Ulcerative Colitis

Complex MONDO:0005101 Pathograph 22 Show in embeddings browser Gastrointestinal Disease Autoimmune Disease

Ulcerative colitis is a chronic relapsing inflammatory bowel disease that causes continuous mucosal inflammation of the colon, beginning in the rectum and extending proximally. A dysregulated mucosal immune response to an altered gut microbiota in genetically susceptible hosts, together with epithelial barrier dysfunction and loss of protective short-chain-fatty-acid-producing bacteria, drives superficial ulceration limited to the mucosa and submucosa. Patients present with bloody diarrhea, urgency, tenesmus, and abdominal pain, and the disease confers an increased long-term risk of colorectal cancer.

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Classifications

Harrison's Part

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Mechanistic Hypotheses

Amplification of polygenic ulcerative colitis risk in adverse contexts via shared mucosal-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. IL23R, HLA-DRB1) exert systematically larger effects in disease-promoting contexts. This entry proposes that the amplification arises because polygenic liability and contextual exposures converge on the shared Mucosal Inflammation node, so their joint effect on the liability-threshold scale is super-additive rather than additive. Notably, several exposures act in the opposite direction to Crohn disease — tobacco smoking and appendectomy are protective in ulcerative colitis — a clear illustration that a "context" is not intrinsically adverse but disease-specific. 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 + contextual exposures → Mucosal Inflammation) 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.

Discussions and Knowledge Gaps

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

KNOWLEDGE GAP OPEN uc_pgsxc_reverse_causation

Attached to

pathophysiology#Mucosal Inflammation biochemical#Fecal Calprotectin biochemical#CRP environmental#Smoking

Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. For ulcerative colitis the biochemical "contexts" fecal calprotectin, CRP and ESR are disease-activity readouts (consequences of active mucosal inflammation) rather than upstream drivers. Smoking is a further caution: it is inversely associated with UC (apparently protective), so treating it as an intrinsically adverse "context" would misdirect intervention — its disease-specific direction must be modelled, not assumed. Distinguishing genuine amplification of genetic effects from reverse causation determines whether the modelled interventions would actually reduce risk.

Proposed experiments

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

uc_pgsxc_mr_direction

Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (smoking, inflammatory biomarkers, diet) causally affects ulcerative colitis versus being a consequence of active disease, accounting for the inverse smoking association, 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 a directional exposure-to-disease effect and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.

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

uc_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.

By what molecular pathway does the shared IBD/UC genetic susceptibility translate into large arterial atherosclerotic stroke (LAS) risk, and does FCGR2A-mediated Fc-receptor signaling causally link colonic mucosal immune activation to systemic atherosclerosis? Why is the genetic correlation with LAS stronger for ulcerative colitis than for Crohn's disease, and which gut microbial, metabolite, and immune-cell intermediaries mediate the IBD/UC to stroke axis?

KNOWLEDGE GAP OPEN gap_uc_stroke_shared_genetic_architecture

Attached to

pathophysiology#Dysregulated Immune Response pathophysiology#Mucosal Inflammation

The epidemiological association between IBD and stroke is well established, but the shared genetic architecture and the causal mechanism have been unclear. A 2026 cross-trait GWAS/Mendelian-randomization study (Wang et al., PMID:42400809) found that common variants contribute more to UC (than to CD) and multiple stroke subtypes, identified a potential causal relationship between IBD/UC and large arterial atherosclerotic stroke, and pinpointed a single colocalized culprit variant (rs7522794) in the FCGR2A promoter: the risk allele is predicted to increase SPI1 binding and FCGR2A expression, plausibly amplifying Fcgamma-receptor-mediated immune activation shared by intestinal inflammation and atherosclerotic vascular disease. This connects directly to the UC "Dysregulated Immune Response" node, but the disease-specific causal chain (how FCGR2A dosage in which immune compartment drives plaque immunity), the UC-versus-CD specificity, and the proposed gut-microbe/blood-metabolite/immune-cell mediation remain unresolved and not yet modeled as pathophysiology edges. Whether dismech should capture this as a dedicated IBD-stroke comorbidity entry (kb/comorbidities/) or as shared pathophysiology nodes on the individual UC and Ischemic Stroke entries is a maintainer scope decision left open here.

Proposed experiments

Compartment-resolved test of FCGR2A dosage linking mucosal immune activation to atherosclerotic plaque immunity

allele-specific expression and cell-type-resolved perturbation study

exp_uc_fcgr2a_stroke_immune_axis

Use the rs7522794 promoter genotype (and allele-specific SPI1-binding reporters) to titrate FCGR2A expression in monocyte/macrophage and other Fcgamma-receptor-bearing immune compartments, then test whether increased FCGR2A signaling amplifies both colonic mucosal inflammatory output and pro-atherogenic macrophage activation. Cross-validate in human UC and carotid atherosclerotic plaque tissue to establish translational relevance of the shared FCGR2A-mediated immune pathway.

Mediation dissection of gut-microbe and blood-metabolite intermediaries in the IBD/UC to LAS axis

mediation Mendelian randomization with multi-omics profiling

exp_uc_stroke_microbe_metabolite_mediation

Apply mediation Mendelian randomization and matched multi-omics (gut microbiome, serum metabolome, circulating immune-cell profiling) in UC cohorts with and without large-artery atherosclerotic stroke to identify which specific microbial taxa, metabolite signatures, and immune-cell populations causally mediate the shared IBD/UC to stroke pathophysiology, and to test whether these mediators are UC-specific relative to Crohn's disease.

Posed by automated curation scanner (high_effort) Posed 2026-07-13T00:00:00Z

Show evidence (2 references)

PMID:42400809 SUPPORT Computational

"common genetic variants contributing more on ulcerative colitis (UC) and multiple stroke subtypes than Crohn's disease (CD). Among them, there is a potential causal relationship between IBD/UC and large arterial atherosclerotic stroke (LAS)"

Cross-trait GWAS and Mendelian-randomization analysis establishes the shared genetic architecture and a potential causal IBD/UC to large-artery-atherosclerotic-stroke relationship, with UC showing stronger correlation than CD, framing the open mechanistic gap.

PMID:42400809 SUPPORT In Vitro

"the variant rs7522794 on the FCGR2A promoter was the culprit of the comorbid phenotype. The rs7522794-T allele predicted to be more prone to bind SPI1, thereby increasing FCGR2A expression and susceptibility to stroke in IBD patients"

Colocalization plus functional verification implicates the FCGR2A promoter variant rs7522794 (SPI1-binding, increased FCGR2A expression) as the candidate molecular link between IBD and stroke susceptibility, anchoring the proposed Fc-receptor immune mechanism.

Copper depletion and penicillamine reverse DLAT oligomerization, FDX1/LIAS loss and barrier damage in chemically induced mouse colitis, but no equivalent rescue has been performed in human ulcerative colitis tissue. Does canonical cuproptosis - copper-dependent, FDX1-lipoylation-driven regulated cell death - actually operate in the human UC colon, or is the causal chain a property of DSS and TNBS models while the human signal remains copper-associated metabolic stress alongside the ferroptosis this entry already models?

HUMAN MODEL MISMATCH OPEN gap_uc_cuproptosis_evidence_hierarchy

Attached to

pathophysiology#Intestinal Epithelial Cell Ferroptosis pathophysiology#Epithelial Barrier Dysfunction pathophysiology#Impaired Colonocyte Energy Metabolism

Ulcerative colitis sits differently from the other dismech entries carrying this gap. For systemic lupus erythematosus, rheumatoid arthritis and ankylosing spondylitis the cuproptosis literature is transcriptomic association; for UC there is functional work, and it is model work. In DSS-induced colitis the copper-depleting agent tetrathiomolybdate and the chelator penicillamine both reverse DLAT oligomerization and restore FDX1 and LIAS, and copper chelation likewise rescues colitis in Grx1-knockout mice - between them these clear copper dependence, lipoylated-protein aggregation, Fe-S cluster destabilization and functional rescue. What is absent is the human arm of exactly those experiments: human UC colon contributes the descriptive half of the signature (raised copper, DLAT oligomerization, reduced FDX1 and LIAS) with no copper-targeted rescue. There is one human interventional observation nearby - golimumab responders with active UC normalize the hub cuproptosis genes - but it does not close the gap, because the intervention is anti-TNF rather than copper-directed and the readout is transcript abundance rather than the canonical criteria. Whether the signature normalizes because cuproptosis was driving the lesion or simply because the mucosa healed is exactly the question left open. The most recent mechanistic study states outright that directly visualizing cuproptosis in vivo remains a future direction. This is therefore recorded as a human/model mismatch rather than a plain knowledge gap: the evidence exists, but in chemically induced rodent colitis, and its translational validity is the open question. No cuproptosis pathophysiology node is added, and the reason is specific to this entry rather than generic caution - the entry already models Intestinal Epithelial Cell Ferroptosis, a metal-dependent regulated cell death converging on the same Epithelial Barrier Dysfunction node. A cuproptosis node would have to be shown to be separable from that one, not merely added beside it, and no study has yet run the two readout panels against each other in the same tissue. Copper chelators are likewise not curated as treatments here; penicillamine and tetrathiomolybdate have been given to mice, not to patients with UC.

Proposed experiments

Canonical-cuproptosis criteria in human ulcerative colitis colon, read out against ferroptosis

mechanism validation study in human tissue and patient-derived organoids

exp_uc_canonical_cuproptosis_in_human_colon

Close the human arm of the rodent experiments rather than repeat them. Take paired inflamed and uninflamed colonic biopsies from patients with active UC and from non-IBD controls and apply the five canonical criteria to the tissue itself: quantify mucosal copper, assay FDX1 and LIAS protein with lipoylated DLAT/DLST aggregation, measure Fe-S cluster protein destabilization, and then supply the rescue arm the human literature lacks by treating patient-derived colonic organoids and biopsy explants with tetrathiomolybdate or penicillamine. Run a matched ferroptosis panel (lipid peroxidation, GPX4, SLC7A11) on the same specimens, and use a ferroptosis inhibitor as a comparator arm, so that a copper-specific program can be separated from the iron-dependent cell death this entry already curates rather than confounded with it.

Assays

mucosal copper quantification FDX1 and LIAS immunoblot and in situ protein detection lipoylated protein aggregation assay Fe-S cluster protein stability assay lipid peroxidation and GPX4 axis profiling

Readouts

Copper-dependent cell death separable from ferroptosis

pathophysiology#Intestinal Epithelial Cell Ferroptosis

Cuproptosis and ferroptosis readout panels measured on the same human UC specimens, with chelator and ferroptosis-inhibitor rescue arms compared head to head.

Direction: ALTERED

Interpretation: A copper-dependent death signal that survives ferroptosis inhibition, and a barrier phenotype rescued by chelation but not by a ferroptosis inhibitor, would justify a separate cuproptosis node; a signal abolished by ferroptosis inhibition would mean it is already captured.

Barrier rescue by copper chelation in human tissue

pathophysiology#Epithelial Barrier Dysfunction

Tight-junction protein expression and permeability in patient-derived colonic organoids and biopsy explants treated with tetrathiomolybdate or penicillamine.

Direction: RESTORED

Interpretation: Restoration of barrier integrity in human tissue would extend the rodent rescue result across the species boundary and resolve the mismatch this discussion records.

Lipoylated TCA enzyme aggregation in colonocytes

pathophysiology#Impaired Colonocyte Energy Metabolism

DLAT and DLST oligomerization measured in colonocytes from inflamed and uninflamed human UC mucosa alongside the entry's existing butyrate-oxidation deficit.

Direction: INCREASED

Interpretation: Aggregation restricted to inflamed mucosa would place copper-dependent mitochondrial injury on the existing colonocyte energy-metabolism node rather than requiring a new one.

Controls

Non-IBD inflamed colon

Infectious or diverticular colitis, to test whether any copper phenotype is specific to ulcerative colitis rather than to mucosal inflammation.

Ferroptosis inhibitor arm

Ferrostatin-1 or equivalent, so that rescue attributable to copper can be distinguished from rescue attributable to blocking the iron-dependent death this entry already models.

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 human ulcerative colitis tissue or patient-derived organoids, and only if the signal is separable from the existing ferroptosis node. Rodent-only satisfaction of the bar is not sufficient; if it remains rodent-only, keep the finding as a model-restricted mechanism recorded here.

Would support

pathophysiology#Intestinal Epithelial Cell Ferroptosis pathophysiology#Epithelial Barrier Dysfunction

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 UC- and CD-specific sources rather than the umbrella review's undiscriminated "inflammatory bowel disease" sentence. The parallel gap on Crohn_Disease is kind KNOWLEDGE_GAP rather than HUMAN_MODEL_MISMATCH, because the CD literature has no functional arm in any species.

Show evidence (9 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 Crohn_Disease, 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 ulcerative colitis from Crohn disease - the reason this gap was originally left off both IBD entries, and the reason it is now curated against UC-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 UC from CD, and states for UC specifically that the function of cuproptosis-linked genes is unresolved.

+ 6 more references

Is epithelial barrier dysfunction purely a downstream consequence of mucosal inflammation in this entry's pathograph, or does it also have a cell-intrinsic component that should feed back into the disease process?

KNOWLEDGE GAP OPEN uc_epithelial_barrier_intrinsic_vs_downstream

Attached to

pathophysiology#Epithelial Barrier Dysfunction experimental_models#Biopsy-derived UC colonoid air-liquid interface model

In this entry, Epithelial Barrier Dysfunction is wired only as a sink: it has inbound edges from pathobiont expansion, impaired colonocyte energy metabolism, and epithelial ferroptosis, and no outgoing `downstream` edge of its own. A biopsy-derived colonoid model that removes UC epithelium from the inflamed tissue environment entirely and still finds graded architectural, differentiation, and mucus-barrier defects argues that at least part of the phenotype is cell-intrinsic and persists independently of active inflammation, rather than being wholly generated by it. That does not by itself justify adding a new outgoing edge — the model does not identify what the intrinsic defect propagates to — but it is a structural gap worth recording rather than silently leaving the node as a pure consequence.

Raised while adding modeled_mechanisms links for the UC biopsy-derived colonoid model (monarch-initiative/dismech#10432).

