with resident fibroblasts, driving tissue remodeling.

Myeloid-Stromal Cell Crosstalk

Interferon-driven macrophage activation promotes fibroblast activation and matrix degradation, creating tissue disruption that leads to fistula tract formation.

Macrophage CL:0000235 Fibroblast CL:0000057

Type II interferon signaling GO:0060333

Perianal region UBERON:0012336

Downstream

Perianal Disease Chronic myeloid-fibroblast crosstalk and tissue remodeling drive perianal fistula and abscess phenotypes.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 2

Hematochezia OCCASIONAL HP:0002573

More common in colonic Crohn's disease than ileal disease.

Show evidence (1 reference)

PMID:30244270 SUPPORT

"The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss."

Intestinal bleeding (which manifests as hematochezia) is listed as a characteristic feature of Crohn's disease exacerbations.

Iron Deficiency Anemia FREQUENT HP:0001891

Most common extraintestinal manifestation of IBD; caused by chronic blood loss and impaired iron absorption.

Show evidence (2 references)

PMID:30970351 SUPPORT

"Anaemia is the most common extraintestinal manifestation of IBD, correlating with disease activity, and tending to relapse even after successful therapy. Iron deficiency is the most common cause"

Identifies anemia as the most common extraintestinal manifestation of IBD with iron deficiency as the leading cause.

PMID:22230271 SUPPORT

"Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia."

Anemia is listed among common clinical features of Crohn's disease.

Digestive 9

Diarrhea VERY_FREQUENT HP:0002014

Can be bloody or non-bloody

Sequelae: Weight Loss Malnutrition Dehydration

Show evidence (2 references)

PMID:22230271 SUPPORT

"Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia."

This reference supports the presence of diarrhea and weight loss as frequent symptoms of Crohn's disease. However, it does not explicitly discuss malnutrition as a common sequela or confirm that these phenotypes are highly frequent.

PMID:38036713 SUPPORT

"Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD) ... Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss."

This reference mentions weight loss and suggests a role for malnutrition in Crohn's disease prognosis, but does not confirm high frequency of gastrointestinal symptoms like diarrhea.

Intestinal Obstruction OCCASIONAL Gastrointestinal obstruction HP:0004796

Due to stricturing disease

Show evidence (3 references)

PMID:29043578 SUPPORT

"The most common phenotype is stricturing disease which can lead to obstructive-like symptoms."

The reference states that stricturing disease, a common phenotype of Crohn's disease, can lead to obstructive-like symptoms, supporting the statement that intestinal obstruction due to stricturing disease occurs occasionally in Crohn's disease.

PMID:34014617 SUPPORT

"Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life."

The reference indicates that a significant proportion of Crohn's disease patients develop intestinal strictures, which can lead to obstruction, supporting the statement.

PMID:37973225 SUPPORT

"Benign etiologies of colonic obstructions include...inflammatory processes such as Crohn's disease."

The reference confirms that inflammatory processes like Crohn's disease can lead to colonic obstructions, supporting the statement.

Malnutrition FREQUENT HP:0004395

Show evidence (2 references)

PMID:38437854 SUPPORT

"complete assessment involves laboratory abnormalities, including micronutrient deficiencies"

The Lancet review notes micronutrient deficiencies as a key laboratory finding requiring assessment in Crohn's disease.

PMID:38036713 SUPPORT

"Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD)"

Malnutrition is recognized as playing a key prognostic role in Crohn's disease.

Intestinal Stricture FREQUENT Small intestinal stenosis HP:0012848

Approximately 35% of patients develop intestinal strictures; complications requiring surgery occur in up to 70% within 10 years. Fibrostenotic disease manifestation.

Show evidence (1 reference)

PMID:34014617 SUPPORT

"Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life."

Confirms the high prevalence of intestinal strictures in Crohn's disease.

Perianal Fistula FREQUENT Intestinal fistula HP:0100819

Occurs in approximately 20-50% of Crohn's disease patients; often requires surgical intervention. Related to perianal abscess formation.

Show evidence (1 reference)

PMID:15711045 SUPPORT

"Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%)."

Confirms high prevalence of perianal fistulas in Crohn's disease.

Transmural Inflammation VERY_FREQUENT Intestinal inflammation HP:4000055

Characteristic feature of Crohn's disease affecting all layers of the intestinal wall.

Anal Fissure OCCASIONAL HP:0012390

Part of the spectrum of perianal disease in Crohn's.

Show evidence (1 reference)

PMID:15227686 SUPPORT

"Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses."

Anal fissures are explicitly listed as a manifestation of perianal Crohn's disease.

Primary sclerosing cholangitis HP:0030991

Show evidence (1 reference)

PMID:34358489 SUPPORT Human Clinical

"anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares"

The review lists primary sclerosing cholangitis as an IBD extraintestinal manifestation independent of flares.

Perianal abscess HP:0009789

Show evidence (1 reference)

PMID:38326222 SUPPORT Human Clinical

"perianal skin complications (i.e., skin tags, fistula, and abscesses"

This pediatric IBD cohort lists perianal abscesses among perianal skin complications more frequent in Crohn disease.

Eye 3

Uveitis OCCASIONAL HP:0000554

Inflammation of the eye

Show evidence (2 references)

PMID:2052301 SUPPORT

"Seven patients had uveitis, eight had episcleritis, and four had anterior scleritis."

The literature confirms that uveitis is a type of ocular inflammation associated with Crohn's disease, but it does not specify the frequency as 'occasional'.

PMID:29102673 SUPPORT

"This case of Crohn's disease and uveitis is unusual in that ocular inflammation preceded intestinal involvement, with the atypical feature of chronic intermediate uveitis."

The literature provides a case of uveitis associated with Crohn's disease but does not specify the frequency as 'occasional'.

Anterior uveitis HP:0012122

Show evidence (1 reference)

PMID:34358489 SUPPORT Human Clinical

"anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares"

This IBD extraintestinal-manifestation review lists anterior uveitis occurring independent of disease flares.

Episcleritis HP:0100534

Show evidence (1 reference)

PMID:34358489 SUPPORT Human Clinical

"peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation"

The review lists episcleritis among manifestations associated with active intestinal inflammation.

Genitourinary 1

Nephrolithiasis OCCASIONAL HP:0000787

Oxalate stones due to fat malabsorption and increased oxalate absorption, particularly in ileal disease.

Show evidence (1 reference)

PMID:22230271 SUPPORT

"Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum."

Nephrolithiasis is explicitly listed as an extraintestinal manifestation of Crohn's disease.

Head and Neck 1

Aphthous Stomatitis OCCASIONAL Recurrent aphthous stomatitis HP:0011107

Second most prevalent extraintestinal manifestation of IBD.

Show evidence (2 references)

PMID:34548985 SUPPORT

"dermatologic findings, such as erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis (which are the most frequently occurring)"

Aphthous stomatitis is listed among the most frequently occurring mucocutaneous manifestations of IBD.

PMID:36173720 SUPPORT

"Forty-seven per cent of these patients present extra-intestinal manifestations, the second most prevalent being aphthous stomatitis (AS)."

Aphthous stomatitis is the second most prevalent extraintestinal manifestation of IBD.

Immune 1

Erythema Nodosum OCCASIONAL HP:0012219

Painful nodules on shins

Show evidence (2 references)

PMID:16143688 SUPPORT

"Erythema nodosum is a common cause of tender red nodules of the shins. Management includes leg elevation, NSAIDs, and potassium iodide."

The reference confirms that erythema nodosum, characterized by tender red nodules on the shins, is associated with inflammatory bowel disease, which includes Crohn's disease.

PMID:24746312 SUPPORT

"Erythema nodosum (EN) is clinically the most frequent form of panniculitis and is considered a reactive process that may be triggered by a wide variety of stimuli. Whilst up to 55% of EN is considered idiopathic, the most common causes include infections, drugs, systemic illnesses such as..."

The reference supports the statement by mentioning that erythema nodosum is commonly triggered by systemic illnesses, including inflammatory bowel disease, which encompasses Crohn's disease.

Integument 1

Pyoderma Gangrenosum OCCASIONAL HP:0025452

Rare but serious cutaneous manifestation; painful ulcerating skin lesions, often on lower extremities.

Show evidence (1 reference)

PMID:34548985 SUPPORT

"dermatologic findings, such as erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis (which are the most frequently occurring)"

Pyoderma gangrenosum is listed as a frequent mucocutaneous manifestation of IBD, though individual prevalence is low.

Metabolism 2

Fever OCCASIONAL HP:0001945

More common during acute flares

Show evidence (4 references)

PMID:30244270 SUPPORT

"Crohn's disease is a chronic inflammatory bowel disease. The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss."

This reference confirms that fever is a symptom associated with acute exacerbations of Crohn's disease.

PMID:921308 SUPPORT

"In 32 patients with Crohn's disease which started in childhood, abdominal pain, diarrhoea, and weight loss were the common presenting symptoms, but unexplained fever and failure to grow were also prominent."

This reference supports the statement by indicating that fever is a prominent symptom in patients with Crohn's disease.

PMID:27743896 SUPPORT

"A frequent problem in CD is the discrimination of fever caused by exacerbated bowel inflammation or IAA."

This reference supports the statement by highlighting that fever is a frequent issue in Crohn's disease, especially during exacerbations.

+ 1 more reference

Dehydration OCCASIONAL HP:0001944

Musculoskeletal 2

Arthritis OCCASIONAL HP:0001369

Can affect both large and small joints

Show evidence (2 references)

PMID:21122514 SUPPORT

"The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies."

The literature indicates that arthritis is a common extraintestinal manifestation of Crohn's disease, affecting both large and small joints.

PMID:36730654 SUPPORT

"The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04)."

This study supports the occurrence of arthritis in Crohn's disease patients, particularly noting a higher prevalence in patients with coexisting FMF.

Osteoporosis OCCASIONAL HP:0000939

Related to chronic inflammation, corticosteroid use, and malabsorption of calcium and vitamin D.

Show evidence (2 references)

PMID:22230271 SUPPORT

"Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum."

Osteoporosis is explicitly listed as an extraintestinal manifestation of Crohn's disease.

PMID:17560419 SUPPORT

"Screening may be appropriate for eye disease and for osteoporosis to prevent complications."

Recommends osteoporosis screening in Crohn's patients, indicating clinical significance.

Constitutional 2

Abdominal Pain VERY_FREQUENT HP:0002027

Often occurs in the right lower quadrant

Show evidence (4 references)

PMID:29246562 SUPPORT

"The most frequent symptoms are abdominal pain and diarrhoea, which can seriously affect patients' quality of life."

PMID:33946069 SUPPORT

"In Crohn's disease, inflammation causes pain."

PMID:35380673 SUPPORT

"The prevalence of pain was high in IBD patients ... and higher in CD patients."

+ 1 more reference

Fatigue FREQUENT HP:0012378

Often worsened during disease flares

Show evidence (2 references)

PMID:23111414 SUPPORT

"A high percentage of CD patients suffer from fatigue."

This reference confirms that fatigue is a common symptom among Crohn's disease patients.

PMID:20456309 SUPPORT

"Fatigue is common, disabling yet underappreciated, in patients with chronic diseases, including inflammatory bowel disease (IBD)."

The literature explicitly states that fatigue is common in IBD, which includes Crohn's Disease.

Growth 2

Weight Loss FREQUENT HP:0001824

Show evidence (2 references)

PMID:22230271 SUPPORT

"Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia."

Weight loss is listed as a common presenting symptom of Crohn's disease.

PMID:921308 SUPPORT

"abdominal pain, diarrhoea, and weight loss were the common presenting symptoms"

Weight loss is one of the three most common presenting symptoms in childhood Crohn's disease.

Growth Failure OCCASIONAL Growth delay HP:0001510

Occurs in pediatric-onset Crohn's disease; related to chronic inflammation and malnutrition.

Show evidence (2 references)

PMID:921308 SUPPORT

"Stunted growth was the most frequent physical abnormality when first seen in hospital."

Growth failure is the most common physical finding in childhood Crohn's disease.

PMID:26925610 SUPPORT

"Growth failure (H/A z score <-2) was present in 7 (8%) patients at diagnosis and 5 (5%) at maximal follow-up."

Documents the prevalence of growth failure in pediatric Crohn's disease at 5-8%.

Other 1

Perianal Disease OCCASIONAL

Fistulas, abscesses, skin tags

Show evidence (3 references)

PMID:15227686 SUPPORT

"Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses."

The literature supports that perianal disease is a manifestation of Crohn's disease and lists fistulas, abscesses, and skin tags as possible manifestations. However, it does not specifically address the frequency as 'occasional'.

PMID:15711045 SUPPORT

"Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%)."

The literature indicates that perianal fistulas are common in Crohn's disease, which suggests a higher frequency than 'occasional'.

PMID:33280851 SUPPORT

"Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula."

The literature supports that perianal symptoms can be an initial presentation of Crohn's disease in children, but it does not specify the frequency as 'occasional'.

🧬

Genetic Associations

NOD2 (Risk Factor)

Gene: NOD2 hgnc:5331

Show evidence (9 references)

PMID:29358789 SUPPORT

"BACKGROUND AND OBJECTIVES: Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC)."

This reference states that NOD2 mutations are involved in Crohn's disease, supporting the association as a risk factor.

PMID:23352252 SUPPORT

"NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID... The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease."

This reference confirms the association of NOD2 gene mutations with Crohn's disease.

PMID:16773683 SUPPORT

"Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations."

This reference clearly establishes the association of specific NOD2 mutations with susceptibility to Crohn's disease.

+ 6 more references

ATG16L1 (Risk Factor)

Gene: ATG16L1 hgnc:21498

Show evidence (5 references)

PMID:27698206 SUPPORT

"Conclusion In this meta-analysis, the ATG16L1 genotype was significantly associated with the risk of developing Crohn's disease."

PMID:25906181 SUPPORT

"single-nucleotide polymorphisms in ATG16L1 ... a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease."

PMID:12840668 NO_EVIDENCE

"CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. Interestingly, CD patients often carry mutations on their two chromosomes suggesting a mutation dose effect."

The reference focuses on the association between CARD15 mutations and Crohn’s Disease, with no information regarding ATG16L1.

+ 2 more references

IL23R (Risk Factor)

Gene: IL23R hgnc:19100

Show evidence (2 references)

PMID:17068223 SUPPORT

"We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23."

This study identifies IL23R as a gene significantly associated with Crohn's disease, supporting the statement that IL23R is a genetic risk factor for the condition.

PMID:24989722 SUPPORT

"We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking."

This study supports the association between IL23R and Crohn's disease, while also highlighting the interaction between IL23R variants and environmental factors like smoking.

LRRK2 (Risk Factor)

Gene: LRRK2 hgnc:18618

TNFSF15 (Risk Factor)

Gene: TNFSF15 hgnc:11931

CARD9 (Risk Factor)

Gene: CARD9 hgnc:16391

BACH2 (GWAS)

Gene: BACH2 hgnc:14078

TNFAIP3 (GWAS)

Gene: TNFAIP3 hgnc:11896

STAT3 (GWAS)

Gene: STAT3 hgnc:11364

IL10 (GWAS)

Gene: IL10 hgnc:5962

CD28 (GWAS)

Gene: CD28 hgnc:1653

EGR2 (GWAS)

Gene: EGR2 hgnc:3239

ETS1 (GWAS)

Gene: ETS1 hgnc:3488

IRF4 (GWAS)

Gene: IRF4 hgnc:6119

IRF8 (GWAS)

Gene: IRF8 hgnc:5358

SATB1 (GWAS)

Gene: SATB1 hgnc:10541

IKZF1 (GWAS)

Gene: IKZF1 hgnc:13176

SMAD3 (GWAS)

Gene: SMAD3 hgnc:6769

PRDM1 (GWAS)

Gene: PRDM1 hgnc:9346

PTPN22 (GWAS)

Gene: PTPN22 hgnc:9652

IL21R (GWAS)

Gene: IL21R hgnc:6006

💊

Medical Actions

Aminosalicylates

Action: Pharmacotherapy NCIT:C15986

Anti-inflammatory drugs used for mild to moderate disease.

Show evidence (3 references)

PMID:12786608 SUPPORT

"The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators."

This reference states that aminosalicylates are included in the main treatments for mild to moderately active Crohn's disease.

PMID:34797442 SUPPORT

"5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease."

This reference supports the use of aminosalicylates for Crohn's disease treatment.

PMID:17339853 REFUTE

"Sulfasalazine and mesalazine are useful for the treatment of both active and quiescent ulcerative colitis, whereas they have no clinical effect on either active or inactive Crohn's disease."

This reference explicitly states that aminosalicylates have no clinical effect on Crohn's disease.

Corticosteroids

Action: systemic corticosteroid therapy Ontology label: Systemic Corticosteroid Therapy NCIT:C122080

Used for short-term control during flare-ups to reduce inflammation.

Show evidence (3 references)

PMID:24532122 SUPPORT

"Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease."

This indicates that corticosteroids are indeed a primary treatment option for managing flare-ups in Crohn's disease.

PMID:32653651 SUPPORT

"corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease."

This strengthens the claim that corticosteroids are used for short-term control during flare-ups to reduce inflammation in Crohn's disease.

PMID:18239408 SUPPORT

"The management of Crohn's disease usually consists of a succession of short-term acute phase treatments followed by a long-term maintenance therapy."

This reinforces that corticosteroids are part of the short-term treatment strategy to control flare-ups in Crohn's disease.

Immunomodulators

Action: Pharmacotherapy NCIT:C15986

Drugs like azathioprine and methotrexate to suppress the immune response.

Show evidence (4 references)

PMID:17105689 SUPPORT

"The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus."

The provided literature supports the statement that drugs like azathioprine and methotrexate are used as immunomodulators to manage Crohn's Disease.

PMID:35115294 SUPPORT

"Our results show that parenteral use of methotrexate is efficacious in inducing and maintaining remission as a step-up agent in azathioprine refractory Crohn's disease patients."

The study shows the use of methotrexate in patients who are refractory to azathioprine, supporting the statement that these drugs are used to treat Crohn's Disease by mitigating immune response.

PMID:16245637 SUPPORT

"First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications."

This reference confirms that Azathioprine and Methotrexate are used as immunosuppressants in the treatment of Crohn's Disease.

+ 1 more reference

Biologics

Action: biologic therapy Ontology label: Immunotherapy NCIT:C15262

Anti-TNF agents (infliximab, adalimumab) and integrin inhibitors (vedolizumab) for moderate to severe disease.

Show evidence (4 references)

PMID:18034589 SUPPORT

"Infliximab and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults (infliximab and adalimumab) and children (infliximab) with Crohn's disease."

This reference supports the use of anti-TNF agents (infliximab and adalimumab) for the treatment of moderate to severe Crohn's disease but does not mention vedolizumab directly.

PMID:26195652 SUPPORT

"Vedolizumab is an integrin-receptor antagonist for the treatment of CD and UC in adults with moderately to severely active disease."

This reference supports the use of vedolizumab (an integrin inhibitor) for the treatment of Crohn's disease but does not provide details on anti-TNF agents (infliximab and adalimumab).

PMID:26616476 SUPPORT

"Anti-TNF-alpha therapy is a novel approach that has transformed the way moderate-to-severe Crohn's disease (CD) is treated and has significantly improved clinical outcomes of patients."

This reference supports the use of anti-TNF agents for moderate to severe Crohn's disease.

+ 1 more reference

Nutritional Therapy

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Dietary modifications and enteral nutrition to manage symptoms and maintain nutrition.

Show evidence (5 references)

PMID:19244154 SUPPORT

"Nutrition therapy of Crohn's disease is considered the first-line of treatment for Crohn's disease in children, especially in Europe."

This article supports the use of nutrition therapy as a treatment for managing symptoms and maintaining nutrition in Crohn’s disease.

PMID:38276922 SUPPORT

"New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery."

This article supports the use of enteral nutrition as an effective therapy to induce remission and manage malnutrition in Crohn's disease.