Show evidence (1 reference)

PMID:41589595 SUPPORT In Vitro

"UC-derived colonoid monolayers display a range of developmental and functional defects that persist in the absence of inflammation."

Reports that the epithelial defect persists ex vivo without an active inflammatory stimulus, the basis for questioning a purely downstream-consequence model.

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Pathophysiology

Mucosal Inflammation

Continuous inflammation limited to the colonic mucosa, starting at the rectum and extending proximally. Crypt abscesses, goblet cell depletion, and mucosal ulceration are characteristic.

Colonic Epithelial Cell CL:0011108

TNFAIP3 hgnc:11896

Inflammatory Response GO:0006954

Show evidence (2 references)

PMID:38314135 SUPPORT In Vitro

"Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β, IL-18, NLRP3)."

Pyroptosis-associated inflammatory cytokines IL-1β and IL-18 are produced in UC mucosa, contributing to the characteristic mucosal inflammation.

PMID:39438660 SUPPORT

"A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC."

Single-cell and spatial analysis of gut biopsies localises interferon-response signatures to T cell aggregates and epithelial damage in UC, the inflammatory infiltrate of the colonic mucosa.

Dysregulated Immune Response

Aberrant immune response to commensal gut bacteria in genetically susceptible individuals. Th2-skewed response with IL-13 driving epithelial dysfunction.

T Helper 2 Cell CL:0000546

IL23R hgnc:19100 STAT3 hgnc:11364 IL10 hgnc:5962 HLA-DRB1 hgnc:4948 BACH2 hgnc:14078 CD28 hgnc:1653

Type 2 immune response GO:0042092 Inflammatory response GO:0006954

Experimental models

Cytokine-conditioned hiPSC-derived colon organoid UC model IPSC DERIVED MODEL Cytokine-conditioned hiPSC colon organoids show inflammatory stromal responses whose molecular signature resembles UC patient colon, with a pharmacologically reversible cytokine output.

Show evidence (3 references)

PMID:39438660 SUPPORT

"A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC."

Single-cell analysis demonstrates interferon-response signatures localize to T cell aggregates and epithelial damage in UC, revealing a key immune dysregulation mechanism.

PMID:39438660 SUPPORT

"Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC."

Increased multi-cellular interferon signaling is associated with disease progression and non-remission in UC, indicating this is a critical pathway in dysregulated immune response.

PMID:39461795 SUPPORT

"Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response that extends dosing intervals up to 3 months."

IL-23 inhibitors target an upstream pathological mechanism in UC with high efficacy (up to 50% in IBD), supporting the role of aberrant immune signaling in disease pathogenesis.

Epithelial Barrier Dysfunction

Disrupted tight junctions and mucus layer allow bacterial translocation, perpetuating inflammation. Goblet cell depletion reduces protective mucus.

HNF4A hgnc:5024 CDH1 hgnc:1748

Epithelial Barrier Function GO:0090557

Experimental models

Biopsy-derived UC colonoid air-liquid interface model PRIMARY CELL CULTURE Patient biopsy-derived colonoid monolayers reproduce graded mucus-layer thinning, increased permeability, and pathobiont susceptibility, and these defects persist ex vivo without an inflammatory stimulus.

Cytokine-conditioned hiPSC-derived colon organoid UC model IPSC DERIVED MODEL Exogenous TNF-alpha/IFN-gamma/IL-1beta conditioning of healthy hiPSC colon organoids produces epithelial damage whose molecular signature resembles UC patient colon tissue.

Human colon-on-chip mucus barrier model ORGAN ON CHIP The chip measures how an inflammatory mediator, prostaglandin E2, changes mucus hydration in normal colonic epithelium.

Show evidence (4 references)

PMID:39438660 SUPPORT

"A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC."

Interferon-response signatures are spatially localized to epithelial damage sites in UC, directly linking immune responses to barrier disruption.

PMID:38724705 SUPPORT

"Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption."

Epithelial cells express interferon-induced signatures associated with apoptosis and increased cell turnover, demonstrating the mechanism of barrier dysfunction in inflammatory colitis.

PMID:38724705 SUPPORT

"Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis."

Epithelial-immune crosstalk is critical to barrier function, confirming that disruption of this interaction underlies epithelial barrier dysfunction in colitis.

+ 1 more reference

Loss of Microbial Diversity

Reduced alpha diversity (species richness and evenness) in the colonic microbiome. Shannon and Chao1 indices are decreased compared to healthy controls, representing ecological collapse of the microbial community.

Microbiome Community Dynamics GO:0044003

Downstream

Loss of Keystone SCFA Producers Diversity loss disproportionately affects beneficial fermenters

Increased Microbial Community Instability Anna Karenina effect - dysbiotic communities become stochastic

Show evidence (1 reference)

PMID:25307765 SUPPORT

"IBD has a consistent signature across studies and allows high classification accuracy of IBD from non-IBD subjects."

Meta-analysis confirms IBD has consistent microbiota signatures distinguishing patients from healthy controls.

Loss of Keystone SCFA Producers

Depletion of butyrate-producing Firmicutes, particularly Faecalibacterium prausnitzii, Roseburia spp., and Eubacterium rectale. These keystone taxa are network hubs supporting community structure through cross-feeding.

Downstream

Decreased Butyrate Production Loss of primary butyrate-synthesizing taxa

Show evidence (2 references)

PMID:18936492 SUPPORT INDIRECT

"A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients."

Sokol et al. report that reduced abundance and biodiversity of Firmicutes - the phylum containing the keystone butyrate producers of this node - is repeatedly observed in Crohn disease. Indirect because the quoted observation is in Crohn disease rather than ulcerative colitis.

PMID:18936492 SUPPORT Model Organism

"F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production."

F. prausnitzii has direct anti-inflammatory properties beyond its role as butyrate producer.

Pathobiont Expansion

Bloom of opportunistic pathobionts including adherent-invasive E. coli (AIEC), Fusobacterium nucleatum, and Enterobacteriaceae. These taxa exploit the ecological niche vacated by depleted commensals and promote inflammation through LPS and direct epithelial invasion.

Downstream

Mucosal Inflammation Pathobionts produce LPS and other pro-inflammatory molecules

Epithelial Barrier Dysfunction AIEC can invade epithelial cells and disrupt tight junctions

Show evidence (1 reference)

PMID:26185088 SUPPORT

"This is often characterized by an increased relative abundance of facultative anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time, depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia."

Dysbiosis in IBD involves expansion of Enterobacteriaceae pathobionts alongside depletion of beneficial obligate anaerobes.

Decreased Butyrate Production

Reduced fecal short-chain fatty acid (SCFA) concentrations, particularly butyrate. Butyrate is the primary energy source for colonocytes (providing ~70% of energy needs) and exerts anti-inflammatory effects via HDAC inhibition and GPR109A signaling.

Short-chain Fatty Acid Metabolism GO:0046459

Downstream

Impaired Colonocyte Energy Metabolism Butyrate deprivation causes epithelial energy deficit

Show evidence (1 reference)

PMID:23023125 NO_EVIDENCE

"Patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens."

While this study focused on T2D, it demonstrates the general principle that dysbiosis involves loss of butyrate producers - a pattern also seen in IBD.

Impaired Colonocyte Energy Metabolism

Colonocytes deprived of butyrate shift from beta-oxidation to glycolysis, causing energy deficit. This impairs tight junction maintenance, mucus production by goblet cells, and epithelial renewal from crypt stem cells.

Colonic Epithelial Cell CL:0011108

Downstream

Epithelial Barrier Dysfunction Energy-deprived colonocytes cannot maintain barrier integrity

Increased Microbial Community Instability

Anna Karenina effect - dysbiotic microbiomes show increased inter-individual variability and temporal instability compared to healthy controls. The community loses resilience and may occupy an alternative stable state that resists therapeutic intervention.

Downstream

Loss of Microbial Diversity Feedback loop - community instability promotes further diversity loss

Show evidence (1 reference)

PMID:28836573 SUPPORT

"The result is an 'Anna Karenina principle' for animal microbiomes, in which dysbiotic individuals vary more in microbial community composition than healthy individuals-paralleling Leo Tolstoy's dictum that 'all happy families look alike; each unhappy family is unhappy in its own way'."

Zaneveld et al. demonstrated the Anna Karenina principle applies to disease-associated microbiomes.

NLRP3 Inflammasome-Mediated Pyroptosis

Epithelial cell pyroptosis driven by NLRP3 inflammasome activation contributes to barrier disruption and inflammation. SLC6A14 promotes pyroptosis by upregulating NLRP3.

Colonic Epithelial Cell CL:0011108

Pyroptosis GO:0070269

Show evidence (3 references)

PMID:38314135 SUPPORT

"SLC6A14 was increased and correlated with NLRP3 in UC tissues."

SLC6A14 expression is elevated and correlates with NLRP3 in UC tissues, establishing a molecular link between this transporter and inflammasome activation.

PMID:38314135 SUPPORT In Vitro

"Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β, IL-18, NLRP3)."

Experimental reduction of SLC6A14 decreases pyroptosis-associated proteins including NLRP3, IL-1β, and IL-18, demonstrating the causal role of this pathway in UC.

PMID:38314135 SUPPORT

"SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis."

SLC6A14 promotes UC progression through NLRP3-mediated pyroptosis, identifying this as a key pathophysiological mechanism and potential therapeutic target.

Intestinal Epithelial Cell Ferroptosis

Iron-dependent regulated cell death driven by lipid peroxidation in intestinal epithelial cells. Ferroptosis in IECs is characterized by iron accumulation, lipid peroxidation, and dysregulation of antioxidant defense systems. Key signaling networks regulating ferroptosis include the Nrf2/HO-1 antioxidant pathway, the SLC7A11/GPX4 lipid peroxidation control system, and the AMPK/mTOR metabolic regulatory pathway. Dysregulation of these pathways leads to uncontrolled ferroptosis that contributes to epithelial barrier dysfunction and inflammation in UC.

Colonic Epithelial Cell CL:0011108

Ferroptosis GO:0097707 Antioxidant Defense GO:0006979

Downstream

Epithelial Barrier Dysfunction Ferroptotic epithelial cell death and loss of barrier integrity

Show evidence (2 references)

PMID:42154151 SUPPORT

"The ferroptosis of intestinal epithelial cells (IECs), an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a critical pathogenic driver of ulcerative colitis (UC)."

Ferroptosis is identified as a critical pathogenic driver in UC, establishing this iron-dependent cell death mechanism as central to UC pathophysiology.

PMID:42154151 SUPPORT

"This review summarizes the core hallmarks of IEC ferroptosis in UC-specifically, lipid peroxidation, iron overload, and antioxidant system dysregulation-and describes key regulatory signaling networks, including the Nrf2/HO-1, SLC7A11/GPX4, and AMPK/mTOR pathways."

Three key signaling pathways regulate ferroptosis in UC, including Nrf2/HO-1 (antioxidant defense), SLC7A11/GPX4 (lipid peroxidation control), and AMPK/mTOR (metabolic regulation). Dysregulation drives ferroptotic cell death in IECs.

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Pathograph

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

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Phenotypes

Blood 1

Anemia FREQUENT HP:0001903

Iron deficiency from blood loss

Show evidence (1 reference)

PMID:25646159 SUPPORT

"Anemia is one of the most frequent complications and/or extraintestinal manifestations of inflammatory bowel disease (IBD). Iron deficiency is the most important cause of anemia in Crohn's disease and ulcerative colitis patients."

Anemia, particularly iron deficiency anemia, is one of the most frequent complications of ulcerative colitis due to chronic blood loss from the inflamed colonic mucosa.

Digestive 4

Bloody Diarrhea VERY_FREQUENT HP:0025085

Show evidence (1 reference)

PMID:38724705 SUPPORT

"Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption."

Epithelial apoptosis and increased cell turnover in inflammatory colitis leads to mucosal ulceration and bleeding, which manifests as bloody diarrhea.

Urgency VERY_FREQUENT Bowel urgency HP:0012701

Fecal urgency

Show evidence (1 reference)

PMID:30837080 SUPPORT

"The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."

Rectal urgency is described as a classic presenting symptom of ulcerative colitis.

Tenesmus FREQUENT HP:0012702

Show evidence (1 reference)

PMID:30837080 SUPPORT

"The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."

Tenesmus is described as a classic presenting symptom of ulcerative colitis.

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 manifestation independent of flares.

Eye 2

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 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.

Head and Neck 2

Facial Diplegia VERY_RARE HP:0001349

Very rare neurological extraintestinal manifestation; Guillain-Barré syndrome facial diplegia variant. Based on an isolated case report (PMID:42143401) explicitly described as "not been previously reported".

Show evidence (2 references)

PMID:42143401 SUPPORT Human Clinical

"GBS can present as a rare extraintestinal manifestation of UC when in remission or relapse."

Case report documents Guillain-Barré syndrome facial diplegia variant as a rare neurological extraintestinal manifestation of UC, supporting recognition of UC as a predisposing factor for this complication.

PMID:42143401 SUPPORT Human Clinical

"This case shows that isolated facial diplegia, a variant of GBS, can occur in patients with UC as a neurological extraintestinal manifestation, which not been previously reported, suggesting that UC can be an underling cause or predisposing factor for bilateral facial palsy."

Confirms that UC may be an underlying cause or predisposing factor for GBS-related facial diplegia as a neurological complication; explicitly identified as a not-previously-reported phenomenon, supporting the VERY_RARE classification.

Oral aphthous ulcers Recurrent aphthous stomatitis HP:0011107

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 oral aphthous ulcers among manifestations associated with active intestinal inflammation.

Immune 1

Erythema nodosum HP:0012219

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 erythema nodosum among manifestations associated with active intestinal inflammation.

Musculoskeletal 1

Peripheral arthritis HP:0001369

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 peripheral arthritis among manifestations associated with active intestinal inflammation.

Constitutional 2

Abdominal Pain VERY_FREQUENT HP:0002027

Show evidence (1 reference)

PMID:31272578 SUPPORT Human Clinical

"Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus."

Mayo Clinic Proceedings review confirms abdominal pain as a typical presenting symptom in UC.

Fatigue FREQUENT HP:0012378

Show evidence (1 reference)

PMID:27310658 SUPPORT

"more severe fatigue was associated with more ulcerative colitis symptoms"

Fatigue is common in ulcerative colitis and tracks reported symptom burden; the same cohort found no association between fatigue scores and objective disease-activity markers (CRP, faecal calprotectin, endoscopic Mayo score).

Growth 1

Weight Loss FREQUENT HP:0001824

Show evidence (1 reference)

PMID:25506359 SUPPORT

"51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss)."

Weight loss is a significant and common symptom in ulcerative colitis patients, with over half experiencing significant weight loss prior to diagnosis.

🧬

Genetic Associations

IL23R (Risk Factor)

Gene: IL23R hgnc:19100

Show evidence (1 reference)

PMID:17068223 SUPPORT Human Clinical

"Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis."

The discovery GWAS found the primary IL23R signal in Crohn's disease and confirmed the association in independent ulcerative colitis cohorts, which is what supports listing IL23R as a UC risk locus here.

HNF4A (Risk Factor)

Gene: HNF4A hgnc:5024

Show evidence (1 reference)

PMID:19915572 SUPPORT Human Clinical

"We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17))"

WTCCC2 ulcerative colitis GWAS reports genome-wide significant association at the 20q13 locus containing HNF4A.

CDH1 (Risk Factor)

Gene: CDH1 hgnc:1748

Show evidence (1 reference)

PMID:19915572 SUPPORT Human Clinical

"16q22 (CDH1 and CDH3; P = 2.8 x 10(-8))"

The same WTCCC2 ulcerative colitis GWAS reports genome-wide significant association at 16q22. Note the locus contains both CDH1 and CDH3, so the association is to the region rather than resolved to CDH1 alone.

HLA-DRB1 (Risk Factor)

Gene: HLA-DRB1 hgnc:4948

BACH2 (GWAS)

Gene: BACH2 hgnc:14078

TNFAIP3 (GWAS)

Gene: TNFAIP3 hgnc:11896

STAT3 (GWAS)

Gene: STAT3 hgnc:11364

IL10 (GWAS)

Gene: IL10 hgnc:5962

Show evidence (1 reference)

PMID:18836448 SUPPORT Human Clinical

"SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples"

A dedicated ulcerative colitis GWAS with independent European replication panels identifies the IL10-flanking variant as its strongest replicated association.

CD28 (GWAS)

Gene: CD28 hgnc:1653

EGR2 (GWAS)

Gene: EGR2 hgnc:3239

ETS1 (GWAS)

Gene: ETS1 hgnc:3488

IRF8 (GWAS)

Gene: IRF8 hgnc:5358

SATB1 (GWAS)

Gene: SATB1 hgnc:10541

IKZF1 (GWAS)

Gene: IKZF1 hgnc:13176

SMAD3 (GWAS)

Gene: SMAD3 hgnc:6769

REL (GWAS)

Gene: REL hgnc:9954

PRDM1 (GWAS)

Gene: PRDM1 hgnc:9346

Show evidence (1 reference)

PMID:21297633 SUPPORT Human Clinical

"we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1"

The 47-locus ulcerative colitis meta-analysis names PRDM1 among the candidate genes annotated to its associated regions. Note this is a candidate-gene annotation of an associated interval, not a demonstration that PRDM1 is the causal gene.

PTPN22 (GWAS)

Gene: PTPN22 hgnc:9652

💊

Medical Actions

5-Aminosalicylates

Action: 5-aminosalicylate therapy Ontology label: Pharmacotherapy NCIT:C15986

First-line for mild-moderate disease (mesalamine).

Show evidence (2 references)

PMID:21407188 SUPPORT Human Clinical

"5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥ 2.0 g/day have greater efficacy"

Systematic review and meta-analysis confirming 5-ASA efficacy in UC remission induction and relapse prevention.

PMID:40701556 SUPPORT Other

"These guidelines were developed to indicate the preferred approach to the management of adult patients with ulcerative colitis as established by valid scientific research and represent the official practice recommendations of the American College of Gastroenterology under the auspices of the..."

The ACG clinical guideline update provides the current official practice recommendations for adult ulcerative colitis, in which 5-aminosalicylates are first-line therapy for mild-to-moderate disease.

Corticosteroids

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

For acute flares (prednisone, budesonide).

Show evidence (1 reference)

PMID:31272578 SUPPORT Human Clinical

"Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission."

Review confirms corticosteroids are used to induce remission with goal of achieving corticosteroid-free maintenance.

Thiopurines

Action: Thiopurine therapy Ontology label: Pharmacotherapy NCIT:C15986

Azathioprine, 6-MP for maintenance.

Show evidence (1 reference)

PMID:31272578 SUPPORT Human Clinical

"In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."

Review confirms thiopurines as a treatment class for moderate-severe UC.

Anti-TNF Therapy

Action: Anti-TNF therapy Ontology label: Pharmacotherapy NCIT:C15986

Infliximab, adalimumab for moderate-severe disease.

Show evidence (1 reference)

PMID:26902011 SUPPORT Human Clinical

"Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy"

Meta-analysis demonstrating significant efficacy of anti-TNF agents in UC clinical response induction.

Vedolizumab

Action: Vedolizumab therapy Ontology label: Pharmacotherapy NCIT:C15986

Gut-selective integrin inhibitor.

Show evidence (1 reference)

PMID:31470005 SUPPORT Human Clinical

"clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively"

Phase 3 RCT demonstrating vedolizumab efficacy with 46% clinical remission vs 14% placebo at week 52.

Tofacitinib

Action: JAK inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

JAK inhibitor for moderate-severe disease.

Show evidence (1 reference)

PMID:31272578 SUPPORT Human Clinical

"In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."

Review confirms JAK inhibitors as approved treatment for moderate-severe UC.

Ustekinumab

Action: IL-12/23 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

IL-12/23 inhibitor.

Show evidence (1 reference)

PMID:39461795 SUPPORT Human Clinical

"Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response"

IL-23 inhibitors demonstrate high efficacy in UC by targeting upstream pathological mechanisms.

Colectomy

Action: Colectomy Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Curative surgery for refractory or complicated disease.

Show evidence (1 reference)

PMID:31272578 SUPPORT Human Clinical

"in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment."

Review confirms 15% of UC patients require colectomy for refractory disease or dysplasia.

🌍

Environmental Factors

Appendectomy

Appendicectomy in established UC protects against relapse. Distinct from the classic epidemiologic claim that appendectomy in youth protects against developing UC, which this entry does not currently cite.

Show evidence (1 reference)

PMID:40228513 SUPPORT Human Clinical

"The 1-year relapse rate was significantly lower in the appendicectomy group than in the control group"

Randomised trial evidence that appendicectomy protects against relapse in established ulcerative colitis.

Smoking

Protective (unlike Crohn's)

Show evidence (1 reference)

PMID:40246988 SUPPORT Human Clinical

"smoking had a protective effect against UC, indicating that it may reduce the risk of developing UC"

Meta-analysis of case-control studies finding a protective association between smoking and ulcerative colitis, the direction opposite to Crohn disease.

NSAIDs

May trigger flares

Show evidence (1 reference)

PMID:25314574 SUPPORT Human Clinical

"Conventional NSAIDs may cause clinical relapse in about 20% of patients with quiescent IBD"

Quantifies the relapse risk conventional NSAIDs carry in quiescent inflammatory bowel disease.

Infections

May trigger onset. Bound to ECTO:3000000 (exposure to organism) rather than the previous XCO:0000236, a cross-ontology move that also broadens pathogen to any organism. ECTO has no generic pathogen- or infectious-agent-exposure term, so the broadening is the deliberate "no term beats a bad one" tradeoff and not an error to be reverted; the pathogen sense is carried by preferred_term.

Show evidence (1 reference)

PMID:39333475 SUPPORT INDIRECT Human Clinical

"This significantly increased risk was seen for both CD (HR: 1.56; 95% CI: 1.34-1.83) and to a lesser extent UC (HR: 1.23; 95% CI: 1.08-1.40)"

Nationwide cohort showing that a specific severe infection (infectious mononucleosis) raises subsequent ulcerative colitis risk. Indirect for the generic "infections" claim, which it evidences via one specific exposure.

Stress

May trigger flares

Show evidence (1 reference)

PMID:10811330 SUPPORT Human Clinical

"long-term perceived stress increases the risk of exacerbation over a period of months to years"

Prospective cohort of patients enrolled in remission. Note the same study found short-term stress did NOT trigger exacerbation, so the timescale matters to the "triggers flares" framing.

🔬

Biochemical Markers

Fecal Calprotectin (Elevated)

Context: Marker of intestinal inflammation

Show evidence (1 reference)

PMID:40943053 SUPPORT Human Clinical

"Non-invasive alternatives like intestinal ultrasound (IUS) and faecal calprotectin (FC) show promise for monitoring mucosal inflammation"

Systematic review of non-invasive markers in ulcerative colitis identifies faecal calprotectin as a marker of mucosal inflammation, which is the role recorded in this entry's context field.

CRP (Elevated)

Context: Systemic inflammation marker

ESR (Elevated)

Context: Active disease

Plasma albumin (Mendelian randomization signal)

Context: This entry records a genetically instrumented, population-level causal signal, and its direction is the opposite of the familiar clinical picture. In active ulcerative colitis measured serum albumin is typically low, reflecting inflammation and protein loss; the atlas instead reports that genetically predicted higher albumin links to a higher incidence of ulcerative colitis, with a reciprocal signal in the disease-to-metabolite direction. The two statements are not in conflict because they describe different quantities: a lifelong genetic propensity to a higher albumin set point versus the measured albumin of a patient with active disease. No presence value is recorded here for that reason, and nothing in this entry should be used to interpret an individual albumin result.

Show evidence (2 references)

PMID:40973818 SUPPORT Human Clinical

"positively linking to a higher incidence of ulcerative colitis, certain types of anaemias and CKD"

Albumin had the most potentially causal disease links of any metabolite in the atlas (15 diseases), and ulcerative colitis is named among the conditions whose incidence it positively linked to.

PMID:40973818 SUPPORT Human Clinical

"Interestingly, albumin levels also showed reciprocal causal associations with genetic liability to the risk of ulcerative colitis, certain types of anaemias and CKD."

Establishes that the albumin-ulcerative colitis signal was bidirectional in the Mendelian randomization analysis, which is why this entry records an association rather than a directional biomarker.

📊

Related Datasets

Human inflammatory bowel disease (IBD) and healthy control 10x Single-cell transcriptomics data cellxgene:7c7bd6c2-925b-4034-baab-620ef1b760e1

Single-cell transcriptomic atlas of human inflammatory bowel disease including ulcerative colitis and Crohn disease samples alongside healthy controls. Characterizes immune and epithelial cell populations in inflamed intestinal tissue.

human SINGLE CELL RNA SEQ

colon tissue UBERON:0001155

Conditions: ulcerative colitis Crohn disease normal

PMID:37488103

CZI CELLxGENE collection. DOI 10.1038/s41467-023-40156-6. Covers both UC and CD for comparative analysis.

🧫

Experimental Models

Biopsy-derived UC colonoid air-liquid interface model PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Biopsy-derived sigmoid colonoids differentiated as air-liquid interface monolayers to model epithelial architecture, mucus production, and pathobiont susceptibility in ulcerative colitis.

Organism

human NCBITaxon:9606

Tissue

colon UBERON:0001155

Cell source

Patient biopsy-derived sigmoid colonic epithelial crypts expanded as colonoids

Culture

Air-liquid interface colonoid monolayers with mucus and pathobiont challenge assays

Publication

PMID:41589595

Pathograph links

Epithelial Barrier Dysfunction recapitulates fidelity: high Patient biopsy-derived colonoid monolayers reproduce graded mucus-layer thinning, increased permeability, and pathobiont susceptibility, and these defects persist ex vivo without an inflammatory stimulus.

Readouts

Mucus layer thickness and permeability

Mucus layer architecture in UC ALI colonoid monolayers versus non-IBD control monolayers.

Direction: DECREASED

Interpretation: A thinner, more permeable mucus layer is the structural correlate of the barrier-dysfunction node, graded by disease severity.

Show evidence (1 reference)

PMID:41589595 SUPPORT In Vitro

"ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."

Directly reports the graded mucus-layer thickness and permeability readout.

E. coli p19A susceptibility

Susceptibility of UC ALI colonoid monolayers to E. coli p19A challenge.

Direction: INCREASED

Interpretation: Increased susceptibility to bacterial challenge is a functional consequence of the barrier defect, linking it to pathobiont exposure.

Show evidence (1 reference)

PMID:41589595 SUPPORT In Vitro

"which also proved significantly more susceptible to E. coli p19A."

Directly reports the pathobiont-susceptibility readout.

Show evidence (1 reference)

PMID:41589595 SUPPORT In Vitro

Establishes the model as informative for the Epithelial Barrier Dysfunction node.

Findings

UC biopsy-derived ALI colonoid monolayers retain persistent epithelial and mucus-barrier defects outside the inflamed tissue environment

Show evidence (2 references)

PMID:41589595 SUPPORT In Vitro

Supports persistent epithelial barrier and mucus-layer defects relevant to Epithelial Barrier Dysfunction.

PMID:34418586 SUPPORT In Vitro

"Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer."

Independently supports durable mucus-barrier defects in patient-derived UC colonoid monolayers.

UC colonoid monolayers provide a tractable epithelial system for linking mucus defects to pathobiont susceptibility

Show evidence (2 references)

PMID:41589595 SUPPORT In Vitro

"With the use of transcriptome analysis, we identified activated pathways associated with extracellular matrix formation and cell signaling, including numerous cancer-associated genes in UC ALI monolayers, which also proved significantly more susceptible to E. coli p19A."

Links epithelial remodeling and barrier compromise to increased susceptibility to bacterial challenge, consistent with mucosal inflammation and host-microbe dysfunction.

PMID:34418586 SUPPORT In Vitro

"Chronic inflammation in UC causes long-term changes in GCs, leading to abnormal mucus secretion."

Supports a mechanistic connection between chronic inflammation and lasting goblet-cell secretory dysfunction in the model.

Show evidence (1 reference)

PMID:41589595 SUPPORT In Vitro

Supports this as a patient-derived UC epithelial model with direct relevance to mucosal inflammation and barrier dysfunction.