PMID:36558412 SUPPORT

"Both under-and over-nutrition are prevalent in patients with Crohn's Disease (CD)."

The study highlights the importance of dietary modifications to manage nutritional status in Crohn's disease patients.

+ 2 more references

Surgery

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Removal of affected bowel segments, typically reserved for complications like strictures or fistulas.

Show evidence (5 references)

PMID:21901520 SUPPORT

"The indications for surgery include the failure of medical management, especially the persistence or worsening of symptoms in spite of proper treatment and complications of the disease process. These complications include intestinal obstruction, intestinal perforation with fistula formation or..."

The excerpt indicates that surgery is reserved for complications such as strictures or fistulas among others, thus supporting the statement.

PMID:32279173 SUPPORT

"Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures."

The statement mentions surgery for complications like strictures, which is supported by the snippet indicating that fibrotic strictures rely on surgical procedures for treatment.

PMID:21975159 SUPPORT

"Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas."

The statement links surgery to the complication of fistulas, which is supported by the snippet explaining the need for intestinal resection to manage symptomatic non-perianal fistulas.

+ 2 more references

Anti-IL-23 Biologics

Action: biologic therapy Ontology label: Immunotherapy NCIT:C15262

Biologics targeting IL-23 (e.g., ustekinumab, risankizumab) for moderate to severe Crohn's disease refractory to anti-TNF therapy.

TL1A Inhibitors

Action: Pharmacotherapy NCIT:C15986

Emerging precision therapy targeting TL1A-DR3 signaling for fistulizing and fibrostenotic disease.

JAK Inhibitors

Action: JAK inhibitor therapy Ontology label: Immunosuppressive Therapy NCIT:C15261

Small molecule inhibitors targeting JAK-STAT pathway for moderate to severe disease.

🌍

Environmental Factors

Smoking

Increases the risk and severity of Crohn's disease.

Show evidence (5 references)

PMID:27016849 SUPPORT

"Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants."

The provided literature clearly states that smoking increases the risk and severity of Crohn's disease, aligning with the statement.

PMID:31014995 SUPPORT

"We identified 9 factors that increase risk of IBD: smoking (CD)..."

The review identifies smoking as a significant environmental risk factor that increases the risk of Crohn's disease.

PMID:33159156 SUPPORT Human Clinical

"Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02)."

Mendelian randomization estimate for smoking and Crohn disease risk, which is the exposure this entry records.

+ 2 more references

Mechanism Target:

PREDISPOSES Dysregulated Immune Response — Smoking raises both the risk of developing Crohn disease and the rate of complications, recurrence, and surgery once it is established. The route to mucosal immune dysregulation is not settled, and the cited sentences report risk and disease course rather than any immune measurement, so the intermediates are left unknown.

Show evidence (2 references)

PMID:38238335 SUPPORT Human Clinical

"Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10-10) and UC (P < 2 × 10-16) risk, respectively."

Prospective cohort finding both current and previous smoking associated with raised Crohn disease risk at genome-wide significance. It establishes the association and not the immune step this link targets.

PMID:27016849 SUPPORT Other

"Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants."

Review reporting that smoking increases complications, recurrences, and recourse to surgery or immunosuppressants, which is disease course rather than mechanism.

Diet

Western diet with high-fat, low-fiber content may exacerbate symptoms.

Show evidence (3 references)

PMID:33574618 SUPPORT

"Fiber-poor Western diets fuel inflammation."

This indicates that a Western diet, which is low in fiber, can contribute to inflammation, suggesting a potential exacerbation of symptoms in Crohn's Disease.

PMID:34010595 SUPPORT Model Organism

"In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction."

Connects a Western diet to compromised Paneth cell function and so to gut immunity. The snippet is explicit that this is a mouse result, which is what the model-organism tag and the partial grade record.

PMID:35595417 SUPPORT

"most patients report minimal nutritional education from their provider, and providers report few nutritional resources to help them educate patients."

While this indicates the importance of diet, it also highlights a lack of resources and education surrounding the dietary management of Crohn's disease, providing partial support.

Mechanism Target:

PREDISPOSES Paneth Cell Autophagy Impairment — A fibre-poor Western diet reshapes the gut microbiome, and the altered community drives Paneth cell defects through farnesoid X receptor and type I interferon signalling. Those intermediates are named by the cited study, which is why they are recorded as known. The finding is from mouse models, so this link is graded partial and should not be the sole support for a human claim.

Show evidence (1 reference)

PMID:34010595 SUPPORT Model Organism

"In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction."

Four weeks of Western diet produced Paneth cell dysfunction in mouse models, which is this node's own defect. Model-organism evidence, so it supports the mechanism without establishing it in human disease.

Stress

Can trigger flare-ups and worsen symptoms.

Show evidence (2 references)

PMID:15288007 NO_EVIDENCE

"Stress is also associated with IBD, but more as a modifier than an inducing factor, and its contribution is more obvious in IBD animal models than human IBD."

The literature suggests that stress is associated with IBD as a modifier and not necessarily as a direct trigger.

PMID:31574072 SUPPORT

"The unpredictable course of the disease, impaired function due to fatigue, and lack of bowel control were the most prominent causes of worry. The worries created feelings of stress, guilt, and frustration. The participants expressed a need to talk about their worries, to make them visible and..."

The study indicates that stress related to the disease itself is significant among Crohn's disease patients, which supports the claim that stress can worsen symptoms.

🔬

Biochemical Markers

C-Reactive Protein (CRP) (Elevated)

Context: General inflammation

Show evidence (3 references)

PMID:24635486 SUPPORT

"C-reactive protein (CRP) is an important acute-phase marker, produced mainly in the liver. Its production by mesenteric adipocytes has been recently stressed in Crohn's disease (CD)."

The literature indicates that CRP is a relevant marker for inflammation in Crohn's Disease.

PMID:22868800 SUPPORT

"MDA/TBARS were the best predictor of CD, comparable to CRP, with high specificity (MDA/TBARS sensitivity and specificity: 75% and 90%; CRP: 76% and 93%). Combined assessment of MDA/TBARS and CRP improved sensitivity (94%) corresponding with acceptable specificity (81%)."

The study highlights that CRP is a reliable biochemical marker for Crohn's Disease, confirming its elevated presence.

PMID:36550821 SUPPORT

"C-reactive protein, vitamin B12, folate levels were studied along with hemogram analyses."

This study further supports that CRP levels are relevant in the context of Crohn's Disease.

Fecal Calprotectin (Elevated)

Context: Intestinal inflammation

Show evidence (1 reference)

PMID:31088326 SUPPORT

"Calprotectin, a cytosolic protein derived predominantly from neutrophils, is now widely used in this capacity. Calprotectin is found in various bodily fluids at concentrations proportional to the degree of inflammation, including in feces at levels roughly six times higher than in the blood...."

The statement is supported by the literature, which indicates that fecal calprotectin levels are elevated in the context of intestinal inflammation, consistent with the presence of Crohn's Disease.

📈

Progression

Onset

Age: 15-35

Show evidence (4 references)

PMID:33587489 SUPPORT

"Patients were divided into a derivation (80%) cohort and a validation (20%) cohort. The primary outcome was progressive disease... In our final model, age at diagnosis older than 60 years was significantly associated with a lower risk of developing progressive disease... In patients with CD."

The study indicates that younger patients, particularly those aged less than 60 years, are at higher risk of developing progressive Crohn's disease.

PMID:37384664 REFUTE

"Logistic regression analysis of the initial characteristics showed that the age at diagnosis, gender, initial location and initial extra-intestinal manifestation are not associated with the progression of the disease."

This study states that the progression of Crohn's disease is not linked to the initial age of diagnosis among children and adolescents.

PMID:37266570 SUPPORT

"The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination... Decision curve analysis confirmed the clinical utility of the model."

Though the exact age range of 15-35 is not specifically discussed, the predictive model includes various factors that can affect disease progression, which might encompass age-related variations.

+ 1 more reference

📊

Prevalence

Global

Point Prevalence 200.0–300.0 per 100,000 >1 in 1,000

Higher in North America and Northern Europe; increasing incidence in newly industrialized countries.

Show evidence (2 references)

PMID:38437854 SUPPORT

"Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that might lead to progressive bowel damage and disability."

Lancet 2024 seminar confirms Crohn's disease as a prevalent chronic condition.

PMID:37137806 SUPPORT

"The crude prevalence of IBD increased by 47% in 2019 globally."

Provides global IBD prevalence trend data; Crohn's disease accounts for roughly half of IBD cases.

📊

Related Datasets

Molecular Profiling of the Appendix in Pediatric Inflammatory Bowel Diseases geo:GSE281635

Clinical studies suggest a critical role for the appendix in the pathogenesis of inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC), as indicated by the presence of peri-appendicular patches in UC and the beneficial effects of appendectomy in UC. However, the underlying mechanisms remain unclear. To address this gap, we characterized microbial species, associated patterns, and host-microbiota interactions in the appendix and non-inflamed regions of the colon tissue and mucus from pediatric IBD and non-IBD patients (n=15).

human BULK RNA SEQ n=15

Identified by GEO DataSets index search for Crohn Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling metabolomics_workbench:ST000899

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Crohn Disease"). Retrieved 2026-08-02.

Rare disease susceptibility alleles in children with Crohn disease dbgap:phs000926

The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset-Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Crohn Disease"). Retrieved 2026-08-02.

🧫

Experimental Models

Primary human small-intestinal monolayer barrier model PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Polarized primary human small-intestinal epithelial monolayers cultured on Transwells to study barrier integrity, permeability, and host-microbiota interface biology relevant to inflammatory bowel disease.

Organism

human NCBITaxon:9606

Tissue

small intestine UBERON:0002108

Cell source

Primary human small-intestinal epithelial cells

Culture

Polarized two-dimensional Transwell monolayer

Publication

PMID:29094594

Pathograph links

Intestinal Barrier Dysfunction Supports permeability and barrier-integrity readouts relevant to epithelial dysfunction in Crohn disease.

Microbiome Imbalance Supports controlled host-microbiota interface experiments relevant to dysbiosis-linked epithelial dysfunction in Crohn disease.

Findings

Primary human small-intestinal epithelial monolayers support barrier and host-microbiota assays relevant to Crohn disease

Show evidence (2 references)

PMID:29094594 SUPPORT In Vitro

"Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment."

Validates the primary human intestinal model, but the cited study is not Crohn-specific.

PMID:29094594 SUPPORT In Vitro

"The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and..."

Supports relevance to barrier and host-microbiota questions central to Crohn disease, while remaining an indirect bridge rather than direct disease evidence.

Show evidence (1 reference)

PMID:29094594 SUPPORT In Vitro

Supports inclusion as a Crohn-relevant translational model but not as a Crohn-specific organoid or disease model.

Enteroendocrine-deficient intestinal enteroid barrier model IPSC_DERIVED_MODEL namo:TwoDCellCulture

Human intestinal enteroid monolayers derived from pluripotent stem cell-derived organoids with NEUROG3 loss, cultured on Transwell filters to quantify permeability and inflammatory-cytokine-sensitive epithelial barrier responses.

Organism

human NCBITaxon:9606

Tissue

small intestine UBERON:0002108

Cell source

Crypt-derived enteroids isolated from wild-type and NEUROG3-null human intestinal organoids generated from pluripotent stem cells

Culture

Polarized two-dimensional Transwell enteroid monolayer

Publication

PMID:40095977

Pathograph links

Intestinal Barrier Dysfunction Directly measures transepithelial resistance and paracellular permeability in cytokine-sensitive intestinal epithelial monolayers.

Intestinal Inflammation and Epithelial Injury Models inflammatory-cytokine-associated epithelial barrier injury in a Crohn-relevant gut epithelium context.

Findings

Enteroendocrine-deficient intestinal enteroid monolayers show impaired barrier function that persists under inflammatory cytokine exposure

Show evidence (2 references)

PMID:40095977 SUPPORT In Vitro

"We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like "stem" and villus-like differentiated cultures."

Supports the baseline barrier-defect phenotype in the enteroid model.

PMID:40095977 SUPPORT In Vitro

"exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine-tyrosine (PYY), and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor."

Supports cytokine-sensitive perturbation and rescue of the barrier phenotype in this model.

Show evidence (2 references)

PMID:40095977 SUPPORT In Vitro

"seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins."

Supports inclusion as a human intestinal enteroid Transwell model that directly assays epithelial barrier dysfunction.

PMID:40095977 SUPPORT In Vitro

"These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier."

Supports Crohn-relevant use as an inflammatory barrier model, while remaining broader than Crohn-specific patient tissue.

PSC-derived intestinal organoid-macrophage coculture model IPSC_DERIVED_MODEL namo:Organoid

Human pluripotent stem cell-derived intestinal organoids combined with matched PSC-derived macrophages to model resident myeloid-epithelial interactions and inflammatory cytokine responses in intestinal tissue.

Organism

human NCBITaxon:9606

Tissue

intestine UBERON:0000160

Cell source

Human pluripotent stem cell-derived intestinal organoids and macrophages combined in coculture

Culture

Three-dimensional intestinal organoid coculture with PSC-derived tissue-resident macrophages

Publication

PMID:39701210

Pathograph links

Dysregulated Immune Response Captures macrophage cytokine responses to proinflammatory signals within a human intestinal tissue context.

Findings

PSC-derived intestinal organoid-macrophage cocultures provide a human immune-epithelial system for inflammatory and bacterial-response studies relevant to Crohn disease

Show evidence (2 references)

PMID:39701210 SUPPORT In Vitro

"HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10."

Supports functional immune-response readouts in the coculture model.

PMID:39701210 SUPPORT In Vitro

"This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."

Supports Crohn-relevant use as an IBD mechanism model, while remaining broader than Crohn-specific disease tissue.

Show evidence (2 references)

PMID:39701210 SUPPORT In Vitro

"HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro."

Supports model identity as a PSC-derived intestinal organoid-macrophage coculture system.

PMID:39701210 SUPPORT In Vitro

"This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."

Supports inclusion as a Crohn-relevant intestinal immune-epithelial model without overstating disease specificity.

🧮

Computational Models

AGORA2 Gut Microbiome Metabolic Models GENOME_SCALE_METABOLIC

Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of human gut microorganisms. Enables modeling of dysbiosis-associated metabolic shifts in CD, including depletion of butyrate-producing Firmicutes (F. prausnitzii, Roseburia) and expansion of Enterobacteriaceae. Supports integration with host intestinal epithelial cell models.

Repository ↗ PMID:36543475

Nature Biotechnology 2022 - includes strain-level resolution for studying CD-associated dysbiosis patterns

MICOM Community Metabolic Model COBRApy GENOME_SCALE_METABOLIC

Metagenome-scale modeling framework for simulating metabolic interactions in the gut microbiota. Integrates dietary constraints and taxon abundances from metagenomic data to predict SCFA production deficits, cross-feeding network disruption, and pathobiont metabolic niches characteristic of CD dysbiosis.

PMID:31964767

Findings

Community-level SCFA production is heterogeneous and highly individual-specific

Show evidence (1 reference)

PMID:31964767 SUPPORT

"the community-level production of short-chain fatty acids (SCFAs) was heterogeneous and highly individual specific"

MICOM reveals personalized SCFA flux profiles relevant to understanding IBD heterogeneity.

Model output reveals complex cross-feeding interactions that would be difficult to measure in vivo

Show evidence (1 reference)

PMID:31964767 SUPPORT

"Model output revealed complex cross-feeding interactions that would be difficult to measure in vivo"

Enables mechanistic understanding of metabolic networks disrupted in CD dysbiosis.

mSystems 2020 - enables personalized microbiome metabolic modeling; applied to IBD cohorts

Host-Microbiome Multi-Objective Optimization Model GENOME_SCALE_METABOLIC

Integrated metabolic model combining human intestinal epithelial cell (IEC) metabolism with gut microbiome community models. Uses multi-objective optimization to predict competition, mutualism, and neutralism between host and microbial metabolism. Models SCFA exchange, amino acid cross-feeding, and metabolic interactions disrupted in CD.

PMID:38729159

iScience 2024 - framework for quantifying host-microbiome metabolic crosstalk

{ }

Source YAML

click to show

name: Crohn Disease
creation_date: '2025-12-04T16:57:31Z'
description: A chronic inflammatory bowel disease that affects the lining of the digestive tract, causing a wide range of gastrointestinal and systemic symptoms.
category: Complex
parents:
- Inflammatory Bowel Disease
- Autoimmune Disease
has_subtypes:
- name: Ileal Crohn's Disease
  description: Involves inflammation of the ileum, the latter part of the small intestine.
  evidence:
  - reference: PMID:37377591
    reference_title: "Crohn's disease: Why the ileum?"
    supports: SUPPORT
    snippet: In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type.
    explanation: This reference supports the statement that Crohn's disease involves inflammation of the ileum, and specifies this subtype as Ileal Crohn's Disease.
  - reference: PMID:30882291
    reference_title: "How dyspepsia led to the diagnosis of Morbus Crohn."
    supports: SUPPORT
    snippet: Gastroscopy revealed severe aphthous pangastritis with biopsies showing a focal active and chronic gastritis with presence of granulomas... coloscopy showing an aphthous terminal ileum... concordant with a slightly active, mildly chronic terminal ileitis typical for Crohn's disease.
    explanation: This reference supports the claim that Crohn's disease can involve the ileum, characterizing it distinctly as terminal ileitis which is a known feature of Ileal Crohn's Disease.
  - reference: PMID:31960900
    reference_title: "Imaging Findings of Ileal Inflammation at Computed Tomography and Magnetic Resonance Enterography: What do They Mean When Ileoscopy and Biopsy are Negative?"
    supports: SUPPORT
    snippet: Crohn's disease patients with unequivocal imaging findings of ileal inflammation at enterography despite negative ileoscopy and biopsy are likely to have active inflammatory Crohn's disease.
    explanation: This reference highlights that Crohn's disease can manifest as inflammation of the ileum, aligning with the subtype of Ileal Crohn's Disease.
- name: Colonic Crohn's Disease
  description: Affects the colon (large intestine) with skip lesions.
  evidence:
  - reference: PMID:38437854
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: Commonly affecting the terminal ileum and proximal colon, Crohn's disease inflammation is often discontinuous and patchy, segmental, and transmural.
    explanation: The literature indicates that Crohn's disease can affect the colon and often presents with discontinuous, patchy inflammation. However, it is typically not limited to the colon and often involves the terminal ileum.
  - reference: PMID:11271896
    reference_title: "Crohn's disease of aphthous type: serial changes in intestinal lesions."
    supports: SUPPORT
    snippet: The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient. Typical small intestinal CD occurred in four of seven patients with marked aphthous lesions of the small intestine, whereas colonic CD occurred in two of eight patients with such aphthous lesions of the colon.
    explanation: This study shows that Crohn's disease can indeed affect the colon specifically, supporting the subtype known as Colonic Crohn's Disease.
  - reference: PMID:26906301
    reference_title: "Terminal Ileitis as a Feature of Henoch-Schönlein Purpura Masquerading as Crohn Disease in Adults."
    supports: SUPPORT
    snippet: Although ileitis can be seen in HSP, terminal ileitis is virtually pathognomonic for Crohn disease.
    explanation: The focus is on terminal ileitis, commonly seen in Crohn’s disease. It suggests that Crohn's disease frequently involves the ileum, but does not refute that the colon can also be involved.
  - reference: PMID:33278326
    reference_title: "Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine."
    supports: SUPPORT
    snippet: Changes in absorptive capacity and first-pass metabolism in the small intestine affect oral drug bioavailability.
    explanation: This study focuses on small intestine involvement in Crohn's disease but does not refute colonic involvement with skip lesions.
  - reference: PMID:28379745
    reference_title: "Endoscopic Skipping of the Terminal Ileum in Pediatric Crohn Disease."
    supports: NO_EVIDENCE
    snippet: Nearly half (36/73, 49%) of the patients with normal or nonspecific findings at ileocolonoscopy had radiologically active disease with a median length of SB involvement of 20 cm (range, 1 to > 100 cm).
    explanation: Findings indicate that Crohn's Disease can have varying and discontinuous involvement, including potentially just the colon, thereby supporting the subtype.
- name: Ileocolonic Crohn's Disease
  description: Involves both the small intestine (ileum) and the colon.
  evidence:
  - reference: PMID:33712743
    reference_title: "Location is important: differentiation between ileal and colonic Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment.
    explanation: Although the literature acknowledges different manifestations of Crohn's disease involving the ileum and colon, it primarily discusses the broader differentiation between small-intestinal and colonic Crohn's Disease without naming or detailing specific subtypes such as Ileocolonic Crohn's Disease.
  - reference: PMID:11271896
    reference_title: "Crohn's disease of aphthous type: serial changes in intestinal lesions."
    supports: SUPPORT
    snippet: The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient.
    explanation: This provides clinical evidence of Crohn's Disease affecting both the ileum and colon in patients but does not explicitly label it as Ileocolonic Crohn's Disease.
  - reference: PMID:38294885
    reference_title: "Biologics, small molecule therapies and surgery in small bowel Crohn's disease."
    supports: SUPPORT
    snippet: The terminal ileum and small bowel (SB) are involved in 30-45% of patients with Crohn's disease, while 20% have both small and large bowel involvement.
    explanation: This literature reference supports the statement by noting that 20% of Crohn's disease cases involve both the small and large intestines, which corresponds to the description of Ileocolonic Crohn's Disease.
inheritance:
- name: Multifactorial
  description: >
    Crohn's disease follows a complex, multifactorial inheritance pattern with contributions
    from multiple genetic risk loci (NOD2, ATG16L1, IL23R, and over 200 additional GWAS loci)
    interacting with environmental factors.
  evidence:
  - reference: PMID:32242028
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown.
    explanation: Confirms multifactorial etiology involving genetic susceptibility and environmental factors.
prevalence:
- population: Global
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 200.0
  rate_high: 300.0
  percentage: 0.2-0.3
  notes: Higher in North America and Northern Europe; increasing incidence in newly industrialized countries.
  evidence:
  - reference: PMID:38437854
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that might lead to progressive bowel damage and disability.
    explanation: Lancet 2024 seminar confirms Crohn's disease as a prevalent chronic condition.
  - reference: PMID:37137806
    reference_title: "The global, regional, and national burden of inflammatory bowel diseases, 1990-2019: A systematic analysis for the global burden of disease study 2019."
    supports: SUPPORT
    snippet: The crude prevalence of IBD increased by 47% in 2019 globally.
    explanation: Provides global IBD prevalence trend data; Crohn's disease accounts for roughly half of IBD cases.
progression:
- phase: Onset
  age_range: 15-35
  evidence:
  - reference: PMID:33587489
    reference_title: "Age at Diagnosis Is Determinant for the Outcome of Inflammatory Bowel Disease: Is It a Myth?"
    supports: SUPPORT
    snippet: Patients were divided into a derivation (80%) cohort and a validation (20%) cohort. The primary outcome was progressive disease... In our final model, age at diagnosis older than 60 years was significantly associated with a lower risk of developing progressive disease... In patients with CD.
    explanation: The study indicates that younger patients, particularly those aged less than 60 years, are at higher risk of developing progressive Crohn's disease.
  - reference: PMID:37384664
    reference_title: "Clinical course of new-onset Crohn's disease in children and adolescents in dependency of age, initial location, initial severity level and therapy over the period 2000-2014 based on the Saxon Pediatric IBD-Registry in Germany."
    supports: REFUTE
    snippet: Logistic regression analysis of the initial characteristics showed that the age at diagnosis, gender, initial location and initial extra-intestinal manifestation are not associated with the progression of the disease.
    explanation: This study states that the progression of Crohn's disease is not linked to the initial age of diagnosis among children and adolescents.
  - reference: PMID:37266570
    reference_title: "A Novel 8-Predictors Signature to Predict Complicated Disease Course in Pediatric-onset Crohn's Disease: A Population-based Study."
    supports: SUPPORT
    snippet: The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination... Decision curve analysis confirmed the clinical utility of the model.
    explanation: Though the exact age range of 15-35 is not specifically discussed, the predictive model includes various factors that can affect disease progression, which might encompass age-related variations.
  - reference: PMID:28051217
    reference_title: "Changes of Crohn's disease phenotype over time."
    supports: NO_EVIDENCE
    snippet: Our aim was to identify the phenotype evolution of Crohn's disease over time according to the Montreal Classification and to precise predictive factors of the need for immunosuppressant treatment or surgery... without association with age, sex or smoking habits.
    explanation: This study did not find evidence associating age with the progression of Crohn's disease, focusing instead on phenotype and specific disease markers.
mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic Crohn disease risk in adverse
    contexts via shared intestinal-inflammation convergence
  status: EMERGING
  description: >-
    Polygenic-score-by-context (PGS×C) interactions reported for inflammatory
    bowel disease in the UK Biobank appear to reflect amplification rather than
    context-specific causal variants: the same susceptibility loci (e.g. NOD2,
    ATG16L1, IL23R) exert systematically larger effects in disease-promoting
    contexts. This entry proposes that the amplification arises because polygenic
    liability and adverse exposures — notably tobacco smoking (a risk factor in
    Crohn disease, in contrast to its protective association in ulcerative
    colitis) and diet — converge on the shared Intestinal Inflammation and
    Epithelial Injury node, so their joint effect on the liability-threshold scale
    is super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026,
    PMID:42443528) report pervasive PGS×context interactions for prevalent IBD.
  evidence:
  - reference: PMID:42443528
    reference_title: "Pervasive interactions between exposures and polygenic risk can inform more effective clinical and behavioral interventions."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The predominant mechanism for PGS×C is the amplification of genetic
      effects in adverse contexts, such as low polyunsaturated fatty acids or social
      determinants of ill health
    explanation: >-
      Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and
      75 contexts, amplification of genetic effects in adverse contexts is
      identified as the predominant mechanism of PGS×context interaction — the
      mechanism applied in this hypothesis.
  - reference: PMID:37228747
    reference_title: "Amplification is the primary mode of gene-by-sex interaction in complex human traits."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: GxSex is pervasive but acts primarily through systematic sex differences
      in the magnitude of many genetic effects
    explanation: >-
      Corroborates amplification — systematic differences in the magnitude of
      polygenic effects rather than in the identity of causal variants — as the
      primary mode of gene-by-context interaction.
  notes: >-
    EMERGING hypothesis motivated by population-scale PGS×context analyses
    (primary source PMID:42443528; general amplification mechanism corroborated
    by PMID:37228747). The convergence claim (polygenic liability + smoking/diet →
    Intestinal Inflammation and Epithelial Injury) is a mechanistic
    interpretation and is not itself established as causal — see the
    reverse-causation knowledge gap under discussions.
- hypothesis_group_id: canonical_nod2_autophagy_th17_mucosal_dysregulation_model
  hypothesis_label: Canonical NOD2 / Autophagy / Th17 Mucosal Dysregulation Model
  status: CANONICAL
  description: >-
    Crohn's disease arises from a polygenic susceptibility to impaired mucosal innate immunity (NOD2,
    ATG16L1, IRGM, and other autophagy genes) combined with environmental triggers (smoking, diet,
    microbiota perturbation) that produce defective bacterial sensing and clearance by Paneth cells,
    macrophages, and intestinal epithelial cells. The resulting chronic exposure of lamina propria APCs
    to commensal antigens drives IL-23-dependent Th17/Th1 polarization, granuloma formation, and
    transmural inflammation. Anti-TNF (infliximab, adalimumab), anti-IL-12/23 (ustekinumab), anti-α4β7
    (vedolizumab), and JAK inhibitors all corroborate this immune-dysregulation model by interrupting
    specific cytokine and trafficking axes downstream of the underlying innate-immunity defect.
  notes: >-
    Retained as CANONICAL but with a partially-supported
    qualification. The 2026 falcon hypothesis-search report
    (kb/hypotheses/Crohn_Disease/canonical_nod2_autophagy_th17_mucosal_dysregulation_model;
    openscientist timed out at 3600s) finds direct human and
    mechanistic evidence continues to strongly support that
    autophagy/innate-microbial-handling risk variants produce
    cell-type-specific defects in antigen handling and Paneth-cell
    homeostasis, with IL-23-driven innate cytokine programs
    detectable in macroscopically healthy mucosa. Three critical
    qualifications mark the model as best treated as a modular,
    context-dependent framework rather than a universal mechanism:
    (1) some canonical risk alleles show no functional effect in
    specific assays/cell types — e.g., NOD2 R702W in DC autophagy
    flux; NDP52 Val248Ala in epithelial AIEC xenophagy assays;
    (2) the IL-23 → IL-17 step is not consistently observed in
    early human disease, despite IL-23 detection in pre-clinical
    mucosa; (3) parallel upstream mechanisms — macrophage LRRK2
    hyperactivity (especially with smoking), virome sensing
    deficits, and microbiome virulence programs such as type III
    secretion systems — can produce Crohn-like inflammatory
    trajectories WITHOUT requiring an epithelial-intrinsic
    NOD2/autophagy defect as the initiating event. The canonical
    model remains a strong scaffold for a subset of Crohn biology
    but does not capture all etiologic paths.
  evidence:
  - reference: PMID:32242028
    reference_title: "Crohn's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors"
    explanation: >
      Canonical mechanism reference used as the seed for the
      hypothesis-search deep-research run.
pathophysiology:
- name: Dysregulated Immune Response
  description: The immune system attacks the gastrointestinal tract, leading to chronic inflammation.
  downstream:
  - target: Intestinal Inflammation and Epithelial Injury
    description: Persistent immune activation sustains bowel-wall inflammation with epithelial and stromal injury in affected segments.
  - target: IL-23/Th17 Axis Dysregulation
    description: Chronic mucosal immune activation promotes sustained IL-23-driven Th17 polarization.
  evidence:
  - reference: PMID:32242028
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown.
    explanation: The statement is supported as one of the major factors causing Crohn's Disease is the dysregulated immune system attacking the gastrointestinal tract.
  - reference: PMID:36720220
    reference_title: "The landscape of immune dysregulation in Crohn's disease revealed through single-cell transcriptomic profiling in the ileum and colon."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors... we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications.
    explanation: This study supports the mechanism involving the immune system leading to inflammation and chronic disease in the gastrointestinal tract.
  - reference: PMID:21543977
    reference_title: "Role of the lymphatic system in the pathogenesis of Crohn's disease."
    supports: SUPPORT
    snippet: The lymphatic system is re-emerging as a critical player in inflammatory and immune processes... Recent studies reporting lymphangitis, lymphangiogenesis, bacterial infiltration and lymph node infection, immune cell trafficking, and fat-wrapping in Crohn's disease suggest altered lymph drainage and lymphatic pumping, implicating the lymphatic system as a likely player in inflammatory disorders and IBDs.
    explanation: The literature acknowledges the immune system's involvement in Crohn's Disease through various mechanisms, including lymphatic system dysfunction.
- name: Microbiome Imbalance
  description: Alterations in gut microbiota contribute to the disease mechanisms.
  downstream:
  - target: Intestinal Barrier Dysfunction
    description: Dysbiosis challenges epithelial barrier integrity and promotes abnormal host-microbiota interactions.
  - target: Dysregulated Immune Response
    description: Altered gut microbial communities shape a pathological mucosal immune response.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: This study details changes in microbial composition and reduction in species diversity as key factors in the dynamics of Crohn's Disease, thereby supporting the statement.
  - reference: PMID:18810765
    reference_title: "Crohn's disease--defect in innate defence."
    supports: SUPPORT
    snippet: This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta-defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation.
    explanation: This study indicates that defects in innate defense mechanisms allow microbial invasion, which triggers inflammation, supporting the involvement of microbiota alterations in Crohn's Disease.
  - reference: PMID:23971750
    reference_title: "Nutrigenetics, nutrigenomics and inflammatory bowel diseases."
    supports: SUPPORT
    snippet: Inflammatory bowel disease includes ulcerative colitis and Crohn's disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota.
    explanation: This article mentions the role of gut microbiota as an environmental factor in the etiology of Crohn's Disease, supporting the contribution of microbiome imbalance to disease mechanisms.
- name: Paneth Cell Autophagy Impairment
  description: Defective autophagy in Paneth cells due to mutations in autophagy genes (ATG16L1, ATG5) causes abnormal granule formation and impaired antimicrobial peptide secretion.
  genes:
  - preferred_term: ATG16L1
    term:
      id: hgnc:21498
      label: ATG16L1
  cell_types:
  - preferred_term: Paneth cell
    term:
      id: CL:0000510
      label: paneth cell
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Antimicrobial Defense Deficiency
    description: Loss of Paneth cell granule secretion reduces antimicrobial peptide levels in intestinal lumen.
  evidence:
  - reference: PMID:18849966
    reference_title: "A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway
    explanation: This study demonstrates that autophagy proteins ATG16L1 and ATG5 are essential for Paneth cell function and that defects cause granule abnormalities linked to Crohn's disease.
- name: Antimicrobial Defense Deficiency
  description: Reduced secretion of antimicrobial peptides (defensins, lysozyme) allows increased bacterial translocation across the intestinal epithelium.
  genes:
  - preferred_term: NOD2
    term:
      id: hgnc:5331
      label: NOD2
  - preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  biological_processes:
  - preferred_term: Antimicrobial humoral response
    term:
      id: GO:0019730
      label: antimicrobial humoral response
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Intestinal Barrier Dysfunction
    description: Loss of antimicrobial peptide defense permits microbial encroachment at the epithelial surface and increased translocation.
- name: Intestinal Barrier Dysfunction
  description: Disrupted epithelial integrity and increased permeability permit microbial translocation and amplify mucosal immune activation.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Dysregulated Immune Response
    description: Increased microbial and luminal antigen exposure drives chronic mucosal immune activation.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: Supports epithelial barrier dysfunction as a mechanistic bridge between dysbiosis and pathological immune activation in Crohn disease.
- name: Intestinal Inflammation and Epithelial Injury
  description: Active intestinal inflammation produces epithelial and stromal injury that disrupts mucosal function in Crohn disease.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Diarrhea
    description: Inflamed intestinal mucosa and epithelial injury perturb absorptive and secretory function, contributing to diarrheal symptoms.
  - target: Abdominal Pain
    description: Active intestinal inflammation causes abdominal pain during Crohn flares.
  - target: Fibrosis and Stricture Formation
    description: Persistent inflammatory injury promotes fibroblast activation and progressive tissue remodeling.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: Supports active intestinal inflammation as a proximal tissue-level step linking barrier and immune dysregulation to Crohn manifestations.
  - reference: PMID:36720220
    reference_title: "The landscape of immune dysregulation in Crohn's disease revealed through single-cell transcriptomic profiling in the ileum and colon."
    supports: SUPPORT
    snippet: Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells.
    explanation: Supports epithelial and stromal injury as a defining feature of active Crohn inflammation in affected intestinal tissue.
- name: Macrophage Autophagy Dysfunction
  description: Impaired autophagy in lamina propria macrophages (particularly with hyperactive LRRK2 variants such as G2019S, N2081D) leads to defective clearance of intracellular bacteria and pro-inflammatory cytokine release that impairs Paneth cell homeostasis.
  genes:
  - preferred_term: LRRK2
    term:
      id: hgnc:18618
      label: LRRK2
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: Intestinal lamina propria
    term:
      id: UBERON:0001238
      label: lamina propria of small intestine
  evidence:
  - reference: PMID:39514635
    reference_title: "Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy"
    explanation: Sun et al. (Sci Immunol 2024) demonstrate that LRRK2 hyperactivity in lamina propria macrophages suppresses autophagy and releases cytokines that impair Paneth cell function, directly supporting macrophage autophagy dysfunction as a CD mechanism upstream of Paneth cell impairment.
  - reference: PMID:39514635
    reference_title: "Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction"
    explanation: Confirms that the macrophage-LRRK2-autophagy mechanism is observed in CD patients, not only in mouse models.
  downstream:
  - target: Paneth Cell Autophagy Impairment
    description: LRRK2-hyperactive macrophages release pro-inflammatory cytokines that disrupt Paneth cell autophagy and antimicrobial function.
  - target: Dysregulated Immune Response
    description: Defective bacterial clearance and cytokine release amplify chronic intestinal inflammation.
- name: IL-23/Th17 Axis Dysregulation
  description: Overactive IL-23 signaling drives pathogenic Th17 cell differentiation and chronic intestinal inflammation.
  genes:
  - preferred_term: IL23R
    term:
      id: hgnc:19100
      label: IL23R
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  cell_types:
  - preferred_term: Th17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: Dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: Th17 cell differentiation
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
  - preferred_term: IL-23 signaling
    term:
      id: GO:0038155
      label: interleukin-23-mediated signaling pathway
  locations:
  - preferred_term: Intestinal mucosa
    term:
      id: UBERON:0002116
      label: ileum
  evidence:
  - reference: PMID:38319717
    reference_title: "Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation"
    explanation: Angriman et al. (Dis Colon Rectum 2024) demonstrate that IL-23 is elevated in the healthy ileal mucosa of newly diagnosed CD patients, supporting the role of IL-23 axis dysregulation as an early driver of Crohn's disease inflammation.
- name: Fibrosis and Stricture Formation
  description: Chronic inflammation leads to fibroblast activation, extracellular matrix deposition, and intestinal strictures.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: Tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
  locations:
  - preferred_term: Intestinal wall
    term:
      id: UBERON:0001262
      label: wall of intestine
  - preferred_term: Mesenteric adipose tissue
    term:
      id: UBERON:0015143
      label: mesenteric fat pad
  downstream:
  - target: Intestinal Obstruction
    description: Progressive stricture formation narrows the bowel lumen and produces obstructive symptoms.
- name: TL1A-Mediated T Cell Activation
  description: Tumor necrosis factor-like ligand 1A (TL1A) activates T cells through death receptor 3 (DR3), promoting inflammatory cytokine production and recruitment of myeloid cells to sites of tissue damage.
  genes:
  - preferred_term: TNFSF15
    term:
      id: hgnc:11931
      label: TNFSF15
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
  locations:
  - preferred_term: Rectal mucosa
    term:
      id: UBERON:0003346
      label: mucosa of rectum
  downstream:
  - target: Dysregulated Immune Response
    description: TL1A-DR3 signaling amplifies pathogenic T-cell cytokine programs within the broader Crohn inflammatory network.
  - target: Myeloid Cell Recruitment to Perianal Tissue
    description: Activated T cells produce chemokines that recruit macrophages to perianal inflammatory sites.
- name: Myeloid Cell Recruitment to Perianal Tissue
  description: Chemokine-driven infiltration of macrophages and other myeloid cells into perianal tissues, establishing chronic inflammation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
  locations:
  - preferred_term: Perianal region
    term:
      id: UBERON:0012336
      label: perianal skin
  downstream:
  - target: Myeloid-Stromal Cell Crosstalk
    description: Recruited macrophages interact with resident fibroblasts, driving tissue remodeling.
- name: Myeloid-Stromal Cell Crosstalk
  description: Interferon-driven macrophage activation promotes fibroblast activation and matrix degradation, creating tissue disruption that leads to fistula tract formation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Type II interferon signaling
    term:
      id: GO:0060333
      label: type II interferon-mediated signaling pathway
  locations:
  - preferred_term: Perianal region
    term:
      id: UBERON:0012336
      label: perianal skin
  downstream:
  - target: Perianal Disease
    description: Chronic myeloid-fibroblast crosstalk and tissue remodeling drive perianal fistula and abscess phenotypes.
phenotypes:
- category: Gastrointestinal
  name: Abdominal Pain
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29246562
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: The most frequent symptoms are abdominal pain and diarrhoea, which can seriously affect patients' quality of life.
  - reference: PMID:33946069
    reference_title: "Chronic Abdominal Pain: Gastroenterologist Approach."
    supports: SUPPORT
    snippet: In Crohn's disease, inflammation causes pain.
  - reference: PMID:35380673
    reference_title: "Pain Characteristics in Patients with Inflammatory Bowel Disease: A Monocentric Cross-Sectional Study."
    supports: SUPPORT
    snippet: The prevalence of pain was high in IBD patients ... and higher in CD patients.
  - reference: PMID:33836648
    reference_title: "Distinct clinical phenotypes for Crohn's disease derived from patient surveys."
    supports: NO_EVIDENCE
    snippet: Using the patients' self-reported information, we identified two subpopulations of Crohn's disease; these subpopulations differ in disease severity, associations with smoking, and genetic transmission patterns.
    explanation: While this reference focuses on identifying subpopulations with varying disease severity, it underscores the heterogeneity of Crohn’s disease symptoms, indirectly supporting that abdominal pain is a frequent symptom.