Cytokine-conditioned hiPSC-derived colon organoid UC model IPSC_DERIVED_MODEL namo:Organoid

Human induced pluripotent stem cell-derived colon organoids exposed to TNF-α, IFN-γ, and IL-1β to model UC-like epithelial injury and stromal inflammatory signaling.

Organism

human NCBITaxon:9606

Tissue

colon UBERON:0001155

Cell source

Human induced pluripotent stem cell-derived colon organoids

Culture

Three-dimensional colon organoid culture with pro-inflammatory cytokine conditioning

Publication

PMID:39435148

Pathograph links

Epithelial Barrier Dysfunction partially recapitulates fidelity: moderate Exogenous TNF-alpha/IFN-gamma/IL-1beta conditioning of healthy hiPSC colon organoids produces epithelial damage whose molecular signature resembles UC patient colon tissue.

Limitations: This is a healthy-background organoid exposed to an exogenous cytokine cocktail, so it models the downstream consequences of a UC-like cytokine milieu, not UC's own genetic or microbial aetiology.

Show evidence (1 reference)

PMID:39435148 SUPPORT In Vitro

"Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."

Establishes the model as informative for the Epithelial Barrier Dysfunction node.

Dysregulated Immune Response partially recapitulates fidelity: moderate Cytokine-conditioned hiPSC colon organoids show inflammatory stromal responses whose molecular signature resembles UC patient colon, with a pharmacologically reversible cytokine output.

Limitations: The inflammatory state is imposed exogenously rather than arising from the patient's own genetically susceptible immune response, so the model captures the cytokine-output arm of this node rather than its upstream genetic-susceptibility trigger.

Readouts

Tofacitinib-mediated cytokine attenuation

Inflammatory cytokine production in 3CK-treated hiPSC colon organoids with and without tofacitinib.

Direction: RESTORED

Interpretation: A JAK-inhibitor rescue arm that reduces the cytokine output supports treating the elevated cytokine production as the node's own output rather than an incidental correlate.

Show evidence (1 reference)

PMID:39435148 SUPPORT In Vitro

"Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib."

Directly reports the pharmacological rescue readout.

Show evidence (1 reference)

PMID:39435148 SUPPORT In Vitro

"Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."

Establishes the model as informative for the Dysregulated Immune Response node.

Findings

Cytokine-conditioned hiPSC colon organoids reproduce epithelial injury and inflammatory stromal responses that resemble UC tissue

Show evidence (2 references)

PMID:39435148 SUPPORT In Vitro

"Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."

Supports alignment with Dysregulated Immune Response and Epithelial Barrier Dysfunction in a human stem-cell-derived system.

PMID:39435148 SUPPORT In Vitro

"Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."

Supports molecular resemblance of the model to UC tissue rather than generic cytokine injury alone.

The model can be used to test whether cytokine-driven inflammatory outputs are pharmacologically reversible

Show evidence (1 reference)

PMID:39435148 SUPPORT In Vitro

"Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib."

Supports translational use of the model for pathway-focused drug testing in a UC-like inflammatory state.

Show evidence (1 reference)

PMID:39435148 SUPPORT In Vitro

"Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."

Supports this as a human iPSC-derived organoid model with molecular similarity to UC tissue.

Human colon-on-chip mucus barrier model ORGAN_ON_CHIP namo:OrganOnChip

Microfluidic human colon chip lined by primary patient-derived colonic epithelial cells to model mucus bilayer formation and inflammatory control of mucus hydration.

Organism

human NCBITaxon:9606

Tissue

colon UBERON:0001155

Cell source

Primary patient-derived colonic epithelial cells

Culture

Microfluidic colon-on-chip device with live imaging of mucus layer formation

Publication

PMID:31778828

Pathograph links

Epithelial Barrier Dysfunction measures fidelity: low The chip measures how an inflammatory mediator, prostaglandin E2, changes mucus hydration in normal colonic epithelium.

Limitations: This is a healthy-physiology model built from non-UC primary cells; no UC-derived tissue is studied. The PGE2 effect is a hydration-state change in an already-formed mucus layer, not new mucus production, so it does not speak to the goblet-cell depletion or mucus-loss claims this node makes.

Readouts

Mucus volume expansion after prostaglandin E2 stimulation

Live-imaged mucus layer hydration state after PGE2 stimulation of the colonic epithelium on-chip.

Direction: INCREASED

Interpretation: PGE2-driven hydration expansion is an acute inflammatory-mediator effect on an intact mucus layer, distinct from the goblet-cell depletion and mucus-loss process this node otherwise describes.

Show evidence (1 reference)

PMID:31778828 SUPPORT In Vitro

"Live imaging of the mucus layer formation on-chip showed that stimulation of the colonic epithelium with prostaglandin E2, which is increased during inflammation, causes rapid mucus volume expansion via an Na-K-Cl cotransporter 1 ion channel-dependent increase in its hydration state, but no..."

Directly reports the PGE2 hydration readout and its limits.

Show evidence (1 reference)

PMID:31778828 SUPPORT In Vitro

"The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer."

The entry's own hedge that this is a restrained UC-adjacent bridge, matching the LOW fidelity and MEASURES relationship recorded here.

Findings

The colon chip reproduces human colonic mucus bilayer structure, making it useful for mechanistic study of mucus-barrier defects relevant to UC

Show evidence (2 references)

PMID:31778828 SUPPORT In Vitro

"The Colon Chip supports spontaneous goblet cell differentiation and accumulation of a mucus bilayer with impenetrable and penetrable layers, and a thickness similar to that observed in the human colon, while maintaining a subpopulation of proliferative epithelial cells."

Supports physiologic mucus-barrier fidelity in a human colon microphysiological system relevant to UC barrier biology.

PMID:31778828 SUPPORT In Vitro

"The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer."

Supports inclusion as a restrained UC-adjacent organ-on-chip bridge rather than a direct disease-specific UC model.

The chip captures inflammatory mediator effects on mucus hydration without requiring animal models

Show evidence (1 reference)

PMID:31778828 SUPPORT In Vitro

Connects the platform to inflammatory mediator responses relevant to mucosal inflammation and mucus-layer physiology in UC.

Show evidence (1 reference)

PMID:31778828 SUPPORT In Vitro

"A human colon-on-a-chip (Colon Chip) microfluidic device lined by primary patient-derived colonic epithelial cells was used to recapitulate mucus bilayer formation, and to visualize mucus accumulation in living cultures noninvasively."

Supports this as a human colon organ-on-chip platform for studying mucus-barrier mechanisms relevant to UC.

🧮

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 UC-associated dysbiosis including loss of keystone SCFA producers (F. prausnitzii, Roseburia, Eubacterium rectale) and expansion of pathobionts (Fusobacterium, Enterobacteriaceae). Supports colonocyte energy metabolism modeling.

Repository ↗ PMID:36543475

Nature Biotechnology 2022 - strain-level resolution for butyrate producer depletion studies

MICOM Community Metabolic Model COBRApy GENOME_SCALE_METABOLIC

Metagenome-scale modeling framework for simulating metabolic interactions in the gut microbiota. Models decreased butyrate production, impaired colonocyte energy metabolism, and Anna Karenina effect (increased community instability) observed in UC. Integrates with dietary intervention modeling.

PMID:31964767

mSystems 2020 - enables personalized SCFA flux predictions from patient metagenomes

Host-Microbiome Multi-Objective Optimization Model GENOME_SCALE_METABOLIC

Integrated metabolic model combining human colonic epithelial cell metabolism with gut microbiome community models. Predicts metabolic crosstalk disruption in UC, including butyrate deprivation effects on colonocyte beta-oxidation and tight junction maintenance.

PMID:38729159

iScience 2024 - models host-microbiome metabolic interactions at community scale

{ }

Source YAML

click to show

name: Ulcerative Colitis
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Ulcerative colitis is a chronic relapsing inflammatory bowel disease that causes
  continuous mucosal inflammation of the colon, beginning in the rectum and
  extending proximally. A dysregulated mucosal immune response to an altered gut
  microbiota in genetically susceptible hosts, together with epithelial barrier
  dysfunction and loss of protective short-chain-fatty-acid-producing bacteria,
  drives superficial ulceration limited to the mucosa and submucosa. Patients
  present with bloody diarrhea, urgency, tenesmus, and abdominal pain, and the
  disease confers an increased long-term risk of colorectal cancer.
category: Complex
parents:
- Gastrointestinal Disease
- Autoimmune Disease
disease_term:
  preferred_term: ulcerative colitis
  term:
    id: MONDO:0005101
    label: ulcerative colitis
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
    notes: >-
      Ulcerative colitis is one of the two inflammatory bowel diseases and is
      covered with the disorders of the gastrointestinal system; this is its
      primary clinical home.
    evidence:
    - reference: PMID:30837080
      reference_title: A comprehensive review and update on ulcerative colitis().
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disorder of the colon that causes continuous mucosal inflammation extending from the rectum to the more proximal colon
      explanation: >-
        UC is defined as a chronic inflammatory bowel disorder of the colon,
        which places its primary clinical home in Harrison's Disorders of the
        Gastrointestinal System Part.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      The disease is driven by a dysregulated mucosal immune response in a
      genetically susceptible host, and its extraintestinal manifestations and
      immune-directed therapies (anti-TNF, anti-integrin, IL-23 blockade) place it
      with the immune-mediated inflammatory disorders. This matches the pairing
      already used on the Crohn_Disease entry.
pathophysiology:
- name: Mucosal Inflammation
  description: >
    Continuous inflammation limited to the colonic mucosa, starting
    at the rectum and extending proximally. Crypt abscesses, goblet
    cell depletion, and mucosal ulceration are characteristic.
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  genes:
  - preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  evidence:
  - reference: PMID:38314135
    reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β,
      IL-18, NLRP3)."
    explanation: Pyroptosis-associated inflammatory cytokines IL-1β and IL-18
      are produced in UC mucosa, contributing to the characteristic mucosal
      inflammation.
  - reference: PMID:39438660
    reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
    supports: SUPPORT
    snippet: "A systems biology-spatial analysis identified granuloma signatures in
      CD and interferon (IFN)-response signatures localising to T cell aggregates
      and epithelial damage in CD and UC."
    explanation: Single-cell and spatial analysis of gut biopsies localises
      interferon-response signatures to T cell aggregates and epithelial damage
      in UC, the inflammatory infiltrate of the colonic mucosa.
- name: Dysregulated Immune Response
  description: >
    Aberrant immune response to commensal gut bacteria in genetically
    susceptible individuals. Th2-skewed response with IL-13 driving
    epithelial dysfunction.
  biological_processes:
  - preferred_term: Type 2 immune response
    term:
      id: GO:0042092
      label: type 2 immune response
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  cell_types:
  - preferred_term: T Helper 2 Cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  genes:
  - preferred_term: IL23R
    term:
      id: hgnc:19100
      label: IL23R
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  - preferred_term: IL10
    term:
      id: hgnc:5962
      label: IL10
  - preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  - preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  - preferred_term: CD28
    term:
      id: hgnc:1653
      label: CD28
  evidence:
  - reference: PMID:39438660
    reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
    supports: SUPPORT
    snippet: "A systems biology-spatial analysis identified granuloma signatures in
      CD and interferon (IFN)-response signatures localising to T cell aggregates
      and epithelial damage in CD and UC."
    explanation: Single-cell analysis demonstrates interferon-response
      signatures localize to T cell aggregates and epithelial damage in UC,
      revealing a key immune dysregulation mechanism.
  - reference: PMID:39438660
    reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
    supports: SUPPORT
    snippet: "Longitudinal comparisons demonstrated disease progression in nonremission:
      myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling
      in UC."
    explanation: Increased multi-cellular interferon signaling is associated
      with disease progression and non-remission in UC, indicating this is a
      critical pathway in dysregulated immune response.
  - reference: PMID:39461795
    reference_title: "IL-23 inhibition for chronic inflammatory disease."
    supports: SUPPORT
    snippet: "Addressing an upstream pathological mechanism shared between these disorders,
      this drug class has high efficacy rates and a durable response that extends
      dosing intervals up to 3 months."
    explanation: IL-23 inhibitors target an upstream pathological mechanism in
      UC with high efficacy (up to 50% in IBD), supporting the role of aberrant
      immune signaling in disease pathogenesis.
- name: Epithelial Barrier Dysfunction
  description: >
    Disrupted tight junctions and mucus layer allow bacterial
    translocation, perpetuating inflammation. Goblet cell depletion
    reduces protective mucus.
  biological_processes:
  - preferred_term: Epithelial Barrier Function
    term:
      id: GO:0090557
      label: establishment of endothelial intestinal barrier
  genes:
  - preferred_term: HNF4A
    term:
      id: hgnc:5024
      label: HNF4A
  - preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  evidence:
  - reference: PMID:39438660
    reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
    supports: SUPPORT
    snippet: "A systems biology-spatial analysis identified granuloma signatures in
      CD and interferon (IFN)-response signatures localising to T cell aggregates
      and epithelial damage in CD and UC."
    explanation: Interferon-response signatures are spatially localized to
      epithelial damage sites in UC, directly linking immune responses to
      barrier disruption.
  - reference: PMID:38724705
    reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
    supports: SUPPORT
    snippet: "Luminal epithelial cells in patients with irColitis expressed PCSK9,
      PD-L1 and interferon-induced signatures associated with apoptosis, increased
      cell turnover and malabsorption."
    explanation: Epithelial cells express interferon-induced signatures
      associated with apoptosis and increased cell turnover, demonstrating the
      mechanism of barrier dysfunction in inflammatory colitis.
  - reference: PMID:38724705
    reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
    supports: SUPPORT
    snippet: "Together, these data suggest roles for circulating T cells and epithelial-immune
      crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and
      identify potential therapeutic targets for irColitis."
    explanation: Epithelial-immune crosstalk is critical to barrier function,
      confirming that disruption of this interaction underlies epithelial
      barrier dysfunction in colitis.
  - reference: PMID:39438660
    reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
    supports: SUPPORT
    snippet: "Pretreatment differences in epithelial and myeloid compartments were
      associated with remission outcomes in both diseases."
    explanation: Epithelial compartment differences predict treatment outcomes,
      emphasizing the central role of epithelial dysfunction in UC pathogenesis.
- name: Loss of Microbial Diversity
  description: >
    Reduced alpha diversity (species richness and evenness) in the colonic
    microbiome. Shannon and Chao1 indices are decreased compared to healthy
    controls, representing ecological collapse of the microbial community.
  biological_processes:
  - preferred_term: Microbiome Community Dynamics
    term:
      id: GO:0044003
      label: symbiont-mediated perturbation of host process
  downstream:
  - target: Loss of Keystone SCFA Producers
    description: Diversity loss disproportionately affects beneficial fermenters
  - target: Increased Microbial Community Instability
    description: Anna Karenina effect - dysbiotic communities become stochastic
  evidence:
  - reference: PMID:25307765
    reference_title: "Meta-analyses of human gut microbes associated with obesity and IBD."
    supports: SUPPORT
    snippet: "IBD has a consistent signature across studies and allows high classification
      accuracy of IBD from non-IBD subjects."
    explanation: Meta-analysis confirms IBD has consistent microbiota signatures
      distinguishing patients from healthy controls.