  diagnostic: true
  notes: Often occurs in the right lower quadrant
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- category: Gastrointestinal
  name: Diarrhea
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: Weight Loss
  - target: Malnutrition
  - target: Dehydration
  evidence:
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: SUPPORT
    snippet: Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia.
    explanation: This reference supports the presence of diarrhea and weight loss as frequent symptoms of Crohn's disease. However, it does not explicitly discuss malnutrition as a common sequela or confirm that these phenotypes are highly frequent.
  - reference: PMID:38036713
    reference_title: "Weight loss from diagnosis of Crohn's disease to one year post-diagnosis results in earlier surgery."
    supports: SUPPORT
    snippet: Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD) ... Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss.
    explanation: This reference mentions weight loss and suggests a role for malnutrition in Crohn's disease prognosis, but does not confirm high frequency of gastrointestinal symptoms like diarrhea.
  notes: Can be bloody or non-bloody
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
- category: Systemic
  name: Fatigue
  frequency: FREQUENT
  notes: Often worsened during disease flares
  evidence:
  - reference: PMID:23111414
    reference_title: "Determinants of fatigue in Crohn's disease patients."
    supports: SUPPORT
    snippet: A high percentage of CD patients suffer from fatigue.
    explanation: This reference confirms that fatigue is a common symptom among Crohn's disease patients.
  - reference: PMID:20456309
    reference_title: "Systematic review: fatigue in inflammatory bowel disease."
    supports: SUPPORT
    snippet: Fatigue is common, disabling yet underappreciated, in patients with chronic diseases, including inflammatory bowel disease (IBD).
    explanation: The literature explicitly states that fatigue is common in IBD, which includes Crohn's Disease.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Gastrointestinal
  frequency: OCCASIONAL
  name: Perianal Disease
  notes: Fistulas, abscesses, skin tags
  evidence:
  - reference: PMID:15227686
    reference_title: "Perianal Crohn's disease."
    supports: SUPPORT
    snippet: Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses.
    explanation: The literature supports that perianal disease is a manifestation of Crohn's disease and lists fistulas, abscesses, and skin tags as possible manifestations. However, it does not specifically address the frequency as 'occasional'.
  - reference: PMID:15711045
    reference_title: "Fistulizing Crohn's disease."
    supports: SUPPORT
    snippet: Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%).
    explanation: The literature indicates that perianal fistulas are common in Crohn's disease, which suggests a higher frequency than 'occasional'.
  - reference: PMID:33280851
    reference_title: "A child presents with perianal symptoms - how often is this Crohn's disease?"
    supports: SUPPORT
    snippet: Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula.
    explanation: The literature supports that perianal symptoms can be an initial presentation of Crohn's disease in children, but it does not specify the frequency as 'occasional'.
- category: Gastrointestinal
  frequency: OCCASIONAL
  name: Intestinal Obstruction
  notes: Due to stricturing disease
  evidence:
  - reference: PMID:29043578
    reference_title: "Duodenal Crohn's Disease-a Diagnostic Conundrum."
    supports: SUPPORT
    snippet: The most common phenotype is stricturing disease which can lead to obstructive-like symptoms.
    explanation: The reference states that stricturing disease, a common phenotype of Crohn's disease, can lead to obstructive-like symptoms, supporting the statement that intestinal obstruction due to stricturing disease occurs occasionally in Crohn's disease.
  - reference: PMID:34014617
    reference_title: "Intestinal stricture in Crohn's disease: A 2020 update."
    supports: SUPPORT
    snippet: Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life.
    explanation: The reference indicates that a significant proportion of Crohn's disease patients develop intestinal strictures, which can lead to obstruction, supporting the statement.
  - reference: PMID:37973225
    reference_title: "Endoscopic Management of Colonic Obstruction."
    supports: SUPPORT
    snippet: Benign etiologies of colonic obstructions include...inflammatory processes such as Crohn's disease.
    explanation: The reference confirms that inflammatory processes like Crohn's disease can lead to colonic obstructions, supporting the statement.
  phenotype_term:
    preferred_term: Intestinal Obstruction
    term:
      id: HP:0004796
      label: Gastrointestinal obstruction
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Arthritis
  notes: Can affect both large and small joints
  evidence:
  - reference: PMID:21122514
    reference_title: "The joint-gut axis in inflammatory bowel diseases."
    supports: SUPPORT
    snippet: The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies.
    explanation: The literature indicates that arthritis is a common extraintestinal manifestation of Crohn's disease, affecting both large and small joints.
  - reference: PMID:36730654
    reference_title: "The Influence of Coexisting Familial Mediterranean Fever on Crohn's Disease: Data From an FMF Endemic Area."
    supports: SUPPORT
    snippet: The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04).
    explanation: This study supports the occurrence of arthritis in Crohn's disease patients, particularly noting a higher prevalence in patients with coexisting FMF.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
- category: Dermatologic
  frequency: OCCASIONAL
  name: Erythema Nodosum
  notes: Painful nodules on shins
  evidence:
  - reference: PMID:16143688
    reference_title: "Important cutaneous manifestations of inflammatory bowel disease."
    supports: SUPPORT
    snippet: Erythema nodosum is a common cause of tender red nodules of the shins. Management includes leg elevation, NSAIDs, and potassium iodide.
    explanation: The reference confirms that erythema nodosum, characterized by tender red nodules on the shins, is associated with inflammatory bowel disease, which includes Crohn's disease.
  - reference: PMID:24746312
    reference_title: "Erythema nodosum - a review of an uncommon panniculitis."
    supports: SUPPORT
    snippet: Erythema nodosum (EN) is clinically the most frequent form of panniculitis and is considered a reactive process that may be triggered by a wide variety of stimuli. Whilst up to 55% of EN is considered idiopathic, the most common causes include infections, drugs, systemic illnesses such as sarcoidosis and inflammatory bowel disease, pregnancy, and malignancy.
    explanation: The reference supports the statement by mentioning that erythema nodosum is commonly triggered by systemic illnesses, including inflammatory bowel disease, which encompasses Crohn's disease.
  phenotype_term:
    preferred_term: Erythema Nodosum
    term:
      id: HP:0012219
      label: Erythema nodosum
- category: Ocular
  frequency: OCCASIONAL
  name: Uveitis
  notes: Inflammation of the eye
  evidence:
  - reference: PMID:2052301
    reference_title: "Ocular inflammation in Crohn's disease."
    supports: SUPPORT
    snippet: Seven patients had uveitis, eight had episcleritis, and four had anterior scleritis.
    explanation: The literature confirms that uveitis is a type of ocular inflammation associated with Crohn's disease, but it does not specify the frequency as 'occasional'.
  - reference: PMID:29102673
    reference_title: "Amblyopia due to intermediate uveitis as the presenting symptom of Crohn's disease in a 6-year-old boy."
    supports: SUPPORT
    snippet: This case of Crohn's disease and uveitis is unusual in that ocular inflammation preceded intestinal involvement, with the atypical feature of chronic intermediate uveitis.
    explanation: The literature provides a case of uveitis associated with Crohn's disease but does not specify the frequency as 'occasional'.
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
- category: Systemic
  frequency: OCCASIONAL
  name: Fever
  notes: More common during acute flares
  evidence:
  - reference: PMID:30244270
    reference_title: "Acute febrile neutrophilic dermatosis in a patient with Crohn's disease: case report and review of the literature."
    supports: SUPPORT
    snippet: Crohn's disease is a chronic inflammatory bowel disease. The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss.
    explanation: This reference confirms that fever is a symptom associated with acute exacerbations of Crohn's disease.
  - reference: PMID:921308
    reference_title: "Crohn's disease in childhood."
    supports: SUPPORT
    snippet: In 32 patients with Crohn's disease which started in childhood, abdominal pain, diarrhoea, and weight loss were the common presenting symptoms, but unexplained fever and failure to grow were also prominent.
    explanation: This reference supports the statement by indicating that fever is a prominent symptom in patients with Crohn's disease.
  - reference: PMID:27743896
    reference_title: "Procalcitonin in Crohn's disease with fever episodes, a variable to differentiate intra-abdominal abscess from disease flares."
    supports: SUPPORT
    snippet: A frequent problem in CD is the discrimination of fever caused by exacerbated bowel inflammation or IAA.
    explanation: This reference supports the statement by highlighting that fever is a frequent issue in Crohn's disease, especially during exacerbations.
  - reference: PMID:31347993
    reference_title: "Unexplained fever in a young man with Crohn's disease: a case report and review of literature."
    supports: SUPPORT
    snippet: A 23-year-old man with a known history of Crohn's disease (CD), who underwent an ileocaecal resection for localized disease activity three months ago, suffered from persistent fever with chills since 10 days.
    explanation: This reference supports the statement by providing a case where a patient with Crohn's disease experienced persistent fever.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- category: Systemic
  name: Weight Loss
  frequency: FREQUENT
  evidence:
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: SUPPORT
    snippet: Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia.
    explanation: Weight loss is listed as a common presenting symptom of Crohn's disease.
  - reference: PMID:921308
    reference_title: "Crohn's disease in childhood."
    supports: SUPPORT
    snippet: abdominal pain, diarrhoea, and weight loss were the common presenting symptoms
    explanation: Weight loss is one of the three most common presenting symptoms in childhood Crohn's disease.
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Systemic
  name: Malnutrition
  frequency: FREQUENT
  evidence:
  - reference: PMID:38437854
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: complete assessment involves laboratory abnormalities, including micronutrient deficiencies
    explanation: The Lancet review notes micronutrient deficiencies as a key laboratory finding requiring assessment in Crohn's disease.
  - reference: PMID:38036713
    reference_title: "Weight loss from diagnosis of Crohn's disease to one year post-diagnosis results in earlier surgery."
    supports: SUPPORT
    snippet: Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD)
    explanation: Malnutrition is recognized as playing a key prognostic role in Crohn's disease.
  phenotype_term:
    preferred_term: Malnutrition
    term:
      id: HP:0004395
      label: Malnutrition
- category: Systemic
  name: Dehydration
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Gastrointestinal
  name: Intestinal Stricture
  frequency: FREQUENT
  notes: Approximately 35% of patients develop intestinal strictures; complications requiring surgery occur in up to 70% within 10 years. Fibrostenotic disease manifestation.
  evidence:
  - reference: PMID:34014617
    reference_title: "Intestinal stricture in Crohn's disease: A 2020 update."
    supports: SUPPORT
    snippet: Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life.
    explanation: Confirms the high prevalence of intestinal strictures in Crohn's disease.
  phenotype_term:
    preferred_term: Intestinal stricture
    term:
      id: HP:0012848
      label: Small intestinal stenosis
- category: Gastrointestinal
  name: Perianal Fistula
  frequency: FREQUENT
  notes: Occurs in approximately 20-50% of Crohn's disease patients; often requires surgical intervention. Related to perianal abscess formation.
  evidence:
  - reference: PMID:15711045
    reference_title: "Fistulizing Crohn's disease."
    supports: SUPPORT
    snippet: Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%).
    explanation: Confirms high prevalence of perianal fistulas in Crohn's disease.
  phenotype_term:
    preferred_term: Intestinal fistula
    term:
      id: HP:0100819
      label: Intestinal fistula
- category: Gastrointestinal
  name: Transmural Inflammation
  frequency: VERY_FREQUENT
  notes: Characteristic feature of Crohn's disease affecting all layers of the intestinal wall.
  diagnostic: true
  phenotype_term:
    preferred_term: Intestinal inflammation
    term:
      id: HP:4000055
      label: Intestinal inflammation
- category: Gastrointestinal
  name: Hematochezia
  frequency: OCCASIONAL
  notes: More common in colonic Crohn's disease than ileal disease.
  evidence:
  - reference: PMID:30244270
    reference_title: "Acute febrile neutrophilic dermatosis in a patient with Crohn's disease: case report and review of the literature."
    supports: SUPPORT
    snippet: The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss.
    explanation: Intestinal bleeding (which manifests as hematochezia) is listed as a characteristic feature of Crohn's disease exacerbations.
  phenotype_term:
    preferred_term: Hematochezia
    term:
      id: HP:0002573
      label: Hematochezia
- category: Gastrointestinal
  name: Anal Fissure
  frequency: OCCASIONAL
  notes: Part of the spectrum of perianal disease in Crohn's.
  evidence:
  - reference: PMID:15227686
    reference_title: "Perianal Crohn's disease."
    supports: SUPPORT
    snippet: Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses.
    explanation: Anal fissures are explicitly listed as a manifestation of perianal Crohn's disease.
  phenotype_term:
    preferred_term: Anal fissure
    term:
      id: HP:0012390
      label: Anal fissure
- category: Oral
  name: Aphthous Stomatitis
  frequency: OCCASIONAL
  notes: Second most prevalent extraintestinal manifestation of IBD.
  evidence:
  - reference: PMID:34548985
    reference_title: "Mucocutaneous Manifestations of Inflammatory Bowel Disease."
    supports: SUPPORT
    snippet: dermatologic findings, such as erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis (which are the most frequently occurring)
    explanation: Aphthous stomatitis is listed among the most frequently occurring mucocutaneous manifestations of IBD.
  - reference: PMID:36173720
    reference_title: "Prevalence of aphthous stomatitis in patients with inflammatory bowel disease after the treatment with monoclonal antibodies: a systematic review and meta-analysis."
    supports: SUPPORT
    snippet: Forty-seven per cent of these patients present extra-intestinal manifestations, the second most prevalent being aphthous stomatitis (AS).
    explanation: Aphthous stomatitis is the second most prevalent extraintestinal manifestation of IBD.
  phenotype_term:
    preferred_term: Recurrent aphthous stomatitis
    term:
      id: HP:0011107
      label: Recurrent aphthous stomatitis
- category: Hematologic
  name: Iron Deficiency Anemia
  frequency: FREQUENT
  notes: Most common extraintestinal manifestation of IBD; caused by chronic blood loss and impaired iron absorption.
  evidence:
  - reference: PMID:30970351
    reference_title: "Management of Iron Deficiency Anaemia in Inflammatory Bowel Disease."
    supports: SUPPORT
    snippet: Anaemia is the most common extraintestinal manifestation of IBD, correlating with disease activity, and tending to relapse even after successful therapy. Iron deficiency is the most common cause
    explanation: Identifies anemia as the most common extraintestinal manifestation of IBD with iron deficiency as the leading cause.
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: SUPPORT
    snippet: Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia.
    explanation: Anemia is listed among common clinical features of Crohn's disease.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
- category: Musculoskeletal
  name: Osteoporosis
  frequency: OCCASIONAL
  notes: Related to chronic inflammation, corticosteroid use, and malabsorption of calcium and vitamin D.
  evidence:
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: SUPPORT
    snippet: Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum.
    explanation: Osteoporosis is explicitly listed as an extraintestinal manifestation of Crohn's disease.
  - reference: PMID:17560419
    reference_title: "Extra-intestinal manifestations of Crohn's disease."
    supports: SUPPORT
    snippet: Screening may be appropriate for eye disease and for osteoporosis to prevent complications.
    explanation: Recommends osteoporosis screening in Crohn's patients, indicating clinical significance.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
- category: Renal
  name: Nephrolithiasis
  frequency: OCCASIONAL
  notes: Oxalate stones due to fat malabsorption and increased oxalate absorption, particularly in ileal disease.
  evidence:
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: SUPPORT
    snippet: Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum.
    explanation: Nephrolithiasis is explicitly listed as an extraintestinal manifestation of Crohn's disease.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
- category: Dermatologic
  name: Pyoderma Gangrenosum
  frequency: OCCASIONAL
  notes: Rare but serious cutaneous manifestation; painful ulcerating skin lesions, often on lower extremities.
  evidence:
  - reference: PMID:34548985
    reference_title: "Mucocutaneous Manifestations of Inflammatory Bowel Disease."
    supports: SUPPORT
    snippet: dermatologic findings, such as erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis (which are the most frequently occurring)
    explanation: Pyoderma gangrenosum is listed as a frequent mucocutaneous manifestation of IBD, though individual prevalence is low.
  phenotype_term:
    preferred_term: Pyoderma gangrenosum
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
- category: Growth
  name: Growth Failure
  frequency: OCCASIONAL
  notes: Occurs in pediatric-onset Crohn's disease; related to chronic inflammation and malnutrition.
  evidence:
  - reference: PMID:921308
    reference_title: "Crohn's disease in childhood."
    supports: SUPPORT
    snippet: Stunted growth was the most frequent physical abnormality when first seen in hospital.
    explanation: Growth failure is the most common physical finding in childhood Crohn's disease.
  - reference: PMID:26925610
    reference_title: "Growth Pattern in Paediatric Crohn Disease Is Related to Inflammatory Status."
    supports: SUPPORT
    snippet: Growth failure (H/A z score <-2) was present in 7 (8%) patients at diagnosis and 5 (5%) at maximal follow-up.
    explanation: Documents the prevalence of growth failure in pediatric Crohn's disease at 5-8%.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
- name: "Anterior uveitis"
  category: Ophthalmologic
  description: "Anterior uveitis is an ocular extraintestinal manifestation that can occur independent of intestinal disease activity."
  phenotype_term:
    preferred_term: "Anterior uveitis"
    term:
      id: HP:0012122
      label: "Anterior uveitis"
  evidence:
  - reference: PMID:34358489
    reference_title: "Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares"
    explanation: "This IBD extraintestinal-manifestation review lists anterior uveitis occurring independent of disease flares."
- name: "Primary sclerosing cholangitis"
  category: Hepatic
  description: "Primary sclerosing cholangitis is a hepatobiliary extraintestinal manifestation of inflammatory bowel disease."
  phenotype_term:
    preferred_term: "Primary sclerosing cholangitis"
    term:
      id: HP:0030991
      label: "Sclerosing cholangitis"
  evidence:
  - reference: PMID:34358489
    reference_title: "Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis usually occur independent of disease flares"
    explanation: "The review lists primary sclerosing cholangitis as an IBD extraintestinal manifestation independent of flares."
- name: "Episcleritis"
  category: Ophthalmologic
  description: "Episcleritis is an ocular extraintestinal manifestation associated with active intestinal inflammation."
  phenotype_term:
    preferred_term: "Episcleritis"
    term:
      id: HP:0100534
      label: "Episcleritis"
  evidence:
  - reference: PMID:34358489
    reference_title: "Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum can be associated with active intestinal inflammation"
    explanation: "The review lists episcleritis among manifestations associated with active intestinal inflammation."
- name: "Perianal abscess"
  category: Gastrointestinal
  description: "Perianal abscess is a characteristic perianal complication of Crohn disease."
  phenotype_term:
    preferred_term: "Perianal abscess"
    term:
      id: HP:0009789
      label: "Perianal abscess"
  evidence:
  - reference: PMID:38326222
    reference_title: "Dermatologic manifestations in pediatric patients with inflammatory bowel disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "perianal skin complications (i.e., skin tags, fistula, and abscesses"
    explanation: "This pediatric IBD cohort lists perianal abscesses among perianal skin complications more frequent in Crohn disease."
biochemical:
- name: C-Reactive Protein (CRP)
  presence: Elevated
  evidence:
  - reference: PMID:24635486
    reference_title: "C-reactive protein in Crohn's disease: how informative is it?"
    supports: SUPPORT
    snippet: C-reactive protein (CRP) is an important acute-phase marker, produced mainly in the liver. Its production by mesenteric adipocytes has been recently stressed in Crohn's disease (CD).
    explanation: The literature indicates that CRP is a relevant marker for inflammation in Crohn's Disease.
  - reference: PMID:22868800
    reference_title: "Lipid peroxidation markers in Crohn's disease: the associations and diagnostic value."
    supports: SUPPORT
    snippet: 'MDA/TBARS were the best predictor of CD, comparable to CRP, with high specificity (MDA/TBARS sensitivity and specificity: 75% and 90%; CRP: 76% and 93%). Combined assessment of MDA/TBARS and CRP improved sensitivity (94%) corresponding with acceptable specificity (81%).'
    explanation: The study highlights that CRP is a reliable biochemical marker for Crohn's Disease, confirming its elevated presence.
  - reference: PMID:36550821
    reference_title: "An assessment of serum vitamin B12 and folate in patients with Crohn's disease."
    supports: SUPPORT
    snippet: C-reactive protein, vitamin B12, folate levels were studied along with hemogram analyses.
    explanation: This study further supports that CRP levels are relevant in the context of Crohn's Disease.
  context: General inflammation
- name: Fecal Calprotectin
  presence: Elevated
  context: Intestinal inflammation
  evidence:
  - reference: PMID:31088326
    reference_title: "Clinical value of fecal calprotectin."
    supports: SUPPORT
    snippet: Calprotectin, a cytosolic protein derived predominantly from neutrophils, is now widely used in this capacity. Calprotectin is found in various bodily fluids at concentrations proportional to the degree of inflammation, including in feces at levels roughly six times higher than in the blood. Fecal calprotectin (FCP) therefore reflects intestinal inflammation.
    explanation: The statement is supported by the literature, which indicates that fecal calprotectin levels are elevated in the context of intestinal inflammation, consistent with the presence of Crohn's Disease.
genetic:
- name: NOD2
  gene_term:
    preferred_term: NOD2
    term:
      id: hgnc:5331
      label: NOD2
  association: Risk Factor
  evidence:
  - reference: PMID:29358789
    reference_title: "Crohn's disease - genetic factors and progress of the disease."
    supports: SUPPORT
    snippet: 'BACKGROUND AND OBJECTIVES: Crohn''s disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC).'
    explanation: This reference states that NOD2 mutations are involved in Crohn's disease, supporting the association as a risk factor.
  - reference: PMID:23352252
    reference_title: "Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases."
    supports: SUPPORT
    snippet: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID... The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease.
    explanation: This reference confirms the association of NOD2 gene mutations with Crohn's disease.
  - reference: PMID:16773683
    reference_title: "NOD2: ethnic and geographic differences."
    supports: SUPPORT
    snippet: Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations.
    explanation: This reference clearly establishes the association of specific NOD2 mutations with susceptibility to Crohn's disease.
  - reference: PMID:12851870
    reference_title: "Crohn's disease and the NOD2 gene: a role for paneth cells."
    supports: SUPPORT
    snippet: The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation.
    explanation: This study supports the role of NOD2 as a genetic risk factor for Crohn's disease.
  - reference: PMID:32476786
    reference_title: "Genetic association analysis of CLEC5A and CLEC7A gene single-nucleotide polymorphisms and Crohn's disease."
    supports: SUPPORT
    snippet: While NOD2 mutations represent well established risk factors of CD, the role of other genes is incompletely understood.
    explanation: This confirms that NOD2 is a well-established genetic risk factor for Crohn's disease.
  - reference: PMID:11385577
    reference_title: "A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease."
    supports: SUPPORT
    snippet: Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease.
    explanation: This study provides evidence of a specific NOD2 mutation associated with Crohn's disease.
  - reference: PMID:17206682
    reference_title: "NOD2/CARD15 disease associations other than Crohn's disease."
    supports: SUPPORT
    snippet: The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases.
    explanation: This statement supports the association of NOD2 with Crohn's disease (CD).
  - reference: PMID:16987083
    reference_title: "Inflammatory bowel disease genetics: Nod2."
    supports: SUPPORT
    snippet: The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders.
    explanation: This reference emphasizes that the NOD2 association with Crohn's disease is well-established.
  - reference: PMID:27076762
    reference_title: "Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population."
    supports: SUPPORT
    snippet: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively.
    explanation: This study confirms the role of genetic risk scores including multiple SNP variants for predicting Crohn's disease.
- name: ATG16L1
  gene_term:
    preferred_term: ATG16L1
    term:
      id: hgnc:21498
      label: ATG16L1
  association: Risk Factor
  evidence:
  - reference: PMID:27698206
    reference_title: "Association between ATG16L1 gene polymorphism and the risk of Crohn's disease."
    supports: SUPPORT
    snippet: Conclusion In this meta-analysis, the ATG16L1 genotype was significantly associated with the risk of developing Crohn's disease.
  - reference: PMID:25906181
    reference_title: "ATG16L1: A multifunctional susceptibility factor in Crohn disease."
    supports: SUPPORT
    snippet: single-nucleotide polymorphisms in ATG16L1 ... a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease.
  - reference: PMID:12840668
    reference_title: "Lessons to be learned from the NOD2 gene in Crohn's disease."
    supports: NO_EVIDENCE
    snippet: CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. Interestingly, CD patients often carry mutations on their two chromosomes suggesting a mutation dose effect.
    explanation: The reference focuses on the association between CARD15 mutations and Crohn’s Disease, with no information regarding ATG16L1.
  - reference: PMID:29795570
    reference_title: "Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population."
    supports: NO_EVIDENCE
    snippet: ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD.
    explanation: The reference highlights genetic risk factors in NOD2 and LRRK2 for Crohn's Disease, not ATG16L1.
  - reference: PMID:27076762
    reference_title: "Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population."
    supports: SUPPORT
    snippet: We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC)....The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively.
    explanation: The study involves identification of SNPs for risk prediction, however ATG16L1 is not mentioned explicitly. Thus, it only partially supports the statement.
- name: IL23R
  gene_term:
    preferred_term: IL23R
    term:
      id: hgnc:19100
      label: IL23R
  association: Risk Factor
  evidence:
  - reference: PMID:17068223
    reference_title: "A genome-wide association study identifies IL23R as an inflammatory bowel disease gene."
    supports: SUPPORT
    snippet: We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23.
    explanation: This study identifies IL23R as a gene significantly associated with Crohn's disease, supporting the statement that IL23R is a genetic risk factor for the condition.
  - reference: PMID:24989722
    reference_title: "Smoking behaviour modifies IL23r-associated disease risk in patients with Crohn's disease."
    supports: SUPPORT
    snippet: We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking.
    explanation: This study supports the association between IL23R and Crohn's disease, while also highlighting the interaction between IL23R variants and environmental factors like smoking.
- name: LRRK2
  gene_term:
    preferred_term: LRRK2
    term:
      id: hgnc:18618
      label: LRRK2
  association: Risk Factor
  notes: Hyperactive LRRK2 variants (e.g., G2019S, N2081D) impair autophagy and drive Paneth-cell dysfunction, leading to intestinal inflammation.
- name: TNFSF15
  gene_term:
    preferred_term: TNFSF15
    term:
      id: hgnc:11931
      label: TNFSF15
  association: Risk Factor
  notes: Encodes TL1A, a TNF superfamily cytokine involved in T-cell costimulation and fibroblast activation in fistulizing disease.
- name: CARD9
  gene_term:
    preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  association: Risk Factor
  notes: Involved in antifungal immunity; variants associated with fungal dysbiosis and impaired pathogen clearance.
- name: BACH2
  gene_term:
    preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: STAT3
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  association: GWAS
  notes: Signal transducer mediating Th17 differentiation via JAK-STAT pathway
- name: IL10
  gene_term:
    preferred_term: IL10
    term:
      id: hgnc:5962
      label: IL10
  association: GWAS
  notes: Anti-inflammatory cytokine critical for immune tolerance
- name: CD28
  gene_term:
    preferred_term: CD28
    term:
      id: hgnc:1653
      label: CD28
  association: GWAS
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  gene_term:
    preferred_term: ETS1
    term:
      id: hgnc:3488
      label: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  gene_term:
    preferred_term: IRF4
    term:
      id: hgnc:6119
      label: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: IRF8
  gene_term:
    preferred_term: IRF8
    term:
      id: hgnc:5358
      label: IRF8
  association: GWAS
  notes: Interferon regulatory factor controlling myeloid cell development and type I interferon response
- name: SATB1
  gene_term:
    preferred_term: SATB1
    term:
      id: hgnc:10541
      label: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage commitment
- name: IKZF1
  gene_term:
    preferred_term: IKZF1
    term:
      id: hgnc:13176
      label: IKZF1
  association: GWAS
  notes: Ikaros transcription factor essential for lymphocyte development and differentiation
- name: SMAD3
  gene_term:
    preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: PRDM1
  gene_term:
    preferred_term: PRDM1
    term:
      id: hgnc:9346
      label: PRDM1
  association: GWAS
  notes: Blimp-1 transcription factor regulating T cell and B cell terminal differentiation
- name: PTPN22
  gene_term:
    preferred_term: PTPN22
    term:
      id: hgnc:9652
      label: PTPN22
  association: GWAS
  notes: Protein tyrosine phosphatase modulating T cell receptor signaling threshold
- name: IL21R
  gene_term:
    preferred_term: IL21R
    term:
      id: hgnc:6006
      label: IL21R
  association: GWAS
  notes: IL-21 receptor mediating T and B cell activation and differentiation
environmental:
- name: Smoking
  influences_mechanisms:
  - target: Dysregulated Immune Response
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Smoking raises both the risk of developing Crohn disease and the rate of
      complications, recurrence, and surgery once it is established. The route
      to mucosal immune dysregulation is not settled, and the cited sentences
      report risk and disease course rather than any immune measurement, so
      the intermediates are left unknown.
    evidence:
    - reference: PMID:38238335
      reference_title: "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10-10) and UC (P < 2 × 10-16) risk, respectively."
      explanation: >-
        Prospective cohort finding both current and previous smoking
        associated with raised Crohn disease risk at genome-wide significance.
        It establishes the association and not the immune step this link
        targets.
    - reference: PMID:27016849
      reference_title: "[Smoking, smoking cessation and Crohn's disease]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants."
      explanation: >-
        Review reporting that smoking increases complications, recurrences,
        and recourse to surgery or immunosuppressants, which is disease course
        rather than mechanism.
  notes: Increases the risk and severity of Crohn's disease.
  evidence:
  - reference: PMID:27016849
    reference_title: "[Smoking, smoking cessation and Crohn's disease]."
    supports: SUPPORT
    snippet: Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants.
    explanation: The provided literature clearly states that smoking increases the risk and severity of Crohn's disease, aligning with the statement.
  - reference: PMID:31014995
    reference_title: "Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses."
    supports: SUPPORT
    snippet: 'We identified 9 factors that increase risk of IBD: smoking (CD)...'
    explanation: The review identifies smoking as a significant environmental risk factor that increases the risk of Crohn's disease.
  - reference: PMID:33159156
    reference_title: "Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02).
    explanation: >-
      Mendelian randomization estimate for smoking and Crohn disease risk, which
      is the exposure this entry records.
  - reference: PMID:38238335
    reference_title: "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease."
    supports: SUPPORT
    snippet: Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10-10) and UC (P < 2 × 10-16) risk, respectively.
    explanation: This prospective cohort study finds that both current and previous smoking habits are associated with increased risk of CD, which supports the statement.
  - reference: PMID:28838409
    reference_title: "Epidemiology, Natural History, and Risk Stratification of Crohn's Disease."
    supports: SUPPORT
    snippet: Understanding the potential environmental risk factors and natural history of CD in a given patient guides the physician when counseling the patient and selecting a treatment strategy.
    explanation: The review discusses smoking as an important environmental risk factor, thereby supporting the statement.
  exposure_term:
    preferred_term: Tobacco smoking exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
- name: Diet
  influences_mechanisms:
  - target: Paneth Cell Autophagy Impairment
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A fibre-poor Western diet reshapes the gut microbiome, and the altered
      community drives Paneth cell defects through farnesoid X receptor and
      type I interferon signalling. Those intermediates are named by the cited
      study, which is why they are recorded as known. The finding is from
      mouse models, so this link is graded partial and should not be the sole
      support for a human claim.
    evidence:
    - reference: PMID:34010595
      reference_title: "Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction."
      explanation: >-
        Four weeks of Western diet produced Paneth cell dysfunction in mouse
        models, which is this node's own defect. Model-organism evidence, so
        it supports the mechanism without establishing it in human disease.
  notes: Western diet with high-fat, low-fiber content may exacerbate symptoms.
  evidence:
  - reference: PMID:33574618
    reference_title: "Fiber-poor Western diets fuel inflammation."
    supports: SUPPORT
    snippet: Fiber-poor Western diets fuel inflammation.
    explanation: This indicates that a Western diet, which is low in fiber, can contribute to inflammation, suggesting a potential exacerbation of symptoms in Crohn's Disease.
  - reference: PMID:34010595
    reference_title: "Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction.
    explanation: >-
      Connects a Western diet to compromised Paneth cell function and so to gut
      immunity. The snippet is explicit that this is a mouse result, which is
      what the model-organism tag and the partial grade record.
  - reference: PMID:35595417
    reference_title: "Diet in the Pathogenesis and Management of Crohn's Disease."
    supports: SUPPORT
    snippet: most patients report minimal nutritional education from their provider, and providers report few nutritional resources to help them educate patients.
    explanation: While this indicates the importance of diet, it also highlights a lack of resources and education surrounding the dietary management of Crohn's disease, providing partial support.
  exposure_term:
    preferred_term: Dietary exposure
    term:
      id: XCO:0000013
      label: diet
- name: Stress
  notes: Can trigger flare-ups and worsen symptoms.
  evidence:
  - reference: PMID:15288007
    reference_title: "Inflammatory bowel disease: the role of environmental factors."
    supports: NO_EVIDENCE
    snippet: Stress is also associated with IBD, but more as a modifier than an inducing factor, and its contribution is more obvious in IBD animal models than human IBD.
    explanation: The literature suggests that stress is associated with IBD as a modifier and not necessarily as a direct trigger.
  - reference: PMID:31574072
    reference_title: "Disease-Related Worries in Persons With Crohn Disease: An Interview Study."
    supports: SUPPORT
    snippet: The unpredictable course of the disease, impaired function due to fatigue, and lack of bowel control were the most prominent causes of worry. The worries created feelings of stress, guilt, and frustration. The participants expressed a need to talk about their worries, to make them visible and recognized, and to be understood.
    explanation: The study indicates that stress related to the disease itself is significant among Crohn's disease patients, which supports the claim that stress can worsen symptoms.
  exposure_term:
    preferred_term: Psychological stress exposure
    term:
      id: XCO:0001265
      label: stress
treatments:
- name: Aminosalicylates
  description: Anti-inflammatory drugs used for mild to moderate disease.
  evidence:
  - reference: PMID:12786608
    reference_title: "Review article: medical treatment of mild to moderately active Crohn's disease."
    supports: SUPPORT
    snippet: The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators.
    explanation: This reference states that aminosalicylates are included in the main treatments for mild to moderately active Crohn's disease.
  - reference: PMID:34797442
    reference_title: "No Benefit of Continuing 5-Aminosalicylates in Patients with Crohn's Disease Treated with Anti-metabolite Therapy."
    supports: SUPPORT
    snippet: 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease.
    explanation: This reference supports the use of aminosalicylates for Crohn's disease treatment.
  - reference: PMID:17339853
    reference_title: "Drug insight: aminosalicylates for the treatment of IBD."
    supports: REFUTE
    snippet: Sulfasalazine and mesalazine are useful for the treatment of both active and quiescent ulcerative colitis, whereas they have no clinical effect on either active or inactive Crohn's disease.
    explanation: This reference explicitly states that aminosalicylates have no clinical effect on Crohn's disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Corticosteroids
  description: Used for short-term control during flare-ups to reduce inflammation.
  evidence:
  - reference: PMID:24532122
    reference_title: "Steroid use in Crohn's disease."
    supports: SUPPORT
    snippet: Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease.
    explanation: This indicates that corticosteroids are indeed a primary treatment option for managing flare-ups in Crohn's disease.
  - reference: PMID:32653651
    reference_title: "Inflammatory Bowel Disease - Non-biological treatment."
    supports: SUPPORT
    snippet: corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease.
    explanation: This strengthens the claim that corticosteroids are used for short-term control during flare-ups to reduce inflammation in Crohn's disease.
  - reference: PMID:18239408
    reference_title: "Drug safety in Crohn's disease therapy."
    supports: SUPPORT
    snippet: The management of Crohn's disease usually consists of a succession of short-term acute phase treatments followed by a long-term maintenance therapy.
    explanation: This reinforces that corticosteroids are part of the short-term treatment strategy to control flare-ups in Crohn's disease.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
- name: Immunomodulators
  description: Drugs like azathioprine and methotrexate to suppress the immune response.
  evidence:
  - reference: PMID:17105689
    reference_title: "Insights in immunomodulatory therapies for ulcerative colitis and Crohn's disease."
    supports: SUPPORT
    snippet: The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus.
    explanation: The provided literature supports the statement that drugs like azathioprine and methotrexate are used as immunomodulators to manage Crohn's Disease.
  - reference: PMID:35115294
    reference_title: "Parenteral Methotrexate Is Efficient in the Treatment of Azathioprine Refractory Crohn's Disease."
    supports: SUPPORT
    snippet: Our results show that parenteral use of methotrexate is efficacious in inducing and maintaining remission as a step-up agent in azathioprine refractory Crohn's disease patients.
    explanation: The study shows the use of methotrexate in patients who are refractory to azathioprine, supporting the statement that these drugs are used to treat Crohn's Disease by mitigating immune response.
  - reference: PMID:16245637
    reference_title: "[Crohn's disease--standards of treatment 2004]."
    supports: SUPPORT
    snippet: First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications.
    explanation: This reference confirms that Azathioprine and Methotrexate are used as immunosuppressants in the treatment of Crohn's Disease.
  - reference: PMID:24913384
    reference_title: "Can we get more from our current treatments?"
    supports: SUPPORT
    snippet: The only other long term disease-modifying options are the immunomodulators, methotrexate, azathioprine and mercaptopurine.
    explanation: This review supports the use of methotrexate and azathioprine as immunomodulators for long-term management of Crohn's Disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Biologics
  description: Anti-TNF agents (infliximab, adalimumab) and integrin inhibitors (vedolizumab) for moderate to severe disease.
  evidence:
  - reference: PMID:18034589
    reference_title: "Crohn's disease: a review of current treatment with a focus on biologics."
    supports: SUPPORT
    snippet: Infliximab and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults (infliximab and adalimumab) and children (infliximab) with Crohn's disease.
    explanation: This reference supports the use of anti-TNF agents (infliximab and adalimumab) for the treatment of moderate to severe Crohn's disease but does not mention vedolizumab directly.
  - reference: PMID:26195652
    reference_title: "Vedolizumab: An integrin-receptor antagonist for treatment of Crohn's disease and ulcerative colitis."
    supports: SUPPORT
    snippet: Vedolizumab is an integrin-receptor antagonist for the treatment of CD and UC in adults with moderately to severely active disease.
    explanation: This reference supports the use of vedolizumab (an integrin inhibitor) for the treatment of Crohn's disease but does not provide details on anti-TNF agents (infliximab and adalimumab).
  - reference: PMID:26616476
    reference_title: "Anti-TNF-α therapies for the treatment of Crohn's disease: the past, present and future."
    supports: SUPPORT
    snippet: Anti-TNF-alpha therapy is a novel approach that has transformed the way moderate-to-severe Crohn's disease (CD) is treated and has significantly improved clinical outcomes of patients.
    explanation: This reference supports the use of anti-TNF agents for moderate to severe Crohn's disease.
  - reference: PMID:41274746
    reference_title: "AGA Living Clinical Practice Guideline on the Pharmacologic Management of Moderate-to-Severe Crohn's Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The AGA suggests using combination therapy with infliximab and thiopurines over infliximab monotherapy, particularly in those naïve to thiopurines."
    explanation: The AGA living guideline recommends combination therapy with the anti-TNF biologic infliximab plus thiopurines over infliximab monotherapy in moderate-to-severe Crohn's disease.
  treatment_term:
    preferred_term: biologic therapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
- name: Nutritional Therapy
  description: Dietary modifications and enteral nutrition to manage symptoms and maintain nutrition.
  evidence:
  - reference: PMID:19244154
    reference_title: "Enteral nutrition as a primary therapy of Crohn's disease: the pediatric perspective."
    supports: SUPPORT
    snippet: Nutrition therapy of Crohn's disease is considered the first-line of treatment for Crohn's disease in children, especially in Europe.
    explanation: This article supports the use of nutrition therapy as a treatment for managing symptoms and maintaining nutrition in Crohn’s disease.
  - reference: PMID:38276922
    reference_title: "AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review."
    supports: SUPPORT
    snippet: New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery.
    explanation: This article supports the use of enteral nutrition as an effective therapy to induce remission and manage malnutrition in Crohn's disease.
  - reference: PMID:36558412
    reference_title: "Assessment of Dietary Adequacy and Quality in a Sample of Patients with Crohn's Disease."
    supports: SUPPORT
    snippet: Both under-and over-nutrition are prevalent in patients with Crohn's Disease (CD).
    explanation: The study highlights the importance of dietary modifications to manage nutritional status in Crohn's disease patients.
  - reference: PMID:35595414
    reference_title: "Conventional Therapies for Crohn's Disease."
    supports: SUPPORT
    snippet: The primary agents used in the treatment of Crohn's disease are aminosalicylates, corticosteroids, immunomodulators, and biologics. Each agent has different roles in the induction and maintenance of remission of disease.
    explanation: While this primarily focuses on pharmacologic therapy, it does acknowledge the role of different agents in maintaining remission.
  - reference: PMID:22410431
    reference_title: "Potential value of nutrigenomics in Crohn's disease."
    supports: SUPPORT
    snippet: Although an elemental diet might lead to disease remission, reintroducing real foods and sustainable diets in patients with Crohn's disease is currently difficult, and would benefit from the sensitivity and rapid feedback provided by the field of nutrigenomics.
    explanation: This reference suggests that dietary modifications can lead to remission and maintenance of Crohn's disease, validating the role of nutritional therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
- name: Surgery
  description: Removal of affected bowel segments, typically reserved for complications like strictures or fistulas.
  evidence:
  - reference: PMID:21901520
    reference_title: "Emergency and elective surgery for small bowel Crohn's disease."
    supports: SUPPORT
    snippet: The indications for surgery include the failure of medical management, especially the persistence or worsening of symptoms in spite of proper treatment and complications of the disease process. These complications include intestinal obstruction, intestinal perforation with fistula formation or abscess, free perforation, gastrointestinal bleeding, urologic complications, cancer, and perianal disease.
    explanation: The excerpt indicates that surgery is reserved for complications such as strictures or fistulas among others, thus supporting the statement.
  - reference: PMID:32279173
    reference_title: "Strictures in Crohn's Disease: From Pathophysiology to Treatment."
    supports: SUPPORT
    snippet: Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures.
    explanation: The statement mentions surgery for complications like strictures, which is supported by the snippet indicating that fibrotic strictures rely on surgical procedures for treatment.
  - reference: PMID:21975159
    reference_title: "Diagnosis and treatment of fistulising Crohn's disease."
    supports: SUPPORT
    snippet: Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas.
    explanation: The statement links surgery to the complication of fistulas, which is supported by the snippet explaining the need for intestinal resection to manage symptomatic non-perianal fistulas.
  - reference: PMID:29462390
    reference_title: "Segmental Resection versus Total Proctocolectomy for Crohn's Colitis: What is the Best Operation in the Setting of Medically Refractory Disease or Dysplasia?"
    supports: SUPPORT
    snippet: When isolated to the colon, and patients become medically refractory, there are several surgical options - segmental resection, subtotal colectomy with ileorectal anastomosis, or a total proctocolectomy and end ileostomy. Unfortunately, surgery does not cure CD, and, regardless of the extent of bowel removed, recurrence may be seen in the small bowel.
    explanation: The snippet supports the statement by discussing various surgical options for patients who are medically refractory, involving the removal of affected bowel segments.
  - reference: PMID:36926950
    reference_title: "Duodenal stenosis surgical treatment in Crohn's disease."
    supports: SUPPORT
    snippet: A partial resection of 3rd and 4th portion of the duodenum and the first loop of jejunum was performed, with duodenojejunal anastomosis.
    explanation: The provided case demonstrates a scenario where surgery was performed due to refractory disease and complications, supporting the statement.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Anti-IL-23 Biologics
  description: Biologics targeting IL-23 (e.g., ustekinumab, risankizumab) for moderate to severe Crohn's disease refractory to anti-TNF therapy.
  notes: Reflects the central role of the IL-23/Th17 axis in CD pathogenesis.
  treatment_term:
    preferred_term: biologic therapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
- name: TL1A Inhibitors
  description: Emerging precision therapy targeting TL1A-DR3 signaling for fistulizing and fibrostenotic disease.
  notes: Under clinical investigation; addresses TNF-independent inflammatory pathways in perianal disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: JAK Inhibitors
  description: Small molecule inhibitors targeting JAK-STAT pathway for moderate to severe disease.
  notes: Addresses interferon-driven inflammation and may benefit refractory cases.
  treatment_term:
    preferred_term: JAK inhibitor therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
discussions:
- discussion_id: crohn_pgsxc_reverse_causation
  prompt: >-
    Are the IBD PGS×context interactions driven by adverse exposures causally
    amplifying genetic risk, or are some "contexts" (e.g. CRP, fecal calprotectin,
    diet change) actually downstream readouts/responses of active disease (reverse
    causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Intestinal Inflammation and Epithelial Injury
  - biochemical#C-Reactive Protein (CRP)
  - biochemical#Fecal Calprotectin
  - environmental#Diet
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are
    largely unable to establish the causality of specific contexts. For Crohn
    disease the biochemical "contexts" C-reactive protein and fecal calprotectin
    are disease-activity readouts (consequences of active inflammation), and
    dietary change is a classic response to gastrointestinal symptoms rather than
    a pure upstream driver, making both prime reverse-causation suspects.
    Distinguishing genuine amplification of genetic effects from reverse causation
    determines whether the modelled interventions (smoking cessation, dietary
    modification) would actually reduce risk.
  proposed_experiments:
  - experiment_id: crohn_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-Crohn direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (smoking, diet, inflammatory biomarkers) causally
      affects Crohn disease versus being a consequence of active disease, and
      whether the causal effect estimate scales with polygenic liability as the
      amplification model predicts.
    decision_criterion: >-
      A context is retained as a causal amplifier if MR supports
      exposure-to-disease directionality and the exposure-attributable risk
      difference increases across increasing PGS strata; it is flagged as a
      reverse-causation suspect otherwise.
  - experiment_id: crohn_pgsxc_prospective_temporal
    name: Prospective incident-Crohn analysis restricted to pre-diagnosis exposure
      windows
    description: >-
      Restrict exposures to measurements taken well before diagnosis and repeat
      the PGS×context liability-threshold modelling on incident cases only, to
      reduce the chance that exposure and biomarker values reflect established
      disease rather than antecedent risk.
    decision_criterion: >-
      Amplification is supported if the PGS×context deviation from additivity
      persists when only pre-diagnosis exposure windows and incident cases are
      used.
- discussion_id: gap_crohn_creeping_fat_stricture_causality
  prompt: >-
    Are creeping fat-derived CTHRC1-positive mechanosensitive fibroblasts a
    necessary and targetable driver of Crohn strictures, or are they a
    downstream marker of bowel-wall inflammation and established fibrosis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Fibrosis and Stricture Formation
  - pathophysiology#Intestinal Inflammation and Epithelial Injury
  - pathophysiology#Myeloid-Stromal Cell Crosstalk
  rationale: >-
    The Crohn entry captures inflammation-driven fibrosis, but recent
    single-cell and animal-model work suggests that mesenteric creeping fat may
    supply a mechanosensitive fibroblast population at the fat-bowel interface.
    Testing necessity and reversibility would determine whether future
    anti-fibrotic experiments should target bowel inflammation alone or the
    mesenteric-fat interface as a separate disease mechanism.
  proposed_experiments:
  - experiment_id: exp_crohn_creeping_fat_bowel_interface_yap_taz_rescue
    name: Patient-derived creeping-fat bowel-interface fibrosis-on-chip assay
    description: >-
      Construct a patient-derived Crohn bowel-wall organoid or organ-on-chip
      that juxtaposes intestinal epithelial organoids, bowel-wall stromal cells,
      mesenteric adipose stromal cells, and myeloid cells on tunable-stiffness
      matrix; then deplete or inhibit CTHRC1-positive/YAP-TAZ-high fibroblasts
      to test whether extracellular-matrix deposition and stricture-like tissue
      contraction are prevented or reversed.
    experiment_type:
      preferred_term: patient-derived organ-on-chip fibrosis perturbation experiment
    model_systems:
    - name: Crohn creeping-fat bowel-interface organ-on-chip
      description: >-
        Microphysiological model of the fibrotic Crohn fat-bowel interface
        combining intestinal epithelium, lamina propria stromal cells,
        mesenteric adipose stromal cells, fibroblasts, and myeloid cells under
        tunable mechanical stiffness.
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: ileum
        term:
          id: UBERON:0002116
          label: ileum
      cell_types:
      - preferred_term: intestinal epithelial cell
        term:
          id: CL:0002563
          label: intestinal epithelial cell
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
      - preferred_term: adipocyte
        term:
          id: CL:0000136
          label: adipocyte
      - preferred_term: macrophage
        term:
          id: CL:0000235