- name: Loss of Keystone SCFA Producers
  description: >
    Depletion of butyrate-producing Firmicutes, particularly Faecalibacterium
    prausnitzii, Roseburia spp., and Eubacterium rectale. These keystone taxa
    are network hubs supporting community structure through cross-feeding.
  notes: >
    F. prausnitzii is anti-inflammatory; its supernatant reduces colitis in
    animal models. Roseburia and Eubacterium are primary butyrate producers
    via the acetyl-CoA pathway.
  downstream:
  - target: Decreased Butyrate Production
    description: Loss of primary butyrate-synthesizing taxa
  evidence:
  - reference: PMID:18936492
    reference_title: "Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients."
    supports: SUPPORT
    directness: INDIRECT
    snippet: "A decrease in the abundance and biodiversity of intestinal bacteria
      within the dominant phylum Firmicutes has been observed repeatedly in Crohn
      disease (CD) patients."
    explanation: Sokol et al. report that reduced abundance and biodiversity of
      Firmicutes - the phylum containing the keystone butyrate producers of this
      node - is repeatedly observed in Crohn disease. Indirect because the quoted
      observation is in Crohn disease rather than ulcerative colitis.
  - reference: PMID:18936492
    reference_title: "Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS
      colitis models, partly due to secreted metabolites able to block NF-kappaB activation
      and IL-8 production."
    explanation: F. prausnitzii has direct anti-inflammatory properties beyond
      its role as butyrate producer.

- name: Pathobiont Expansion
  description: >
    Bloom of opportunistic pathobionts including adherent-invasive E. coli (AIEC),
    Fusobacterium nucleatum, and Enterobacteriaceae. These taxa exploit the
    ecological niche vacated by depleted commensals and promote inflammation
    through LPS and direct epithelial invasion.
  downstream:
  - target: Mucosal Inflammation
    description: Pathobionts produce LPS and other pro-inflammatory molecules
  - target: Epithelial Barrier Dysfunction
    description: AIEC can invade epithelial cells and disrupt tight junctions
  evidence:
  - reference: PMID:26185088
    reference_title: "The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection."
    supports: SUPPORT
    snippet: "This is often characterized by an increased relative abundance of facultative
      anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time,
      depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia."
    explanation: Dysbiosis in IBD involves expansion of Enterobacteriaceae
      pathobionts alongside depletion of beneficial obligate anaerobes.

- name: Decreased Butyrate Production
  description: >
    Reduced fecal short-chain fatty acid (SCFA) concentrations, particularly
    butyrate. Butyrate is the primary energy source for colonocytes (providing
    ~70% of energy needs) and exerts anti-inflammatory effects via HDAC
    inhibition and GPR109A signaling.
  biological_processes:
  - preferred_term: Short-chain Fatty Acid Metabolism
    term:
      id: GO:0046459
      label: short-chain fatty acid metabolic process
  downstream:
  - target: Impaired Colonocyte Energy Metabolism
    description: Butyrate deprivation causes epithelial energy deficit
  evidence:
  - reference: PMID:23023125
    reference_title: "A metagenome-wide association study of gut microbiota in type 2 diabetes."
    supports: NO_EVIDENCE
    snippet: "Patients with type 2 diabetes were characterized by a moderate degree
      of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing
      bacteria and an increase in various opportunistic pathogens."
    explanation: While this study focused on T2D, it demonstrates the general
      principle that dysbiosis involves loss of butyrate producers - a pattern
      also seen in IBD.

- name: Impaired Colonocyte Energy Metabolism
  description: >
    Colonocytes deprived of butyrate shift from beta-oxidation to glycolysis,
    causing energy deficit. This impairs tight junction maintenance, mucus
    production by goblet cells, and epithelial renewal from crypt stem cells.
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  downstream:
  - target: Epithelial Barrier Dysfunction
    description: Energy-deprived colonocytes cannot maintain barrier integrity

- name: Increased Microbial Community Instability
  description: >
    Anna Karenina effect - dysbiotic microbiomes show increased inter-individual
    variability and temporal instability compared to healthy controls. The
    community loses resilience and may occupy an alternative stable state that
    resists therapeutic intervention.
  notes: >
    "All healthy microbiomes are alike; each dysbiotic microbiome is dysbiotic
    in its own way." This increased stochasticity complicates biomarker discovery
    and explains heterogeneous treatment responses.
  downstream:
  - target: Loss of Microbial Diversity
    description: Feedback loop - community instability promotes further
      diversity loss
  evidence:
  - reference: PMID:28836573
    reference_title: "Stress and stability: applying the Anna Karenina principle to animal microbiomes."
    supports: SUPPORT
    snippet: "The result is an 'Anna Karenina principle' for animal microbiomes, in
      which dysbiotic individuals vary more in microbial community composition than
      healthy individuals-paralleling Leo Tolstoy's dictum that 'all happy families
      look alike; each unhappy family is unhappy in its own way'."
    explanation: Zaneveld et al. demonstrated the Anna Karenina principle
      applies to disease-associated microbiomes.
- name: NLRP3 Inflammasome-Mediated Pyroptosis
  description: >
    Epithelial cell pyroptosis driven by NLRP3 inflammasome activation
    contributes to barrier disruption and inflammation. SLC6A14 promotes
    pyroptosis by upregulating NLRP3.
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  biological_processes:
  - preferred_term: Pyroptosis
    term:
      id: GO:0070269
      label: pyroptotic inflammatory response
  evidence:
  - reference: PMID:38314135
    reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
    supports: SUPPORT
    snippet: "SLC6A14 was increased and correlated with NLRP3 in UC tissues."
    explanation: SLC6A14 expression is elevated and correlates with NLRP3 in UC
      tissues, establishing a molecular link between this transporter and
      inflammasome activation.
  - reference: PMID:38314135
    reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β,
      IL-18, NLRP3)."
    explanation: Experimental reduction of SLC6A14 decreases
      pyroptosis-associated proteins including NLRP3, IL-1β, and IL-18,
      demonstrating the causal role of this pathway in UC.
  - reference: PMID:38314135
    reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
    supports: SUPPORT
    snippet: "SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic
      potential of modulating the SLC6A14/NLRP3 axis."
    explanation: SLC6A14 promotes UC progression through NLRP3-mediated
      pyroptosis, identifying this as a key pathophysiological mechanism and
      potential therapeutic target.

- name: Intestinal Epithelial Cell Ferroptosis
  description: >
    Iron-dependent regulated cell death driven by lipid peroxidation in intestinal
    epithelial cells. Ferroptosis in IECs is characterized by iron accumulation,
    lipid peroxidation, and dysregulation of antioxidant defense systems. Key signaling
    networks regulating ferroptosis include the Nrf2/HO-1 antioxidant pathway, the
    SLC7A11/GPX4 lipid peroxidation control system, and the AMPK/mTOR metabolic
    regulatory pathway. Dysregulation of these pathways leads to uncontrolled ferroptosis
    that contributes to epithelial barrier dysfunction and inflammation in UC.
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  biological_processes:
  - preferred_term: Ferroptosis
    term:
      id: GO:0097707
      label: ferroptosis
  - preferred_term: Antioxidant Defense
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Epithelial Barrier Dysfunction
    description: Ferroptotic epithelial cell death and loss of barrier integrity
  evidence:
  - reference: PMID:42154151
    reference_title: "Intestinal Epithelial Cell Ferroptosis in Ulcerative Colitis: Pathogenesis, Signaling Networks, and Therapeutic Implications."
    supports: SUPPORT
    snippet: "The ferroptosis of intestinal epithelial cells (IECs), an iron-dependent form of
      cell death driven by lipid peroxidation, has emerged as a critical pathogenic
      driver of ulcerative colitis (UC)."
    explanation: Ferroptosis is identified as a critical pathogenic driver in UC,
      establishing this iron-dependent cell death mechanism as central to UC
      pathophysiology.
  - reference: PMID:42154151
    reference_title: "Intestinal Epithelial Cell Ferroptosis in Ulcerative Colitis: Pathogenesis, Signaling Networks, and Therapeutic Implications."
    supports: SUPPORT
    snippet: "This review summarizes the core hallmarks of IEC ferroptosis in UC-specifically,
      lipid peroxidation, iron overload, and antioxidant system dysregulation-and
      describes key regulatory signaling networks, including the Nrf2/HO-1, SLC7A11/GPX4,
      and AMPK/mTOR pathways."
    explanation: Three key signaling pathways regulate ferroptosis in UC, including
      Nrf2/HO-1 (antioxidant defense), SLC7A11/GPX4 (lipid peroxidation control),
      and AMPK/mTOR (metabolic regulation). Dysregulation drives ferroptotic cell
      death in IECs.

mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic ulcerative colitis risk in adverse
    contexts via shared mucosal-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. IL23R,
    HLA-DRB1) exert systematically larger effects in disease-promoting contexts.
    This entry proposes that the amplification arises because polygenic liability
    and contextual exposures converge on the shared Mucosal Inflammation node, so
    their joint effect on the liability-threshold scale is super-additive rather
    than additive. Notably, several exposures act in the opposite direction to
    Crohn disease — tobacco smoking and appendectomy are protective in ulcerative
    colitis — a clear illustration that a "context" is not intrinsically adverse
    but disease-specific. 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 + contextual
    exposures → Mucosal Inflammation) is a mechanistic interpretation and is not
    itself established as causal — see the reverse-causation knowledge gap under
    discussions.
phenotypes:
- name: Bloody Diarrhea
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Bloody Diarrhea
    term:
      id: HP:0025085
      label: Bloody diarrhea
  evidence:
  - reference: PMID:38724705
    reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
    supports: SUPPORT
    snippet: "Luminal epithelial cells in patients with irColitis expressed PCSK9,
      PD-L1 and interferon-induced signatures associated with apoptosis, increased
      cell turnover and malabsorption."
    explanation: Epithelial apoptosis and increased cell turnover in
      inflammatory colitis leads to mucosal ulceration and bleeding, which
      manifests as bloody diarrhea.
- name: Abdominal Pain
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abdominal Pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:31272578
    reference_title: "Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus."
    explanation: Mayo Clinic Proceedings review confirms abdominal pain as a typical presenting symptom in UC.
- name: Urgency
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  notes: Fecal urgency
  phenotype_term:
    preferred_term: Fecal Urgency
    term:
      id: HP:0012701
      label: Bowel urgency
  evidence:
  - reference: PMID:30837080
    reference_title: "A comprehensive review and update on ulcerative colitis()."
    supports: SUPPORT
    snippet: "The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."
    explanation: Rectal urgency is described as a classic presenting symptom of ulcerative colitis.
- name: Tenesmus
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tenesmus
    term:
      id: HP:0012702
      label: Tenesmus
  evidence:
  - reference: PMID:30837080
    reference_title: "A comprehensive review and update on ulcerative colitis()."
    supports: SUPPORT
    snippet: "The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."
    explanation: Tenesmus is described as a classic presenting symptom of ulcerative colitis.
- name: Weight Loss
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:25506359
    reference_title: "Determinants of Weight Loss prior to Diagnosis in Inflammatory Bowel Disease: A Retrospective Observational Study."
    supports: SUPPORT
    snippet: "51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss)."
    explanation: Weight loss is a significant and common symptom in ulcerative colitis patients, with over half experiencing significant weight loss prior to diagnosis.
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:27310658
    reference_title: "Conventional treatment regimens for ulcerative colitis alleviate fatigue - an observational cohort study."
    supports: SUPPORT
    snippet: "more severe fatigue was associated with more ulcerative colitis symptoms"
    explanation: Fatigue is common in ulcerative colitis and tracks reported symptom burden; the same cohort found no association between fatigue scores and objective disease-activity markers (CRP, faecal calprotectin, endoscopic Mayo score).
- name: Anemia
  category: Hematologic
  frequency: FREQUENT
  notes: Iron deficiency from blood loss
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:25646159
    reference_title: "Anemia in inflammatory bowel disease: an under-estimated problem?"
    supports: SUPPORT
    snippet: "Anemia is one of the most frequent complications and/or extraintestinal manifestations of inflammatory bowel disease (IBD). Iron deficiency is the most important cause of anemia in Crohn's disease and ulcerative colitis patients."
    explanation: Anemia, particularly iron deficiency anemia, is one of the most frequent complications of ulcerative colitis due to chronic blood loss from the inflamed colonic mucosa.
- name: Facial Diplegia
  category: Neurological
  frequency: VERY_RARE
  notes: Very rare neurological extraintestinal manifestation; Guillain-Barré syndrome facial diplegia variant. Based on an isolated case report (PMID:42143401) explicitly described as "not been previously reported".
  phenotype_term:
    preferred_term: Facial diplegia
    term:
      id: HP:0001349
      label: Facial diplegia
  evidence:
  - reference: PMID:42143401
    reference_title: "A Young Woman With Ulcerative Colitis Presenting With Facial Diplegia, a Variant of Guillain-Barré Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GBS can present as a rare extraintestinal manifestation of UC when in remission or relapse."
    explanation: Case report documents Guillain-Barré syndrome facial diplegia variant as a rare neurological extraintestinal manifestation of UC, supporting recognition of UC as a predisposing factor for this complication.
  - reference: PMID:42143401
    reference_title: "A Young Woman With Ulcerative Colitis Presenting With Facial Diplegia, a Variant of Guillain-Barré Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case shows that isolated facial diplegia, a variant of GBS, can occur in patients with UC as a neurological extraintestinal manifestation, which not been previously reported, suggesting that UC can be an underling cause or predisposing factor for bilateral facial palsy."
    explanation: Confirms that UC may be an underlying cause or predisposing factor for GBS-related facial diplegia as a neurological complication; explicitly identified as a not-previously-reported phenomenon, supporting the VERY_RARE classification.
- name: "Anterior uveitis"
  category: Ophthalmologic
  description: "Anterior uveitis is an ocular extraintestinal manifestation of inflammatory bowel disease."
  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 review lists anterior uveitis occurring independent of disease flares."
- name: "Primary sclerosing cholangitis"
  category: Hepatic
  description: "Primary sclerosing cholangitis is strongly associated with ulcerative colitis as a hepatobiliary manifestation."
  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 manifestation independent of flares."
- name: "Erythema nodosum"
  category: Dermatologic
  description: "Erythema nodosum is a cutaneous extraintestinal manifestation tracking active intestinal inflammation."
  phenotype_term:
    preferred_term: "Erythema nodosum"
    term:
      id: HP:0012219
      label: "Erythema nodosum"
  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 erythema nodosum among manifestations associated with active intestinal inflammation."
- name: "Oral aphthous ulcers"
  category: Oral
  description: "Oral aphthous ulcers are a mucosal extraintestinal manifestation associated with active disease."
  phenotype_term:
    preferred_term: "Oral aphthous ulcers"
    term:
      id: HP:0011107
      label: "Recurrent aphthous stomatitis"
  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 oral aphthous ulcers among manifestations associated with active intestinal inflammation."
- name: "Peripheral arthritis"
  category: Musculoskeletal
  description: "Peripheral arthritis is a musculoskeletal extraintestinal manifestation tracking intestinal inflammation."
  phenotype_term:
    preferred_term: "Peripheral arthritis"
    term:
      id: HP:0001369
      label: "Arthritis"
  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 peripheral arthritis among manifestations associated with active intestinal inflammation."
- 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."
biochemical:
- name: Fecal Calprotectin
  presence: Elevated
  context: Marker of intestinal inflammation
  evidence:
  - reference: PMID:40943053
    reference_title: "Non-Invasive vs. Invasive Markers in Ulcerative Colitis: A Systematic Review of Intestinal Ultrasound, Biopsy, and Faecal Calprotectin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-invasive alternatives like intestinal ultrasound (IUS) and faecal calprotectin (FC) show promise for monitoring mucosal inflammation
    explanation: >-
      Systematic review of non-invasive markers in ulcerative colitis identifies
      faecal calprotectin as a marker of mucosal inflammation, which is the role
      recorded in this entry's context field.
- name: CRP
  presence: Elevated
  context: Systemic inflammation marker
- name: ESR
  presence: Elevated
  context: Active disease
- name: Plasma albumin (Mendelian randomization signal)
  specificity: >
    Not the clinical albumin measurement used to assess disease activity.
    Recorded because albumin was the metabolite with the largest number of
    potentially causal disease links in a 274,241-participant UK Biobank
    metabolome atlas, and ulcerative colitis was one of them.
  context: >
    This entry records a genetically instrumented, population-level causal
    signal, and its direction is the opposite of the familiar clinical picture.
    In active ulcerative colitis measured serum albumin is typically low,
    reflecting inflammation and protein loss; the atlas instead reports that
    genetically predicted higher albumin links to a higher incidence of
    ulcerative colitis, with a reciprocal signal in the disease-to-metabolite
    direction. The two statements are not in conflict because they describe
    different quantities: a lifelong genetic propensity to a higher albumin set
    point versus the measured albumin of a patient with active disease. No
    presence value is recorded here for that reason, and nothing in this entry
    should be used to interpret an individual albumin result.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "positively linking to a higher incidence of ulcerative colitis, certain types of anaemias and CKD"
    explanation: >
      Albumin had the most potentially causal disease links of any metabolite
      in the atlas (15 diseases), and ulcerative colitis is named among the
      conditions whose incidence it positively linked to.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, albumin levels also showed reciprocal causal associations with genetic liability to the risk of ulcerative colitis, certain types of anaemias and CKD."
    explanation: >
      Establishes that the albumin-ulcerative colitis signal was bidirectional
      in the Mendelian randomization analysis, which is why this entry records
      an association rather than a directional biomarker.
genetic:
- 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
    evidence_source: HUMAN_CLINICAL
    snippet: "Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis."
    explanation: >-
      The discovery GWAS found the primary IL23R signal in Crohn's disease and
      confirmed the association in independent ulcerative colitis cohorts, which is
      what supports listing IL23R as a UC risk locus here.
- name: HNF4A
  gene_term:
    preferred_term: HNF4A
    term:
      id: hgnc:5024
      label: HNF4A
  association: Risk Factor
  evidence:
  - reference: PMID:19915572
    reference_title: "Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17))"
    explanation: >-
      WTCCC2 ulcerative colitis GWAS reports genome-wide significant association at
      the 20q13 locus containing HNF4A.
- name: CDH1
  gene_term:
    preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  association: Risk Factor
  evidence:
  - reference: PMID:19915572
    reference_title: "Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "16q22 (CDH1 and CDH3; P = 2.8 x 10(-8))"
    explanation: >-
      The same WTCCC2 ulcerative colitis GWAS reports genome-wide significant
      association at 16q22. Note the locus contains both CDH1 and CDH3, so the
      association is to the region rather than resolved to CDH1 alone.
- name: HLA-DRB1
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  association: Risk Factor
- 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
  evidence:
  - reference: PMID:18836448
    reference_title: "Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples"
    explanation: >-
      A dedicated ulcerative colitis GWAS with independent European replication
      panels identifies the IL10-flanking variant as its strongest replicated
      association.
- 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: 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: REL
  gene_term:
    preferred_term: REL
    term:
      id: hgnc:9954
      label: REL
  association: GWAS
  notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
- 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
  evidence:
  - reference: PMID:21297633
    reference_title: "Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1"
    explanation: >-
      The 47-locus ulcerative colitis meta-analysis names PRDM1 among the candidate
      genes annotated to its associated regions. Note this is a candidate-gene
      annotation of an associated interval, not a demonstration that PRDM1 is the
      causal gene.
- 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
environmental:
- name: Appendectomy
  notes: Appendicectomy in established UC protects against relapse. Distinct from
    the classic epidemiologic claim that appendectomy in youth protects against
    developing UC, which this entry does not currently cite.
  evidence:
  - reference: PMID:40228513
    reference_title: "Appendicectomy plus standard medical therapy versus standard medical therapy alone for maintenance of remission in ulcerative colitis (ACCURE): a pragmatic, open-label, international, randomised trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 1-year relapse rate was significantly lower in the appendicectomy
      group than in the control group
    explanation: Randomised trial evidence that appendicectomy protects against relapse
      in established ulcerative colitis.
- name: Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  notes: Protective (unlike Crohn's)
  evidence:
  - reference: PMID:40246988
    reference_title: "Relationship between smoking status and ulcerative colitis: a meta-analysis based on a case-control study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: smoking had a protective effect against UC, indicating that it may reduce
      the risk of developing UC
    explanation: Meta-analysis of case-control studies finding a protective association
      between smoking and ulcerative colitis, the direction opposite to Crohn disease.
- name: NSAIDs
  exposure_term:
    preferred_term: NSAID exposure
    term:
      id: ECTO:9001720
      label: exposure to non-steroidal anti-inflammatory drug
  notes: May trigger flares
  evidence:
  - reference: PMID:25314574
    reference_title: Nonsteroidal anti-inflammatory drugs and exacerbations of inflammatory
      bowel disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Conventional NSAIDs may cause clinical relapse in about 20% of patients
      with quiescent IBD
    explanation: Quantifies the relapse risk conventional NSAIDs carry in quiescent
      inflammatory bowel disease.
- name: Infections
  exposure_term:
    preferred_term: Infectious agent exposure
    term:
      id: ECTO:3000000
      label: exposure to organism
  notes: >-
    May trigger onset. Bound to ECTO:3000000 (exposure to organism) rather than
    the previous XCO:0000236, a cross-ontology move that also broadens pathogen
    to any organism. ECTO has no generic pathogen- or infectious-agent-exposure
    term, so the broadening is the deliberate "no term beats a bad one" tradeoff
    and not an error to be reverted; the pathogen sense is carried by
    preferred_term.
  evidence:
  - reference: PMID:39333475
    reference_title: "Risk of inflammatory bowel disease following hospitalisation with infectious mononucleosis: nationwide cohort study from Denmark"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This significantly increased risk was seen for both CD (HR: 1.56; 95%
      CI: 1.34-1.83) and to a lesser extent UC (HR: 1.23; 95% CI: 1.08-1.40)'
    explanation: Nationwide cohort showing that a specific severe infection (infectious
      mononucleosis) raises subsequent ulcerative colitis risk. Indirect for the
      generic "infections" claim, which it evidences via one specific exposure.
- name: Stress
  exposure_term:
    preferred_term: psychological stress
    term:
      id: XCO:0001265
      label: stress
  notes: May trigger flares
  evidence:
  - reference: PMID:10811330
    reference_title: "Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: long-term perceived stress increases the risk of exacerbation over a
      period of months to years
    explanation: Prospective cohort of patients enrolled in remission. Note the
      same study found short-term stress did NOT trigger exacerbation, so the
      timescale matters to the "triggers flares" framing.
treatments:
- name: 5-Aminosalicylates
  description: First-line for mild-moderate disease (mesalamine).
  treatment_term:
    preferred_term: 5-aminosalicylate therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:21407188
    reference_title: "Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥ 2.0 g/day have greater efficacy"
    explanation: Systematic review and meta-analysis confirming 5-ASA efficacy in UC remission induction and relapse prevention.
  - reference: PMID:40701556
    reference_title: "ACG Clinical Guideline Update: Ulcerative Colitis in Adults."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These guidelines were developed to indicate the preferred approach to the management of adult patients with ulcerative colitis as established by valid scientific research and represent the official practice recommendations of the American College of Gastroenterology under the auspices of the Practice Parameters Committee."
    explanation: The ACG clinical guideline update provides the current official practice recommendations for adult ulcerative colitis, in which 5-aminosalicylates are first-line therapy for mild-to-moderate disease.
- name: Corticosteroids
  description: For acute flares (prednisone, budesonide).
  treatment_term:
    preferred_term: Corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
  evidence:
  - reference: PMID:31272578
    reference_title: "Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission."
    explanation: Review confirms corticosteroids are used to induce remission with goal of achieving corticosteroid-free maintenance.