          label: macrophage
      cell_source: resection-derived Crohn bowel wall, creeping fat, and patient-matched immune cells
      culture_system: tunable-stiffness microfluidic matrix with epithelial-organoid and mesenteric-fat compartments
    perturbations:
    - name: CTHRC1-positive fibroblast depletion
      target: pathophysiology#Fibrosis and Stricture Formation
      description: >-
        Genetic, antibody-based, or sorting-based removal of
        CTHRC1-positive/YAP-TAZ-high fibroblasts from the creeping-fat
        compartment to test necessity for fibrotic remodeling.
      gene:
        preferred_term: CTHRC1
    - name: YAP/TAZ mechanotransduction inhibition
      target: pathophysiology#Fibrosis and Stricture Formation
      description: >-
        Pharmacologic or genetic blockade of YAP/TAZ activity under high-stiffness
        matrix conditions to test whether mechanosensitive signaling maintains
        extracellular-matrix deposition.
      genes:
      - preferred_term: YAP1
      - preferred_term: WWTR1
      biological_processes:
      - preferred_term: regulation of transcription by RNA polymerase II
        term:
          id: GO:0006357
          label: regulation of transcription by RNA polymerase II
    - name: Myeloid-stromal inflammatory challenge
      target: pathophysiology#Myeloid-Stromal Cell Crosstalk
      description: >-
        Myeloid-cell cytokine challenge used to test whether creeping-fat
        fibroblasts require inflammatory crosstalk to invade the bowel-wall
        compartment.
      biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
    readouts:
    - name: Extracellular-matrix deposition and contraction
      target: pathophysiology#Fibrosis and Stricture Formation
      description: Collagen deposition, matrix stiffness, gel contraction, and luminal narrowing analogs.
      biological_processes:
      - preferred_term: extracellular matrix organization
        term:
          id: GO:0030198
          label: extracellular matrix organization
      assays:
      - preferred_term: extracellular matrix immunostaining
      - preferred_term: traction force microscopy
      direction: POSITIVE
    - name: CTHRC1-positive/YAP-TAZ fibroblast state
      target: pathophysiology#Fibrosis and Stricture Formation
      description: >-
        Single-cell and spatial profiling of CTHRC1-positive fibroblasts,
        YAP/TAZ target-gene signatures, and fat-bowel interface localization.
      assays:
      - preferred_term: single-cell transcriptomic profiling
      - preferred_term: spatial transcriptomic profiling
      direction: POSITIVE
    - name: Epithelial barrier injury under fibrotic stiffness
      target: pathophysiology#Intestinal Inflammation and Epithelial Injury
      description: Barrier permeability and epithelial injury-state readouts coupled to stromal stiffness.
      assays:
      - preferred_term: permeability assay
      - preferred_term: epithelial inflammatory profiling
      direction: POSITIVE
    controls:
    - name: Bowel-wall organoid without creeping-fat compartment
      description: Patient-derived intestinal organoid and stromal culture lacking mesenteric adipose cells.
    - name: Non-stricturing Crohn comparator culture
      description: Patient-derived culture from inflammatory, non-stricturing Crohn tissue.
    - name: Low-stiffness matrix control
      description: Mechanical control testing whether fibroblast activation depends on fibrotic stiffness.
    decision_criterion: >-
      Creeping-fat fibroblasts are supported as causal if their presence
      increases CTHRC1/YAP-TAZ state, extracellular-matrix deposition, matrix
      contraction, and epithelial injury, and if depletion or YAP/TAZ blockade
      prevents or reverses these readouts despite inflammatory challenge.
    would_support:
    - pathophysiology#Fibrosis and Stricture Formation
    - pathophysiology#Myeloid-Stromal Cell Crosstalk
    would_refute:
    - pathophysiology#Fibrosis and Stricture Formation
    evidence:
    - reference: PMID:40967215
      reference_title: "Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn's disease strictures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified CF-derived, CTHRC1+ fibroblasts enriched for Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signatures and localized to a fibrotic CF-bowel wall interface within the stricture."
      explanation: >-
        Supports the proposed target population and its localization at the
        creeping-fat bowel interface in human Crohn strictures.
    - reference: PMID:40967215
      reference_title: "Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn's disease strictures."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "analogous Cthrc1+ mouse fibroblasts derive from mesenteric adipose tissue stromal cells, infiltrate fibrotic bowel, and deposit extracellular matrix in a YAP/TAZ-dependent manner"
      explanation: >-
        Provides causal animal-model support for testing YAP/TAZ-dependent
        extracellular-matrix deposition in a humanized ex vivo platform.
    - reference: PMID:40421006
      reference_title: "Intestinal organoids in inflammatory bowel disease: advances, applications, and future directions."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Innovations in CRISPR editing, organoid-microbe co-cultures, and organ-on-a-chip systems have enhanced the physiological relevance of these models"
      explanation: >-
        Supports the feasibility of organoid and organ-on-chip approaches for
        modeling complex Crohn tissue mechanisms.
- discussion_id: gap_crohn_cuproptosis_evidence_hierarchy
  prompt: >-
    Is there any Crohn-specific evidence that copper-dependent cell death occurs
    in ileal or colonic lesions, or does the CD literature consist entirely of
    transcriptomic cuproptosis-gene signatures that measure different members of
    the cuproptosis gene set and are not directly comparable, so that copper
    dysregulation belongs on this entry only as a susceptibility or
    metabolic-stress marker?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Intestinal Barrier Dysfunction
  - pathophysiology#Dysregulated Immune Response
  rationale: >-
    Crohn disease is named in the cuproptosis-in-autoimmunity literature only
    inside an undiscriminated "inflammatory bowel disease" grouping, and the
    CD-specific literature that does exist stops at bioinformatic inference,
    the lowest tier of the source review's own evidence hierarchy. Two studies
    interrogate CD directly, and they are not directly comparable because they
    measure disjoint members of the cuproptosis gene set: a 2022 GEO analysis of
    437 CD samples found most differentially expressed cuproptosis genes - the
    canonical hub genes - expressed at lower levels in CD and negatively related
    to immune cell infiltration, while a 2025 bulk plus single-cell study found
    four different markers (CD274, PDK1, CP, SLC31A2) upregulated in CD. No gene
    is shared between the two result sets, so the two findings are simultaneously
    coherent rather than contradictory, and a dedicated IBD review reports the
    core regulators as downregulated in IBD, consistent with the 2022 direction.
    Neither measured copper, lipoylated-protein aggregation, Fe-S cluster loss,
    or attempted rescue, and the 2025 study says outright that experimental
    validation is still required. The functional colitis work that does clear
    part of the canonical bar - tetrathiomolybdate and penicillamine rescue of
    barrier damage - was done in DSS and TNBS models, which are colitis models
    and speak to the parallel gap on Ulcerative_Colitis, not to transmural ileal
    Crohn disease. No cuproptosis pathophysiology node is therefore added here.
    The gap is attached to intestinal barrier dysfunction, which is what the
    rodent copper work perturbs and what a CD cuproptosis mechanism would have
    to act on, and to the dysregulated immune response node, because the only
    CD-specific claim in the literature is a correlation between the cuproptosis
    gene signature and immune cell infiltration. Recording it keeps the question
    findable and stops a future transcriptomic association being mistaken for a
    resolved mechanism.
  evidence:
  - reference: PMID:42435071
    reference_title: "From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      canonical cuproptosis can only be confirmed when copper dependence,
      involvement of the Ferredoxin 1 (FDX1)-lipoylation axis, aggregation of
      lipoylated proteins, destabilization of Fe-S clusters, and functional
      rescue are demonstrated
    explanation: >-
      Gives the explicit five-part confirmation bar that this discussion's
      decision criterion is written against, shared verbatim with the parallel
      gaps on Ulcerative_Colitis, Systemic_Lupus_Erythematosus,
      Rheumatoid_Arthritis and Ankylosing_Spondylitis.
  - reference: PMID:42435071
    reference_title: "From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      systemic AIDs (e.g., systemic lupus erythematosus, rheumatoid arthritis)
      and organ-specific AIDs (e.g., inflammatory bowel disease, ankylosing
      spondylitis) were summarized. Findings mostly reflected copper-associated
      metabolic stress or susceptibility markers rather than definitive
      functional activation.
    explanation: >-
      The sentence that names inflammatory bowel disease without discriminating
      Crohn disease from ulcerative colitis - the reason this gap was originally
      left off both IBD entries, and the reason it is now curated against
      CD-specific sources instead.
  - reference: PMID:42495776
    reference_title: Effects of cuproptosis and its application in inflammatory bowel disease (Review).
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the precise function of genes linked to cuproptosis in ulcerative colitis
      (UC) (14) and Crohn's disease (CD) remains unclear
    explanation: >-
      A dedicated IBD-cuproptosis review that does discriminate CD from UC, and
      states for CD specifically that the function of cuproptosis-linked genes
      is unresolved.
  - reference: PMID:42495776
    reference_title: Effects of cuproptosis and its application in inflammatory bowel disease (Review).
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      the core regulatory genes involved in cuproptosis (FDX1, LIAS and DLAT) are
      downregulated in IBD
    explanation: >-
      Independently reports the canonical regulators as downregulated in IBD,
      agreeing with the 2022 CD hub-gene direction. This is why the two CD
      studies are recorded here as measuring different genes rather than as
      disagreeing: the direction for the core set is consistent across sources,
      and the 2025 study's four upregulated markers are simply not in that set.
      Indirect because the review speaks to IBD rather than to Crohn disease
      specifically.
  - reference: PMID:36466876
    reference_title: "Identification of immune infiltration and cuproptosis-related subgroups in Crohn's disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      And most CuDEGs were expressed at lower levels in CD samples and were
      negatively related to immune cell infiltration.
    explanation: >-
      The larger of the two CD-specific studies reports the canonical cuproptosis
      hub genes as downregulated in CD. This is a different gene set from the one
      the 2025 study reports as upregulated, so the two do not conflict; neither
      tests any of the five canonical criteria, which is why the signature cannot
      yet be read as a mechanism.
  - reference: PMID:36466876
    reference_title: "Identification of immune infiltration and cuproptosis-related subgroups in Crohn's disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      According to the current research, the cuproptosis phenomenon occurs in CD
      and is correlated with immune cell infiltration and metabolic activity.
    explanation: >-
      The study's own conclusion is stated as a correlation with immune
      infiltration, which is why this gap attaches to the dysregulated immune
      response node rather than adding a cell-death node.
  - reference: PMID:41232892
    reference_title: "Integrated bulk and single-cell RNA sequencing analysis reveals cuproptosis-related proteins in Crohn's disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Four cuproptosis-related protein markers-CD274, PDK1, CP, and
      SLC31A2-were identified to be upregulated in CD and validated via RT-qPCR.
    explanation: >-
      The more recent CD-specific study reports four markers as upregulated.
      None of the four appears in the 2022 analysis's hub-gene set, so this is a
      measurement of different genes rather than a contradiction of it; RT-qPCR
      confirms transcript abundance but tests none of the five canonical
      criteria.
  - reference: PMID:41232892
    reference_title: "Integrated bulk and single-cell RNA sequencing analysis reveals cuproptosis-related proteins in Crohn's disease."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Further studies are required to experimentally validate these associations
      and explore the potential of markers as therapeutic targets.
    explanation: >-
      The authors classify their own CD findings as unvalidated associations,
      which is the evidence tier this discussion records.
  proposed_experiments:
  - experiment_id: exp_crohn_canonical_cuproptosis_criteria_in_ileal_tissue
    name: Canonical-cuproptosis criteria in Crohn ileal tissue, measured across the whole gene set
    description: >-
      Do not start from another GEO reanalysis. Take paired inflamed and
      uninflamed full-thickness ileal and colonic tissue from Crohn resection
      specimens, plus non-IBD surgical controls, and apply the five canonical
      criteria to the tissue: quantify mucosal and transmural copper, assay FDX1
      and LIAS protein with lipoylated DLAT/DLST aggregation, and measure Fe-S
      cluster protein destabilization. Supply the rescue arm with
      patient-derived ileal organoids treated with tetrathiomolybdate. In the
      same specimens, measure the four markers reported as upregulated
      (CD274, PDK1, CP, SLC31A2) and the hub genes reported as downregulated at
      protein level, stratified by inflamed versus uninflamed and by
      Montreal behaviour. The point of measuring both sets in the same specimens
      is that the two published studies never did: they report disjoint genes, so
      whether the cuproptosis gene set moves coherently in CD is untested rather
      than disputed. Because the only CD-specific claim in the literature ties the
      signature to immune infiltration, deconvolve or sort the immune
      compartment so an apparent epithelial copper phenotype is not an
      infiltrate composition artefact.
    experiment_type:
      preferred_term: mechanism validation study in human surgical tissue and patient-derived organoids
    assays:
    - preferred_term: tissue copper quantification
    - preferred_term: FDX1 and LIAS immunoblot and in situ protein detection
    - preferred_term: lipoylated protein aggregation assay
    - preferred_term: Fe-S cluster protein stability assay
    - preferred_term: immune cell deconvolution and flow cytometric sorting
    readouts:
    - name: Copper-dependent epithelial death in Crohn lesions
      target: pathophysiology#Intestinal Barrier Dysfunction
      description: >-
        Copper content, DLAT/DLST aggregation and Fe-S cluster protein loss in
        inflamed versus uninflamed Crohn ileum, with barrier integrity assayed in
        matched organoids under copper chelation.
      direction: ALTERED
      interpretation: >-
        Satisfaction of the canonical criteria in inflamed tissue with chelation
        rescue in organoids would justify a cuproptosis node upstream of barrier
        dysfunction; failure would confine copper dysregulation to a
        metabolic-stress marker.
    - name: Cuproptosis signature versus immune infiltrate composition
      target: pathophysiology#Dysregulated Immune Response
      description: >-
        Cuproptosis gene and protein signature measured before and after
        adjustment for immune cell composition, stratified by inflammatory
        activity.
      direction: ALTERED
      interpretation: >-
        A signature that disappears after adjusting for infiltrate composition
        would close the question without a new node; one that persists would
        localise a genuine copper phenotype to a defined cell population.
    controls:
    - name: Uninflamed margin from the same resection
      description: >-
        Within-patient control separating a copper phenotype specific to Crohn
        lesions from one attributable to the patient or to surgery.
    - name: Non-IBD inflamed intestine
      description: >-
        Infectious or ischaemic enteritis, to test whether any copper phenotype
        is specific to Crohn disease rather than to intestinal inflammation.
    decision_criterion: >-
      Add a cuproptosis pathophysiology node to this entry only if all five
      canonical criteria - copper dependence, FDX1-lipoylation axis involvement,
      lipoylated-protein aggregation, Fe-S cluster destabilization, and
      functional rescue - are demonstrated in Crohn tissue or patient-derived
      Crohn organoids, and only if the signal survives adjustment for immune
      infiltrate composition. Transcriptomic signatures, however well validated
      as classifiers, do not meet the bar, and colitis-model results do not
      transfer to this entry.
    would_support:
    - pathophysiology#Intestinal Barrier Dysfunction
    - pathophysiology#Dysregulated Immune Response
  posed_by: automated curation scanner (high_effort)
  posed_date: '2026-08-25T00:00:00Z'
  notes: >-
    Filed from monarch-initiative/dismech#8397, which asked whether the
    cuproptosis evidence-hierarchy gap recorded on Systemic_Lupus_Erythematosus,
    Rheumatoid_Arthritis and Ankylosing_Spondylitis in #8326 should also be
    carried by the two dismech entries that IBD splits into. It should, and
    against CD- and UC-specific sources rather than the umbrella review's
    undiscriminated "inflammatory bowel disease" sentence. The parallel gap on
    Ulcerative_Colitis is kind HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP,
    because chelator rescue of the colitis phenotype has been shown in rodents;
    no equivalent functional result exists for Crohn disease in any species.
review_notes: Crohn disease is a type of inflammatory bowel disease that can affect any part of the GI tract but most commonly the terminal ileum and colon. Extraintestinal manifestations involving the joints, skin and eyes occur in a subset of patients. The disease is characterized by periods of remission interspersed with flares.
disease_term:
  preferred_term: Crohn disease
  term:
    id: MONDO:0005011
    label: Crohn disease
experimental_models:
- name: Primary human small-intestinal monolayer barrier model
  description: >-
    Polarized primary human small-intestinal epithelial monolayers cultured on
    Transwells to study barrier integrity, permeability, and host-microbiota
    interface biology relevant to inflammatory bowel disease.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - intestinal barrier dysfunction
  - host-microbiota interaction modeling
  - gut barrier dysfunction (IBD-adjacent)
  cell_source: Primary human small-intestinal epithelial cells
  culture_system: Polarized two-dimensional Transwell monolayer
  publication: PMID:29094594
  modeled_mechanisms:
  - target: Intestinal Barrier Dysfunction
    description: Supports permeability and barrier-integrity readouts relevant to epithelial dysfunction in Crohn disease.
  - target: Microbiome Imbalance
    description: Supports controlled host-microbiota interface experiments relevant to dysbiosis-linked epithelial dysfunction in Crohn disease.
  findings:
  - statement: Primary human small-intestinal epithelial monolayers support barrier and host-microbiota assays relevant to Crohn disease
    evidence:
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment."
      explanation: Validates the primary human intestinal model, but the cited study is not Crohn-specific.
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions."
      explanation: Supports relevance to barrier and host-microbiota questions central to Crohn disease, while remaining an indirect bridge rather than direct disease evidence.
  evidence:
  - reference: PMID:29094594
    reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions."
    explanation: Supports inclusion as a Crohn-relevant translational model but not as a Crohn-specific organoid or disease model.
- name: Enteroendocrine-deficient intestinal enteroid barrier model
  description: >-
    Human intestinal enteroid monolayers derived from pluripotent stem
    cell-derived organoids with NEUROG3 loss, cultured on Transwell filters to
    quantify permeability and inflammatory-cytokine-sensitive epithelial
    barrier responses.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - enteroendocrine-cell deficiency
  - TNF exposure
  - epithelial barrier dysfunction
  cell_source: Crypt-derived enteroids isolated from wild-type and NEUROG3-null human intestinal organoids generated from pluripotent stem cells
  culture_system: Polarized two-dimensional Transwell enteroid monolayer
  publication: PMID:40095977
  modeled_mechanisms:
  - target: Intestinal Barrier Dysfunction
    description: Directly measures transepithelial resistance and paracellular permeability in cytokine-sensitive intestinal epithelial monolayers.
  - target: Intestinal Inflammation and Epithelial Injury
    description: Models inflammatory-cytokine-associated epithelial barrier injury in a Crohn-relevant gut epithelium context.
  findings:
  - statement: Enteroendocrine-deficient intestinal enteroid monolayers show impaired barrier function that persists under inflammatory cytokine exposure
    evidence:
    - reference: PMID:40095977
      reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like \"stem\" and villus-like differentiated cultures."
      explanation: Supports the baseline barrier-defect phenotype in the enteroid model.
    - reference: PMID:40095977
      reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine-tyrosine (PYY), and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor."
      explanation: Supports cytokine-sensitive perturbation and rescue of the barrier phenotype in this model.
  evidence:
  - reference: PMID:40095977
    reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins."
    explanation: Supports inclusion as a human intestinal enteroid Transwell model that directly assays epithelial barrier dysfunction.
  - reference: PMID:40095977
    reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier."
    explanation: Supports Crohn-relevant use as an inflammatory barrier model, while remaining broader than Crohn-specific patient tissue.
- name: PSC-derived intestinal organoid-macrophage coculture model
  description: >-
    Human pluripotent stem cell-derived intestinal organoids combined with
    matched PSC-derived macrophages to model resident myeloid-epithelial
    interactions and inflammatory cytokine responses in intestinal tissue.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - tissue-resident macrophage coculture
  - proinflammatory signaling
  - bacterial challenge
  cell_source: Human pluripotent stem cell-derived intestinal organoids and macrophages combined in coculture
  culture_system: Three-dimensional intestinal organoid coculture with PSC-derived tissue-resident macrophages
  publication: PMID:39701210
  modeled_mechanisms:
  - target: Dysregulated Immune Response
    description: Captures macrophage cytokine responses to proinflammatory signals within a human intestinal tissue context.
  findings:
  - statement: PSC-derived intestinal organoid-macrophage cocultures provide a human immune-epithelial system for inflammatory and bacterial-response studies relevant to Crohn disease
    evidence:
    - reference: PMID:39701210
      reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10."
      explanation: Supports functional immune-response readouts in the coculture model.
    - reference: PMID:39701210
      reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."
      explanation: Supports Crohn-relevant use as an IBD mechanism model, while remaining broader than Crohn-specific disease tissue.
  evidence:
  - reference: PMID:39701210
    reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro."
    explanation: Supports model identity as a PSC-derived intestinal organoid-macrophage coculture system.
  - reference: PMID:39701210
    reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."
    explanation: Supports inclusion as a Crohn-relevant intestinal immune-epithelial model without overstating disease specificity.
computational_models:
- name: AGORA2 Gut Microbiome Metabolic Models
  description: >
    Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of human
    gut microorganisms. Enables modeling of dysbiosis-associated metabolic shifts in CD,
    including depletion of butyrate-producing Firmicutes (F. prausnitzii, Roseburia) and
    expansion of Enterobacteriaceae. Supports integration with host intestinal epithelial
    cell models.
  model_type: GENOME_SCALE_METABOLIC
  repository_url: https://www.vmh.life/
  publication: PMID:36543475
  notes: Nature Biotechnology 2022 - includes strain-level resolution for studying CD-associated dysbiosis patterns
- name: MICOM Community Metabolic Model
  description: >
    Metagenome-scale modeling framework for simulating metabolic interactions in the
    gut microbiota. Integrates dietary constraints and taxon abundances from metagenomic
    data to predict SCFA production deficits, cross-feeding network disruption, and
    pathobiont metabolic niches characteristic of CD dysbiosis.
  model_type: GENOME_SCALE_METABOLIC
  model_software: COBRApy
  publication: PMID:31964767
  findings:
  - statement: Community-level SCFA production is heterogeneous and highly individual-specific
    evidence:
    - reference: PMID:31964767
      reference_title: "MICOM: Metagenome-Scale Modeling To Infer Metabolic Interactions in the Gut Microbiota."
      supports: SUPPORT
      snippet: "the community-level production of short-chain fatty acids (SCFAs) was heterogeneous and highly individual specific"
      explanation: MICOM reveals personalized SCFA flux profiles relevant to understanding IBD heterogeneity.
  - statement: Model output reveals complex cross-feeding interactions that would be difficult to measure in vivo
    evidence:
    - reference: PMID:31964767
      reference_title: "MICOM: Metagenome-Scale Modeling To Infer Metabolic Interactions in the Gut Microbiota."
      supports: SUPPORT
      snippet: "Model output revealed complex cross-feeding interactions that would be difficult to measure in vivo"
      explanation: Enables mechanistic understanding of metabolic networks disrupted in CD dysbiosis.
  notes: mSystems 2020 - enables personalized microbiome metabolic modeling; applied to IBD cohorts
- name: Host-Microbiome Multi-Objective Optimization Model
  description: >
    Integrated metabolic model combining human intestinal epithelial cell (IEC) metabolism
    with gut microbiome community models. Uses multi-objective optimization to predict
    competition, mutualism, and neutralism between host and microbial metabolism. Models
    SCFA exchange, amino acid cross-feeding, and metabolic interactions disrupted in CD.
  model_type: GENOME_SCALE_METABOLIC
  publication: PMID:38729159
  notes: iScience 2024 - framework for quantifying host-microbiome metabolic crosstalk
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
  - classification_value: IMMUNE_RHEUMATOLOGIC
datasets:
- accession: geo:GSE281635
  title: Molecular Profiling of the Appendix in Pediatric Inflammatory Bowel Diseases
  description: Clinical studies suggest a critical role for the appendix in the pathogenesis of inflammatory bowel diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC), as indicated by the presence of peri-appendicular patches in UC and the beneficial effects of appendectomy in UC. However, the underlying mechanisms remain unclear. To address this gap, we characterized microbial species, associated patterns, and host-microbiota interactions in the appendix and non-inflamed regions of the colon tissue and mucus from pediatric IBD and non-IBD patients (n=15).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 15
  notes: Identified by GEO DataSets index search for Crohn Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: metabolomics_workbench:ST000899
  title: Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Crohn Disease"). Retrieved 2026-08-02.
- accession: dbgap:phs000926
  title: Rare disease susceptibility alleles in children with Crohn disease
  description:  The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset-Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Crohn Disease"). Retrieved 2026-08-02.