- name: Thiopurines
  description: Azathioprine, 6-MP for maintenance.
  treatment_term:
    preferred_term: Thiopurine therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:31272578
    reference_title: "Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."
    explanation: Review confirms thiopurines as a treatment class for moderate-severe UC.
- name: Anti-TNF Therapy
  description: Infliximab, adalimumab for moderate-severe disease.
  treatment_term:
    preferred_term: Anti-TNF therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:26902011
    reference_title: "Anti-TNF-A Therapy about Infliximab and Adalimamab for the Effectiveness in Ulcerative Colitis Compared with Conventional Therapy: A Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy"
    explanation: Meta-analysis demonstrating significant efficacy of anti-TNF agents in UC clinical response induction.
- name: Vedolizumab
  description: Gut-selective integrin inhibitor.
  treatment_term:
    preferred_term: Vedolizumab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:31470005
    reference_title: "Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively"
    explanation: Phase 3 RCT demonstrating vedolizumab efficacy with 46% clinical remission vs 14% placebo at week 52.
- name: Tofacitinib
  description: JAK inhibitor for moderate-severe disease.
  treatment_term:
    preferred_term: JAK inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:31272578
    reference_title: "Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."
    explanation: Review confirms JAK inhibitors as approved treatment for moderate-severe UC.
- name: Ustekinumab
  description: IL-12/23 inhibitor.
  treatment_term:
    preferred_term: IL-12/23 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39461795
    reference_title: "IL-23 inhibition for chronic inflammatory disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response"
    explanation: IL-23 inhibitors demonstrate high efficacy in UC by targeting upstream pathological mechanisms.
- name: Colectomy
  description: Curative surgery for refractory or complicated disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Colectomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:31272578
    reference_title: "Ulcerative Colitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment."
    explanation: Review confirms 15% of UC patients require colectomy for refractory disease or dysplasia.
discussions:
- discussion_id: uc_pgsxc_reverse_causation
  prompt: >-
    Are the IBD PGS×context interactions driven by contextual exposures causally
    amplifying genetic risk, or are some "contexts" (e.g. fecal calprotectin, CRP,
    ESR) actually downstream readouts of active colitis (reverse causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Mucosal Inflammation
  - biochemical#Fecal Calprotectin
  - biochemical#CRP
  - environmental#Smoking
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are
    largely unable to establish the causality of specific contexts. For
    ulcerative colitis the biochemical "contexts" fecal calprotectin, CRP and ESR
    are disease-activity readouts (consequences of active mucosal inflammation)
    rather than upstream drivers. Smoking is a further caution: it is
    inversely associated with UC (apparently protective), so treating it as an
    intrinsically adverse "context" would misdirect intervention — its
    disease-specific direction must be modelled, not assumed. Distinguishing
    genuine amplification of genetic effects from reverse causation determines
    whether the modelled interventions would actually reduce risk.
  proposed_experiments:
  - experiment_id: uc_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-UC direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (smoking, inflammatory biomarkers, diet) causally
      affects ulcerative colitis versus being a consequence of active disease,
      accounting for the inverse smoking association, 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 a directional
      exposure-to-disease effect and the exposure-attributable risk difference
      increases across increasing PGS strata; it is flagged as a reverse-causation
      suspect otherwise.
  - experiment_id: uc_pgsxc_prospective_temporal
    name: Prospective incident-UC 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_uc_stroke_shared_genetic_architecture
  prompt: >-
    By what molecular pathway does the shared IBD/UC genetic susceptibility
    translate into large arterial atherosclerotic stroke (LAS) risk, and does
    FCGR2A-mediated Fc-receptor signaling causally link colonic mucosal immune
    activation to systemic atherosclerosis? Why is the genetic correlation with
    LAS stronger for ulcerative colitis than for Crohn's disease, and which gut
    microbial, metabolite, and immune-cell intermediaries mediate the
    IBD/UC to stroke axis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated Immune Response
  - pathophysiology#Mucosal Inflammation
  rationale: >-
    The epidemiological association between IBD and stroke is well established,
    but the shared genetic architecture and the causal mechanism have been
    unclear. A 2026 cross-trait GWAS/Mendelian-randomization study (Wang et al.,
    PMID:42400809) found that common variants contribute more to UC (than to CD)
    and multiple stroke subtypes, identified a potential causal relationship
    between IBD/UC and large arterial atherosclerotic stroke, and pinpointed a
    single colocalized culprit variant (rs7522794) in the FCGR2A promoter: the
    risk allele is predicted to increase SPI1 binding and FCGR2A expression,
    plausibly amplifying Fcgamma-receptor-mediated immune activation shared by
    intestinal inflammation and atherosclerotic vascular disease. This connects
    directly to the UC "Dysregulated Immune Response" node, but the
    disease-specific causal chain (how FCGR2A dosage in which immune compartment
    drives plaque immunity), the UC-versus-CD specificity, and the proposed
    gut-microbe/blood-metabolite/immune-cell mediation remain unresolved and not
    yet modeled
    as pathophysiology edges. Whether dismech should capture this as a dedicated
    IBD-stroke comorbidity entry (kb/comorbidities/) or as shared pathophysiology
    nodes on the individual UC and Ischemic Stroke entries is a maintainer scope
    decision left open here.
  proposed_experiments:
  - experiment_id: exp_uc_fcgr2a_stroke_immune_axis
    name: Compartment-resolved test of FCGR2A dosage linking mucosal immune activation to atherosclerotic plaque immunity
    description: >-
      Use the rs7522794 promoter genotype (and allele-specific SPI1-binding
      reporters) to titrate FCGR2A expression in monocyte/macrophage and other
      Fcgamma-receptor-bearing immune compartments, then test whether increased
      FCGR2A signaling amplifies both colonic mucosal inflammatory output and
      pro-atherogenic macrophage activation. Cross-validate in human UC and
      carotid atherosclerotic plaque tissue to establish translational relevance
      of the shared FCGR2A-mediated immune pathway.
    experiment_type:
      preferred_term: allele-specific expression and cell-type-resolved perturbation study
  - experiment_id: exp_uc_stroke_microbe_metabolite_mediation
    name: Mediation dissection of gut-microbe and blood-metabolite intermediaries in the IBD/UC to LAS axis
    description: >-
      Apply mediation Mendelian randomization and matched multi-omics (gut
      microbiome, serum metabolome, circulating immune-cell profiling) in UC
      cohorts with and without large-artery atherosclerotic stroke to identify
      which specific microbial taxa, metabolite signatures, and immune-cell
      populations causally mediate the shared IBD/UC to stroke pathophysiology,
      and to test whether these mediators are UC-specific relative to Crohn's
      disease.
    experiment_type:
      preferred_term: mediation Mendelian randomization with multi-omics profiling
  evidence:
  - reference: PMID:42400809
    reference_title: "FCGR2A promoter variant reveals shared genetic susceptibility between IBD and stroke."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      common genetic variants contributing more on ulcerative colitis (UC) and
      multiple stroke subtypes than Crohn's disease (CD). Among them, there is a
      potential causal relationship between IBD/UC and large arterial
      atherosclerotic stroke (LAS)
    explanation: >-
      Cross-trait GWAS and Mendelian-randomization analysis establishes the
      shared genetic architecture and a potential causal IBD/UC to
      large-artery-atherosclerotic-stroke relationship, with UC showing stronger
      correlation than CD, framing the open mechanistic gap.
  - reference: PMID:42400809
    reference_title: "FCGR2A promoter variant reveals shared genetic susceptibility between IBD and stroke."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the variant rs7522794 on the FCGR2A promoter was the culprit of the
      comorbid phenotype. The rs7522794-T allele predicted to be more prone to
      bind SPI1, thereby increasing FCGR2A expression and susceptibility to
      stroke in IBD patients
    explanation: >-
      Colocalization plus functional verification implicates the FCGR2A promoter
      variant rs7522794 (SPI1-binding, increased FCGR2A expression) as the
      candidate molecular link between IBD and stroke susceptibility, anchoring
      the proposed Fc-receptor immune mechanism.
  posed_by: automated curation scanner (high_effort)
  posed_date: '2026-07-13T00:00:00Z'
- discussion_id: gap_uc_cuproptosis_evidence_hierarchy
  prompt: >-
    Copper depletion and penicillamine reverse DLAT oligomerization, FDX1/LIAS
    loss and barrier damage in chemically induced mouse colitis, but no
    equivalent rescue has been performed in human ulcerative colitis tissue.
    Does canonical cuproptosis - copper-dependent, FDX1-lipoylation-driven
    regulated cell death - actually operate in the human UC colon, or is the
    causal chain a property of DSS and TNBS models while the human signal
    remains copper-associated metabolic stress alongside the ferroptosis this
    entry already models?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Intestinal Epithelial Cell Ferroptosis
  - pathophysiology#Epithelial Barrier Dysfunction
  - pathophysiology#Impaired Colonocyte Energy Metabolism
  rationale: >-
    Ulcerative colitis sits differently from the other dismech entries carrying
    this gap. For systemic lupus erythematosus, rheumatoid arthritis and
    ankylosing spondylitis the cuproptosis literature is transcriptomic
    association; for UC there is functional work, and it is model work. In
    DSS-induced colitis the copper-depleting agent tetrathiomolybdate and the
    chelator penicillamine both reverse DLAT oligomerization and restore FDX1
    and LIAS, and copper chelation likewise rescues colitis in Grx1-knockout
    mice - between them these clear copper dependence, lipoylated-protein
    aggregation, Fe-S cluster destabilization and functional rescue. What is
    absent is the human arm of exactly those experiments: human UC colon
    contributes the descriptive half of the signature (raised copper, DLAT
    oligomerization, reduced FDX1 and LIAS) with no copper-targeted rescue. There
    is one human interventional observation nearby - golimumab responders with
    active UC normalize the hub cuproptosis genes - but it does not close the
    gap, because the intervention is anti-TNF rather than copper-directed and the
    readout is transcript abundance rather than the canonical criteria. Whether
    the signature normalizes because cuproptosis was driving the lesion or simply
    because the mucosa healed is exactly the question left open. The most recent
    mechanistic study states outright that directly visualizing cuproptosis in
    vivo remains a future direction. This is therefore recorded as a
    human/model mismatch rather than a plain knowledge gap: the evidence exists,
    but in chemically induced rodent colitis, and its translational validity is
    the open question. No cuproptosis pathophysiology node is added, and the
    reason is specific to this entry rather than generic caution - the entry
    already models Intestinal Epithelial Cell Ferroptosis, a metal-dependent
    regulated cell death converging on the same Epithelial Barrier Dysfunction
    node. A cuproptosis node would have to be shown to be separable from that
    one, not merely added beside it, and no study has yet run the two readout
    panels against each other in the same tissue. Copper chelators are likewise
    not curated as treatments here; penicillamine and tetrathiomolybdate have
    been given to mice, not to patients with UC.
  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 Crohn_Disease, 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
      ulcerative colitis from Crohn disease - the reason this gap was originally
      left off both IBD entries, and the reason it is now curated against
      UC-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 UC from CD, and
      states for UC 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: HUMAN_CLINICAL
    snippet: >-
      In patients with active UC, golimumab responders alleviate defective
      intestinal mucosal cuproptosis by controlling hub differentially expressed
      cuproptosis genes
    explanation: >-
      The one human interventional observation bearing on rescue, recorded here
      so the rationale's "no copper-targeted rescue" is not read as "no human
      interventional data at all". It does not close the gap: golimumab is
      anti-TNF rather than copper-directed, and the readout is hub-gene
      transcript abundance rather than the canonical criteria, so normalization
      alongside mucosal healing does not establish that cuproptosis was driving
      the lesion.
  - reference: PMID:40969742
    reference_title: Penicillamine ameliorates intestinal barrier damage in dextran sulfate sodium-induced experimental colitis mice by inhibiting cuproptosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cuproptosis was closely related to intestinal barrier damage in patients
      with UC and in DSS-induced colitis mice, characterized by increased copper
      levels and dihydrolipoamide S-acetyltransferase (DLAT) oligomerization and
      reduced Fe-S cluster-containing proteins ferredoxin 1 (FDX1) and lipoyl
      synthase (LIAS) levels.
    explanation: >-
      Establishes the biochemical signature in both human UC colon and DSS mice,
      which is what makes this a mismatch rather than an absence - but the human
      observation is descriptive and the causal manipulation is not. Graded
      MODEL_ORGANISM because the quoted sentence is atomic and spans both arms;
      the human arm is carried separately by the specimen-provenance item below
      so that it is queryable as human evidence.
  - reference: PMID:40969742
    reference_title: Penicillamine ameliorates intestinal barrier damage in dextran sulfate sodium-induced experimental colitis mice by inhibiting cuproptosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Colon mucosa specimens were obtained from healthy controls and symptomatic
      patients with UC (Mayo endoscopic score ≥ 2)
    explanation: >-
      Records that the descriptive half of the signature was measured in human UC
      colon against healthy controls, which is what makes this a human/model
      mismatch rather than a rodent-only finding. Split from the combined
      human-and-mouse sentence above so the human evidence carries its own
      evidence_source rather than being hidden under a MODEL_ORGANISM tag.
  - reference: PMID:40969742
    reference_title: Penicillamine ameliorates intestinal barrier damage in dextran sulfate sodium-induced experimental colitis mice by inhibiting cuproptosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice were treated with the copper-depleting agent tetrathiomolybdate to
      establish causality between cuproptosis and intestinal barrier damage in
      mice with DSS-induced colitis.
    explanation: >-
      The functional-rescue arm that clears part of the canonical bar exists
      only in mice, which is precisely the translational question this
      discussion records.
  - reference: PMID:41985411
    reference_title: Glutaredoxin 1 promotes intestinal epithelial cell copper toxicity in inflammatory bowel disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      with Grx1 loss inducing copper overload and cuproptosis in vitro. Copper
      chelation therapy rescued colitis progression in Grx1-/- mice.
    explanation: >-
      A second, independent chelation-rescue result, again in a mouse model and
      with the cuproptosis step demonstrated in vitro rather than in the animal.
  - reference: PMID:41985411
    reference_title: Glutaredoxin 1 promotes intestinal epithelial cell copper toxicity in inflammatory bowel disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Directly visualizing cuproptosis in vivo would represent a critical
      direction for future research.
    explanation: >-
      The authors of the strongest mechanistic study in this area state that in
      vivo demonstration of cuproptosis has not yet been achieved - the residual
      gap that keeps a cuproptosis node out of this entry.
  proposed_experiments:
  - experiment_id: exp_uc_canonical_cuproptosis_in_human_colon
    name: Canonical-cuproptosis criteria in human ulcerative colitis colon, read out against ferroptosis
    description: >-
      Close the human arm of the rodent experiments rather than repeat them.
      Take paired inflamed and uninflamed colonic biopsies from patients with
      active UC and from non-IBD controls and apply the five canonical criteria
      to the tissue itself: quantify mucosal copper, assay FDX1 and LIAS protein
      with lipoylated DLAT/DLST aggregation, measure Fe-S cluster protein
      destabilization, and then supply the rescue arm the human literature lacks
      by treating patient-derived colonic organoids and biopsy explants with
      tetrathiomolybdate or penicillamine. Run a matched ferroptosis panel
      (lipid peroxidation, GPX4, SLC7A11) on the same specimens, and use a
      ferroptosis inhibitor as a comparator arm, so that a copper-specific
      program can be separated from the iron-dependent cell death this entry
      already curates rather than confounded with it.
    experiment_type:
      preferred_term: mechanism validation study in human tissue and patient-derived organoids
    assays:
    - preferred_term: mucosal 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: lipid peroxidation and GPX4 axis profiling
    readouts:
    - name: Copper-dependent cell death separable from ferroptosis
      target: pathophysiology#Intestinal Epithelial Cell Ferroptosis
      description: >-
        Cuproptosis and ferroptosis readout panels measured on the same human UC