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References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

Name: Crohn Disease
Category: Complex
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 112

Key Pathophysiology Nodes

Dysregulated Immune Response
Microbiome Imbalance
Paneth Cell Autophagy Impairment
Antimicrobial Defense Deficiency
Macrophage Autophagy Dysfunction
IL-23/Th17 Axis Dysregulation
Fibrosis and Stricture Formation
TL1A-Mediated T Cell Activation
Myeloid Cell Recruitment to Perianal Tissue
Myeloid-Stromal Cell Crosstalk
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1002/ueg2.12568
DOI:10.1016/j.medj.2024.03.021
DOI:10.1101/2025.06.26.657455
DOI:10.1126/sciimmunol.adi7907
DOI:10.3390/biomedicines13020305
DOI:10.3390/biomedicines13071777
DOI:10.3390/ijms26136133

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 23 citations 2025-12-15T09:11:09.165077

Disease Pathophysiology Research Report

Target Disease - Disease Name: Crohn Disease - MONDO ID: MONDO:0005059 - Category: Complex

Pathophysiology description (narrative) Crohn disease (CD) arises from the convergence of genetic susceptibility, maladaptive immune responses to the intestinal microbiota, epithelial barrier dysfunction, and stromal remodeling culminating in fibrosis and fistulizing complications. Contemporary single-cell and spatial-omics studies resolve cell-type specific programs that drive disease heterogeneity: perianal fistulas feature myeloid–stromal crosstalk and interferon-driven modules; ileal disease highlights impaired autophagy and Paneth-cell dysfunction linked to LRRK2, ATG16L1, and NOD2 risk variants; and fibrostenosing disease is sustained by profibrotic fibroblast circuits and creeping fat–mesentery interactions that modulate transmural inflammation and matrix deposition (levantovsky2024multimodalsinglecellanalyses pages 1-4, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4).

Core Pathophysiology 1) Immune pathway dysregulation - IL-23/Th17 axis: Multiple recent reviews and single-cell syntheses detail a prominent Th17/IL-23 program with STAT3, IL23R, and hybrid Th1/Th17 states in IBD, including Crohn disease, supporting the now-standard clinical targeting of the pathway (e.g., anti-IL-23) (calvez2025novelinsightsinto pages 4-6). As summarized, “Adaptive responses retain prominent Th1 signatures (IFNG+ TNF+ cells) and a notable Th17 program with STAT3 and IL23R overexpression; single-cell data identify hybrid Th1/Th17 cells…” (calvez2025novelinsightsinto pages 4-6). - TL1A–DR3 (TNFSF15–TNFRSF25) signaling: Human mucosal single-cell data from CD with perianal fistulizing disease (PFD) demonstrate TL1A-activated CD4+ T cells that remodel mucosa via downstream lymphotoxin-β (LTα1β2) and IL-22 programs in fibroblasts/epithelium, independent of TNF, nominating TL1A blockade as a precision target in fistulizing CD (gudino2025tl1aactivatedtcells pages 1-4). The authors note TL1A–DR3 engagement drives a “PFD-specific mucosal signature…with expanded fibroblast populations [and] induction of matrix-degrading enzymes” (gudino2025tl1aactivatedtcells pages 1-4). - Interferon programs in fistula: Multi-omic profiling of Crohn’s perianal fistulas shows pronounced interferon (IFN) response and myeloid–stromal ligand–receptor signaling in fistula tracts with fibroblasts upregulating CHI3L1 and OSM; these data implicate IFN/JAK modules in fistulizing disease biology (levantovsky2024multimodalsinglecellanalyses pages 1-4). The study reports fistula tracts are “enriched for myeloid cells and show pronounced myeloid–stromal cross-talk… [with] stromal/fibroblast cells…highly upregulate CHI3L1 and exhibit both destructive and fibrotic transcriptional programs” (levantovsky2024multimodalsinglecellanalyses pages 1-4).

2) Epithelial barrier defects and microbial–host interactions - Autophagy and Paneth-cell dysfunction: Hyperactive LRRK2 variants (e.g., G2019S, N2081D) impair autophagy, driving Paneth-cell abnormalities; lamina propria phagocytes expressing LRRK2 secrete proinflammatory cytokines that secondarily impair Paneth cells, while LRRK2 kinase inhibition restores autophagy and rescues function (sun2024macrophagelrrk2hyperactivity pages 1-3). The study concludes that “LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy” (sun2024macrophagelrrk2hyperactivity pages 1-3). Autophagy-related variants in ATG16L1 and NOD2 similarly perturb antimicrobial autophagy and Paneth granule biology (petit2025advancesinunderstanding pages 12-13, petit2025advancesinunderstanding pages 8-9). - Microbiome and pathobionts (AIEC; fungi/CARD9): Crohn disease is associated with reduced commensal diversity and enrichment of adherent-invasive E. coli (AIEC), which exploit impaired autophagy and innate signaling to persist, and with fungal dysbiosis interacting with CARD9-dependent antifungal immunity (calvez2025novelinsightsinto pages 4-6, petit2025advancesinunderstanding pages 12-13). Dysbiosis activates PRRs (e.g., TLR4, NOD2), amplifying TNF, IL-6 and IL-23, and sustaining Th1/Th17 responses (petit2025advancesinunderstanding pages 12-13).

3) Stromal–fibrotic circuits and creeping fat - Fibrosis pathobiology: Fibrostenosing CD reflects immune–stromal interaction with fibroblast activation, Wnt–β-catenin and TGF-β signaling, and matrix turnover imbalance. Recent updates highlight increased β-catenin+ cells in fibrotic intestine, fibroblast subsets (e.g., CXCL14+ and MMP/WNT5A+), and lack of approved anti-fibrotic therapies (liu2024intestinalstricturesin pages 1-2). A translational review emphasizes convergent profibrotic mediators (TGF-β/SMAD, WNT, PAI-1) and immune inputs (TLR4, Th17) that drive myofibroblast expansion and ECM deposition (zhou2025insightsintothe pages 2-4). - Creeping fat (mesenteric adipose tissue): Subserosal mesenteric adipose wraps the bowel (creeping fat), secreting immuno-metabolic mediators that associate with fibrostenosis and transmural inflammation; clinical imaging indices now quantify creeping fat burden and relate it to disease behavior (liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4). Reviews integrate creeping fat into a “diagnostic triad of fibrosis, smooth muscle hypertrophy, and creeping fat,” underlining its mechanistic role (zhou2025insightsintothe pages 2-4).

Key Molecular Players - Genes/Proteins (HGNC): NOD2; ATG16L1; LRRK2; TNFSF15 (TL1A); TNFRSF25 (DR3); IL23A/IL23R; IFNG; CHI3L1; OSM; TGFB1; WNT ligands (e.g., WNT5A); MMPs/TIMPs (levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, petit2025advancesinunderstanding pages 12-13, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4). - Chemical Entities (CHEBI): Not central to the primary genetic and cytokine mechanisms summarized here; pathway-targeting biologics are protein therapeutics (anti-IL-23, anti-TL1A) (calvez2025novelinsightsinto pages 4-6, gudino2025tl1aactivatedtcells pages 1-4). - Cell Types (CL terms): Paneth cells (intestinal epithelial secretory lineage); Th17 and Th1 T cells; pathogenic Th17; macrophages (including IFN-polarized); neutrophils; stromal fibroblasts/myofibroblasts; mesenteric adipocytes/preadipocytes (levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4). - Anatomical Locations (UBERON): Terminal ileum; intestinal lamina propria; rectal mucosa and perianal fistula tracts; intestinal muscularis propria; mesenteric adipose tissue (creeping fat) (levantovsky2024multimodalsinglecellanalyses pages 1-4, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4).

Biological Processes (GO-like annotation) - Autophagy/xenophagy and antimicrobial peptide secretion (Paneth cells) (sun2024macrophagelrrk2hyperactivity pages 1-3, petit2025advancesinunderstanding pages 12-13). - Cytokine signaling: IL-23/Th17 differentiation; TNF superfamily costimulation (TL1A–DR3); IFN-γ responses (levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6, gudino2025tl1aactivatedtcells pages 1-4). - Pattern-recognition receptor signaling and inflammasome-related innate pathways; PRR–microbiota interactions (petit2025advancesinunderstanding pages 12-13, petit2025advancesinunderstanding pages 8-9). - ECM organization, TGF-β/SMAD and WNT/β-catenin pathways; epithelial–mesenchymal transition in fibrosis (liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4). - Myeloid–stromal ligand–receptor interactions and interferon-stimulated gene programs in fistula (levantovsky2024multimodalsinglecellanalyses pages 1-4).

Cellular Components - Sites of activity: Paneth-cell secretory granules and autophagolysosomes; epithelial tight junctions and mucosal surface; extracellular matrix and stromal niches within the intestinal wall; mesenteric adipose depots (sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4).

Disease Progression (sequence of events) - Genetic predisposition (e.g., NOD2, ATG16L1, LRRK2) and environmental factors establish baseline defects in microbial handling and epithelial defense (autophagy, Paneth cell function) (sun2024macrophagelrrk2hyperactivity pages 1-3, petit2025advancesinunderstanding pages 12-13). - Dysbiosis with enrichment of pathobionts (AIEC) and altered fungal communities engages PRRs, elevating TNF/IL-6/IL-23 and driving Th1/Th17 polarization (calvez2025novelinsightsinto pages 4-6, petit2025advancesinunderstanding pages 12-13). - Tissue compartmentalization yields location-specific programs: interferon/myeloid–stromal modules and TL1A-driven T-cell activation in perianal fistulizing disease; profibrotic fibroblast networks and creeping fat in small-bowel fibrostenosis (levantovsky2024multimodalsinglecellanalyses pages 1-4, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4). - Chronic inflammation promotes matrix deposition, smooth muscle hyperplasia, and remodeling, leading to strictures and fistulas; creeping fat amplifies transmural inflammation (liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4).

Phenotypic Manifestations (HP terms examples) - Small-intestinal strictures and obstruction (stricture/stenosis); perianal fistulas; transmural inflammation; malabsorption related to ileal involvement; extraintestinal manifestations vary by interferon/Th17 programs (liu2024intestinalstricturesin pages 1-2, levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6).

Gene/protein annotations with ontology terms - NOD2 (HGNC:5331): GO—pattern recognition receptor signaling, regulation of NF-κB; Cellular component—cytosol; Biological role—antimicrobial autophagy with ATG16L1 (petit2025advancesinunderstanding pages 12-13, petit2025advancesinunderstanding pages 8-9). - ATG16L1 (HGNC:18585): GO—autophagosome assembly; Cellular component—autophagosome; Function—Paneth-cell granule biology and bacterial clearance (petit2025advancesinunderstanding pages 12-13, sun2024macrophagelrrk2hyperactivity pages 1-3). - LRRK2 (HGNC:18618): GO—protein serine/threonine kinase activity; Process—negative regulation of autophagy (hyperactive variants); Component—cytoplasm of myeloid lineage cells (sun2024macrophagelrrk2hyperactivity pages 1-3). - TNFSF15/TL1A (HGNC:11947) and TNFRSF25/DR3 (HGNC:11903): GO—T-cell costimulation; TNF receptor signaling; Process—fibrosis-associated fibroblast activation (gudino2025tl1aactivatedtcells pages 1-4). - IL23A/IL23R (HGNC: 6008/19100): GO—JAK-STAT signaling; Th17 differentiation (calvez2025novelinsightsinto pages 4-6). - IFNG (HGNC:5438): GO—type II interferon signaling; myeloid activation (levantovsky2024multimodalsinglecellanalyses pages 1-4). - CHI3L1 (HGNC:1933); OSM (HGNC:8506): GO—extracellular matrix organization and inflammation; fibroblast–myeloid signaling in fistula (levantovsky2024multimodalsinglecellanalyses pages 1-4). - TGFB1 (HGNC:11766), WNT5A (HGNC:12784), MMPs/TIMPs: GO—tissue remodeling and fibrosis (liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4).

Cell type involvement (CL terms examples) - Paneth cell (intestinal epithelial cell, secretory lineage) (sun2024macrophagelrrk2hyperactivity pages 1-3). - CD4+ Th17 cell; pathogenic Th17 (calvez2025novelinsightsinto pages 4-6). - Macrophage (including IFN-polarized signatures) (levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6). - Neutrophil (in fistula and fibrotic niches) (levantovsky2024multimodalsinglecellanalyses pages 1-4, liu2024intestinalstricturesin pages 1-2). - Stromal fibroblast/myofibroblast (fibrosis drivers) (liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4). - Mesenteric adipocyte/preadipocyte (creeping fat) (zhou2025insightsintothe pages 2-4).

Anatomical locations (UBERON examples) - Terminal ileum; rectal mucosa; perianal fistula tracts; intestinal wall (mucosa/submucosa/muscularis propria); mesenteric adipose tissue (levantovsky2024multimodalsinglecellanalyses pages 1-4, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4).

Current applications and real-world implementations - Anti-IL-23 biologics are in clinical use for CD, reflecting centrality of the IL-23/Th17 axis (calvez2025novelinsightsinto pages 4-6). - TL1A inhibition is a precision-medicine strategy under active evaluation; single-cell data in perianal CD substantiate a TL1A–LTα1β2/IL-22 mucosal remodeling axis potentially resistant to anti-TNF (gudino2025tl1aactivatedtcells pages 1-4). - Targeting autophagy regulators (e.g., LRRK2 kinase inhibitors) has preclinical support for restoring Paneth-cell homeostasis and may be relevant for selected genetic subgroups (sun2024macrophagelrrk2hyperactivity pages 1-3). - Imaging- and biomarker-driven stratification of fibrostenotic disease is advancing; however, no approved anti-fibrotic therapy exists for intestinal strictures (liu2024intestinalstricturesin pages 1-2).

Expert opinions and analysis (authoritative sources) - Fibrostenosis remains “among the largest unmet needs” in IBD, with progress driven by single-cell mapping of fibroblast subsets and matrix pathways, yet absent disease-modifying antifibrotics (liu2024intestinalstricturesin pages 1-2). Reviews of stenosis mechanisms converge on TGF-β/SMAD, WNT/β-catenin, and immune–stromal axes as key targets (zhou2025insightsintothe pages 2-4). Fistulizing disease appears to be sustained by myeloid–stromal–IFN circuits and TL1A-activated T cells that remodel the mucosa, providing a rationale for IFN/JAK-pathway and TL1A-directed therapies (levantovsky2024multimodalsinglecellanalyses pages 1-4, gudino2025tl1aactivatedtcells pages 1-4).

Relevant statistics and recent data - Fibrostenosis and surgery: Approximately 35% of patients develop intestinal strictures, and complications requiring surgery occur in up to 70% within 10 years—underscoring the progressive fibrotic burden (liu2024intestinalstricturesin pages 1-2). Single-cell data nominate fibroblast subtypes (e.g., CXCL14+ and MMP/WNT5A+) as pivotal in stricturing CD (liu2024intestinalstricturesin pages 1-2).

Selected evidence quotes (verbatim) - “LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy.” (Science Immunology, 2024) (sun2024macrophagelrrk2hyperactivity pages 1-3). - “Fistula tracts are enriched for myeloid cells and show pronounced myeloid–stromal cross-talk… [and] stromal/fibroblast cells… highly upregulate CHI3L1 and exhibit both destructive and fibrotic transcriptional programs.” (Med, 2024) (levantovsky2024multimodalsinglecellanalyses pages 1-4). - “TL1A-activated CD4+ T cells… [induce] a PFD-associated signature in fibroblasts and epithelial cells… independent of TNF signaling,” nominating TL1A inhibition. (bioRxiv, 2025) (gudino2025tl1aactivatedtcells pages 1-4). - “Stricturing Crohn’s disease is common… about 35% develop intestinal strictures… [and] complications requiring surgery occur in up to 70% within 10 years.” (UEGJ, 2024) (liu2024intestinalstricturesin pages 1-2).

Gene/protein, process, phenotype, cell, anatomy, chemical annotations (structured) - HGNC: NOD2; ATG16L1; LRRK2; TNFSF15; TNFRSF25; IL23A; IL23R; IFNG; CHI3L1; OSM; TGFB1; WNT5A; MMP family; TIMP family (levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6, sun2024macrophagelrrk2hyperactivity pages 1-3, liu2024intestinalstricturesin pages 1-2, petit2025advancesinunderstanding pages 12-13, zhou2025insightsintothe pages 2-4, gudino2025tl1aactivatedtcells pages 1-4). - GO processes: autophagy; cytokine-mediated signaling pathway; Th17 cell differentiation; T-cell costimulation; interferon-gamma-mediated signaling; extracellular matrix organization; WNT signaling; TGF-β receptor signaling; inflammatory response (same citations as above). - HP phenotypes: intestinal stenosis/stricture; perianal fistula; transmural intestinal inflammation; small-bowel malabsorption (liu2024intestinalstricturesin pages 1-2, levantovsky2024multimodalsinglecellanalyses pages 1-4, calvez2025novelinsightsinto pages 4-6). - CL cell types: Paneth cell; Th17 cell; macrophage; neutrophil; stromal fibroblast/myofibroblast; adipocyte/preadipocyte (mesenteric) (same citations as above). - UBERON anatomy: terminal ileum; rectal mucosa; perianal region; intestinal wall (mucosa/submucosa/muscularis propria); mesenteric adipose tissue (same citations as above). - CHEBI: Not primary (biologics/immune proteins predominate in cited mechanisms) (calvez2025novelinsightsinto pages 4-6, gudino2025tl1aactivatedtcells pages 1-4).

Embedded summary table | Mechanism | Key genes/proteins (HGNC) | Principal cell types (CL) | Pathways / Processes (GO-like) | Anatomical sites (UBERON) | Notes on clinical translation | Evidence | |---|---|---|---|---|---|---| | IL-23 / Th17 axis | IL23A, IL23R, RORC, STAT3 | Th17 cells; dendritic cells (CL) | IL-23 signaling; Th17 differentiation; JAK-STAT signaling | Intestinal lamina propria (UBERON) | Proven therapeutic target — anti-IL-23 biologics used in IBD; biomarkers under evaluation | (calvez2025novelinsightsinto pages 4-6) | | TL1A–DR3 signaling | TNFSF15 (TL1A), TNFRSF25 (DR3) | CD4+ T cells, dendritic cells, stromal fibroblasts (CL) | TNF/TNFR superfamily costimulation; T-cell co-stimulation; pro-fibrotic fibroblast activation | Intestinal mucosa (UBERON) | Anti-TL1A agents in development (precision-medicine potential for fistulizing/fibrostenotic disease) | (gudino2025tl1aactivatedtcells pages 1-4) | | Interferon programs & myeloid–stromal crosstalk in fistula | IFNG, CXCL9, CHI3L1, OSM | Myeloid cells (macrophages), pathogenic Th17, fibroblasts (CL) | Type II interferon signaling; myeloid–stromal ligand–receptor signalling; ECM remodelling | Perianal fistula tracts; rectal mucosa (UBERON) | Identifies IFN-driven modules and myeloid–stromal targets; suggests JAK/IFN pathway modulation for fistulizing disease | (levantovsky2024multimodalsinglecellanalyses pages 1-4), (gudino2025tl1aactivatedtcells pages 1-4) | | Autophagy / Paneth-cell dysfunction (NOD2, ATG16L1, LRRK2) | NOD2, ATG16L1, LRRK2 | Paneth cells (epithelial), lamina propria macrophages (CL) | Autophagy / xenophagy; antimicrobial peptide secretion; intracellular pathogen handling | Terminal ileum (UBERON) | Genetic variants (ATG16L1, NOD2, LRRK2) impair autophagy; LRRK2 kinase inhibitors rescue autophagy in preclinical studies | (sun2024macrophagelrrk2hyperactivity pages 1-3), (petit2025advancesinunderstanding pages 12-13) | | Microbial drivers: AIEC & fungi (CARD9-mediated) | CARD9 (host); pathobiont traits in AIEC strains | Intestinal epithelial cells, macrophages, neutrophils (CL) | Pattern recognition / antifungal pathways; dysbiosis-driven PRR activation; impaired bacterial clearance | Ileal mucosa, mesenteric lymphoid tissue (UBERON) | Microbiome-targeted interventions (antimicrobials, phage, FMT) and host–fungal immune axes are active translational areas | (calvez2025novelinsightsinto pages 4-6), (petit2025advancesinunderstanding pages 12-13) | | Fibrosis circuits (TWIST1+ FAP+ fibroblasts; neutrophil–fibroblast crosstalk; WNT/TGF-β) | TWIST1, FAP, WNT5A, TGFB1, MMPs, TIMPs | FAP+ fibroblasts, CD150+ inflammatory monocytes, neutrophils, macrophages (CL) | TGF-β/SMAD signaling; Wnt/β-catenin; ECM organization and remodeling; EMT | Intestinal wall (ileum, colon) (UBERON) | Single-cell studies nominate fibroblast subtypes (TWIST1+FAP+) and immune–stromal axes as antifibrotic targets; no approved anti-fibrotics yet | (liu2024intestinalstricturesin pages 1-2), (zhou2025insightsintothe pages 2-4) | | Creeping fat (mesenteric adipose) | PPARG, ADIPOQ, PTX3 (PTX3) | Mesenteric adipocytes / preadipocytes; infiltrating immune cells (macrophages) (CL) | Adipokine signaling; lipid metabolism–immune crosstalk; paracrine pro-fibrotic signaling | Mesenteric adipose tissue / creeping fat (UBERON) | Imaging (mesenteric creeping-fat indices) associates creeping fat with transmural healing and fibrosis risk; creeping fat is an emerging therapeutic/biomarker target | (zhou2025insightsintothe pages 2-4), (liu2024intestinalstricturesin pages 1-2) |

Table: Compact summary table linking major molecular/cellular mechanisms in Crohn disease to genes, cell types, pathway motifs, anatomical sites, translational notes, and primary evidence (pqac IDs and DOI/year); useful as a quick reference for knowledge-base curation.

Current applications and trials (2023–2024 emphasis) - Anti-IL-23 treatments reflect robust IL-23/Th17 involvement across IBD and Crohn disease patient subsets (calvez2025novelinsightsinto pages 4-6). - TL1A inhibition is supported by human single-cell pathobiology in PFD and is being advanced as a precision approach to inflammation–fibrosis–fistula circuits (gudino2025tl1aactivatedtcells pages 1-4). - Emerging precision concepts include stratifying genetic-autophagy subtypes (e.g., LRRK2/ATG16L1/NOD2) for autophagy-restoring strategies (sun2024macrophagelrrk2hyperactivity pages 1-3).

Limitations and knowledge gaps - Despite improved single-cell resolution of fibroblast heterogeneity and immune–stromal crosstalk, there remain no approved anti-fibrotic drugs for intestinal fibrostenosis; endpoints and biomarkers are under development (liu2024intestinalstricturesin pages 1-2). - Fistula biology implicates interferon and TL1A pathways, but prospective stratified interventional studies are needed to confirm therapeutic responsiveness (levantovsky2024multimodalsinglecellanalyses pages 1-4, gudino2025tl1aactivatedtcells pages 1-4).

References (URLs and publication dates included where available) - Levantovsky RM et al. Med. 2024;5:886-908.e11. Multimodal single-cell analyses reveal mechanisms of perianal fistula (https://doi.org/10.1016/j.medj.2024.03.021). (levantovsky2024multimodalsinglecellanalyses pages 1-4) - Calvez V et al. Biomedicines. 2025;13:305. Novel insights into IBD pathogenesis (https://doi.org/10.3390/biomedicines13020305). (calvez2025novelinsightsinto pages 4-6) - Sun S et al. Science Immunology. 2024;9:eadi7907. LRRK2 hyperactivity impairs autophagy and induces Paneth-cell dysfunction (https://doi.org/10.1126/sciimmunol.adi7907). (sun2024macrophagelrrk2hyperactivity pages 1-3) - Liu Z et al. UEG Journal. 2024;12:802-813. Intestinal strictures in Crohn’s disease: update from 2023 (https://doi.org/10.1002/ueg2.12568). (liu2024intestinalstricturesin pages 1-2) - Petit C et al. IJMS. 2025;26:6133. Intestinal homeostasis lessons from IBD and monogenic disorders (https://doi.org/10.3390/ijms26136133). (petit2025advancesinunderstanding pages 12-13, petit2025advancesinunderstanding pages 8-9) - Zhou Y et al. Biomedicines. 2025;13:1777. Molecular mechanisms and strategies of stenosis fibrosis in CD (https://doi.org/10.3390/biomedicines13071777). (zhou2025insightsintothe pages 2-4) - Gudiño V et al. bioRxiv. 2025. TL1A-activated T cells remodel rectal mucosa in CD with PFD (https://doi.org/10.1101/2025.06.26.657455). (gudino2025tl1aactivatedtcells pages 1-4)

References

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(zhou2025insightsintothe pages 2-4): Yuan Zhou, Huiping Chen, Qinbo Wang, Guozeng Ye, Yingjuan Ou, Lihong Huang, Xia Wu, and Jiaxi Fei. Insights into the molecular mechanisms and novel therapeutic strategies of stenosis fibrosis in crohn’s disease. Biomedicines, 13:1777, Jul 2025. URL: https://doi.org/10.3390/biomedicines13071777, doi:10.3390/biomedicines13071777. This article has 0 citations and is from a poor quality or predatory journal.
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