        specimens, with chelator and ferroptosis-inhibitor rescue arms compared
        head to head.
      direction: ALTERED
      interpretation: >-
        A copper-dependent death signal that survives ferroptosis inhibition, and
        a barrier phenotype rescued by chelation but not by a ferroptosis
        inhibitor, would justify a separate cuproptosis node; a signal abolished
        by ferroptosis inhibition would mean it is already captured.
    - name: Barrier rescue by copper chelation in human tissue
      target: pathophysiology#Epithelial Barrier Dysfunction
      description: >-
        Tight-junction protein expression and permeability in patient-derived
        colonic organoids and biopsy explants treated with tetrathiomolybdate or
        penicillamine.
      direction: RESTORED
      interpretation: >-
        Restoration of barrier integrity in human tissue would extend the rodent
        rescue result across the species boundary and resolve the mismatch this
        discussion records.
    - name: Lipoylated TCA enzyme aggregation in colonocytes
      target: pathophysiology#Impaired Colonocyte Energy Metabolism
      description: >-
        DLAT and DLST oligomerization measured in colonocytes from inflamed and
        uninflamed human UC mucosa alongside the entry's existing
        butyrate-oxidation deficit.
      direction: INCREASED
      interpretation: >-
        Aggregation restricted to inflamed mucosa would place copper-dependent
        mitochondrial injury on the existing colonocyte energy-metabolism node
        rather than requiring a new one.
    controls:
    - name: Non-IBD inflamed colon
      description: >-
        Infectious or diverticular colitis, to test whether any copper phenotype
        is specific to ulcerative colitis rather than to mucosal inflammation.
    - name: Ferroptosis inhibitor arm
      description: >-
        Ferrostatin-1 or equivalent, so that rescue attributable to copper can be
        distinguished from rescue attributable to blocking the iron-dependent
        death this entry already models.
    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 human ulcerative colitis tissue or
      patient-derived organoids, and only if the signal is separable from the
      existing ferroptosis node. Rodent-only satisfaction of the bar is not
      sufficient; if it remains rodent-only, keep the finding as a
      model-restricted mechanism recorded here.
    would_support:
    - pathophysiology#Intestinal Epithelial Cell Ferroptosis
    - pathophysiology#Epithelial Barrier Dysfunction
  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 UC- and CD-specific sources rather than the umbrella review's
    undiscriminated "inflammatory bowel disease" sentence. The parallel gap on
    Crohn_Disease is kind KNOWLEDGE_GAP rather than HUMAN_MODEL_MISMATCH,
    because the CD literature has no functional arm in any species.
- discussion_id: uc_epithelial_barrier_intrinsic_vs_downstream
  prompt: >-
    Is epithelial barrier dysfunction purely a downstream consequence of
    mucosal inflammation in this entry's pathograph, or does it also have a
    cell-intrinsic component that should feed back into the disease process?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Epithelial Barrier Dysfunction
  - experimental_models#Biopsy-derived UC colonoid air-liquid interface model
  rationale: >-
    In this entry, Epithelial Barrier Dysfunction is wired only as a sink: it
    has inbound edges from pathobiont expansion, impaired colonocyte energy
    metabolism, and epithelial ferroptosis, and no outgoing `downstream` edge
    of its own. A biopsy-derived colonoid model that removes UC epithelium
    from the inflamed tissue environment entirely and still finds graded
    architectural, differentiation, and mucus-barrier defects argues that at
    least part of the phenotype is cell-intrinsic and persists independently
    of active inflammation, rather than being wholly generated by it. That
    does not by itself justify adding a new outgoing edge — the model does
    not identify what the intrinsic defect propagates to — but it is a
    structural gap worth recording rather than silently leaving the node as a
    pure consequence.
  evidence:
  - reference: PMID:41589595
    reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UC-derived colonoid monolayers display a range of developmental and functional defects that persist in the absence of inflammation."
    explanation: Reports that the epithelial defect persists ex vivo without an active inflammatory stimulus, the basis for questioning a purely downstream-consequence model.
  notes: >-
    Raised while adding modeled_mechanisms links for the UC biopsy-derived
    colonoid model (monarch-initiative/dismech#10432).
experimental_models:
- name: Biopsy-derived UC colonoid air-liquid interface model
  description: >
    Biopsy-derived sigmoid colonoids differentiated as air-liquid interface
    monolayers to model epithelial architecture, mucus production, and
    pathobiont susceptibility in ulcerative colitis.
  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: colon
    term:
      id: UBERON:0001155
      label: colon
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  conditions:
  - ulcerative colitis
  - non-IBD control
  - pathobiont challenge
  cell_source: Patient biopsy-derived sigmoid colonic epithelial crypts expanded
    as colonoids
  culture_system: Air-liquid interface colonoid monolayers with mucus and
    pathobiont challenge assays
  publication: PMID:41589595
  findings:
  - statement: UC biopsy-derived ALI colonoid monolayers retain persistent epithelial and mucus-barrier defects outside the inflamed tissue environment
    evidence:
    - reference: PMID:41589595
      reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
      explanation: Supports persistent epithelial barrier and mucus-layer defects relevant to Epithelial Barrier Dysfunction.
    - reference: PMID:34418586
      reference_title: "Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer."
      explanation: Independently supports durable mucus-barrier defects in patient-derived UC colonoid monolayers.
  - statement: UC colonoid monolayers provide a tractable epithelial system for linking mucus defects to pathobiont susceptibility
    evidence:
    - reference: PMID:41589595
      reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "With the use of transcriptome analysis, we identified activated pathways associated with extracellular matrix formation and cell signaling, including numerous cancer-associated genes in UC ALI monolayers, which also proved significantly more susceptible to E. coli p19A."
      explanation: Links epithelial remodeling and barrier compromise to increased susceptibility to bacterial challenge, consistent with mucosal inflammation and host-microbe dysfunction.
    - reference: PMID:34418586
      reference_title: "Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Chronic inflammation in UC causes long-term changes in GCs, leading to abnormal mucus secretion."
      explanation: Supports a mechanistic connection between chronic inflammation and lasting goblet-cell secretory dysfunction in the model.
  modeled_mechanisms:
  - target: Epithelial Barrier Dysfunction
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Patient biopsy-derived colonoid monolayers reproduce graded mucus-layer
      thinning, increased permeability, and pathobiont susceptibility, and
      these defects persist ex vivo without an inflammatory stimulus.
    readouts:
    - name: Mucus layer thickness and permeability
      target: Epithelial Barrier Dysfunction
      description: Mucus layer architecture in UC ALI colonoid monolayers versus non-IBD control monolayers.
      direction: DECREASED
      interpretation: A thinner, more permeable mucus layer is the structural correlate of the barrier-dysfunction node, graded by disease severity.
      evidence:
      - reference: PMID:41589595
        reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
        explanation: Directly reports the graded mucus-layer thickness and permeability readout.
    - name: E. coli p19A susceptibility
      target: Epithelial Barrier Dysfunction
      description: Susceptibility of UC ALI colonoid monolayers to E. coli p19A challenge.
      direction: INCREASED
      interpretation: Increased susceptibility to bacterial challenge is a functional consequence of the barrier defect, linking it to pathobiont exposure.
      evidence:
      - reference: PMID:41589595
        reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "which also proved significantly more susceptible to E. coli p19A."
        explanation: Directly reports the pathobiont-susceptibility readout.
    evidence:
    - reference: PMID:41589595
      reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
      explanation: Establishes the model as informative for the Epithelial Barrier Dysfunction node.
  evidence:
  - reference: PMID:41589595
    reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
    explanation: Supports this as a patient-derived UC epithelial model with direct relevance to mucosal inflammation and barrier dysfunction.
- name: Cytokine-conditioned hiPSC-derived colon organoid UC model
  description: >
    Human induced pluripotent stem cell-derived colon organoids exposed to
    TNF-α, IFN-γ, and IL-1β to model UC-like epithelial injury and stromal
    inflammatory signaling.
  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: colon
    term:
      id: UBERON:0001155
      label: colon
  conditions:
  - ulcerative colitis-like cytokine exposure
  - TNF-α/IFN-γ/IL-1β stimulation
  - tofacitinib response testing
  cell_source: Human induced pluripotent stem cell-derived colon organoids
  culture_system: Three-dimensional colon organoid culture with pro-inflammatory
    cytokine conditioning
  publication: PMID:39435148
  findings:
  - statement: Cytokine-conditioned hiPSC colon organoids reproduce epithelial injury and inflammatory stromal responses that resemble UC tissue
    evidence:
    - reference: PMID:39435148
      reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."
      explanation: Supports alignment with Dysregulated Immune Response and Epithelial Barrier Dysfunction in a human stem-cell-derived system.
    - reference: PMID:39435148
      reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."
      explanation: Supports molecular resemblance of the model to UC tissue rather than generic cytokine injury alone.
  - statement: The model can be used to test whether cytokine-driven inflammatory outputs are pharmacologically reversible
    evidence:
    - reference: PMID:39435148
      reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib."
      explanation: Supports translational use of the model for pathway-focused drug testing in a UC-like inflammatory state.
  modeled_mechanisms:
  - target: Epithelial Barrier Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Exogenous TNF-alpha/IFN-gamma/IL-1beta conditioning of healthy hiPSC
      colon organoids produces epithelial damage whose molecular signature
      resembles UC patient colon tissue.
    limitations: >-
      This is a healthy-background organoid exposed to an exogenous cytokine
      cocktail, so it models the downstream consequences of a UC-like
      cytokine milieu, not UC's own genetic or microbial aetiology.
    evidence:
    - reference: PMID:39435148
      reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."
      explanation: Establishes the model as informative for the Epithelial Barrier Dysfunction node.
  - target: Dysregulated Immune Response
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cytokine-conditioned hiPSC colon organoids show inflammatory stromal
      responses whose molecular signature resembles UC patient colon, with a
      pharmacologically reversible cytokine output.
    limitations: >-
      The inflammatory state is imposed exogenously rather than arising from
      the patient's own genetically susceptible immune response, so the model
      captures the cytokine-output arm of this node rather than its upstream
      genetic-susceptibility trigger.
    readouts:
    - name: Tofacitinib-mediated cytokine attenuation
      target: Dysregulated Immune Response
      description: Inflammatory cytokine production in 3CK-treated hiPSC colon organoids with and without tofacitinib.
      direction: RESTORED
      interpretation: >-
        A JAK-inhibitor rescue arm that reduces the cytokine output supports
        treating the elevated cytokine production as the node's own output
        rather than an incidental correlate.
      evidence:
      - reference: PMID:39435148
        reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib."
        explanation: Directly reports the pharmacological rescue readout.
    evidence:
    - reference: PMID:39435148
      reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."
      explanation: Establishes the model as informative for the Dysregulated Immune Response node.
  evidence:
  - reference: PMID:39435148
    reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."
    explanation: Supports this as a human iPSC-derived organoid model with molecular similarity to UC tissue.
- name: Human colon-on-chip mucus barrier model
  description: >
    Microfluidic human colon chip lined by primary patient-derived colonic
    epithelial cells to model mucus bilayer formation and inflammatory control
    of mucus hydration.
  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: colon
    term:
      id: UBERON:0001155
      label: colon
  cell_types:
  - preferred_term: Colonic Epithelial Cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  conditions:
  - mucus barrier physiology
  - prostaglandin E2 stimulation
  - ulcerative colitis-relevant mucus barrier dysfunction
  cell_source: Primary patient-derived colonic epithelial cells
  culture_system: Microfluidic colon-on-chip device with live imaging of mucus
    layer formation
  publication: PMID:31778828
  findings:
  - statement: The colon chip reproduces human colonic mucus bilayer structure, making it useful for mechanistic study of mucus-barrier defects relevant to UC
    evidence:
    - reference: PMID:31778828
      reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Colon Chip supports spontaneous goblet cell differentiation and accumulation of a mucus bilayer with impenetrable and penetrable layers, and a thickness similar to that observed in the human colon, while maintaining a subpopulation of proliferative epithelial cells."
      explanation: Supports physiologic mucus-barrier fidelity in a human colon microphysiological system relevant to UC barrier biology.
    - reference: PMID:31778828
      reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer."
      explanation: Supports inclusion as a restrained UC-adjacent organ-on-chip bridge rather than a direct disease-specific UC model.
  - statement: The chip captures inflammatory mediator effects on mucus hydration without requiring animal models
    evidence:
    - reference: PMID:31778828
      reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Live imaging of the mucus layer formation on-chip showed that stimulation of the colonic epithelium with prostaglandin E2, which is increased during inflammation, causes rapid mucus volume expansion via an Na-K-Cl cotransporter 1 ion channel-dependent increase in its hydration state, but no increase in de novo mucus secretion."
      explanation: Connects the platform to inflammatory mediator responses relevant to mucosal inflammation and mucus-layer physiology in UC.
  modeled_mechanisms:
  - target: Epithelial Barrier Dysfunction
    relationship: MEASURES
    fidelity: LOW
    description: >-
      The chip measures how an inflammatory mediator, prostaglandin E2,
      changes mucus hydration in normal colonic epithelium.
    limitations: >-
      This is a healthy-physiology model built from non-UC primary cells; no
      UC-derived tissue is studied. The PGE2 effect is a hydration-state
      change in an already-formed mucus layer, not new mucus production, so
      it does not speak to the goblet-cell depletion or mucus-loss claims
      this node makes.
    readouts:
    - name: Mucus volume expansion after prostaglandin E2 stimulation
      target: Epithelial Barrier Dysfunction
      description: Live-imaged mucus layer hydration state after PGE2 stimulation of the colonic epithelium on-chip.
      direction: INCREASED
      interpretation: >-
        PGE2-driven hydration expansion is an acute inflammatory-mediator
        effect on an intact mucus layer, distinct from the goblet-cell
        depletion and mucus-loss process this node otherwise describes.
      evidence:
      - reference: PMID:31778828
        reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Live imaging of the mucus layer formation on-chip showed that stimulation of the colonic epithelium with prostaglandin E2, which is increased during inflammation, causes rapid mucus volume expansion via an Na-K-Cl cotransporter 1 ion channel-dependent increase in its hydration state, but no increase in de novo mucus secretion."
        explanation: Directly reports the PGE2 hydration readout and its limits.
    evidence:
    - reference: PMID:31778828
      reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer."
      explanation: The entry's own hedge that this is a restrained UC-adjacent bridge, matching the LOW fidelity and MEASURES relationship recorded here.
  evidence:
  - reference: PMID:31778828
    reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A human colon-on-a-chip (Colon Chip) microfluidic device lined by primary patient-derived colonic epithelial cells was used to recapitulate mucus bilayer formation, and to visualize mucus accumulation in living cultures noninvasively."
    explanation: Supports this as a human colon organ-on-chip platform for studying mucus-barrier mechanisms relevant to UC.
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 UC-associated dysbiosis including loss
    of
    keystone SCFA producers (F. prausnitzii, Roseburia, Eubacterium rectale) and expansion
    of pathobionts (Fusobacterium, Enterobacteriaceae). Supports colonocyte energy
    metabolism
    modeling.
  model_type: GENOME_SCALE_METABOLIC
  repository_url: https://www.vmh.life/
  publication: PMID:36543475
  notes: Nature Biotechnology 2022 - strain-level resolution for butyrate
    producer depletion studies
- name: MICOM Community Metabolic Model
  description: >
    Metagenome-scale modeling framework for simulating metabolic interactions in the
    gut microbiota. Models decreased butyrate production, impaired colonocyte energy
    metabolism, and Anna Karenina effect (increased community instability) observed
    in
    UC. Integrates with dietary intervention modeling.
  model_type: GENOME_SCALE_METABOLIC
  model_software: COBRApy
  publication: PMID:31964767
  notes: mSystems 2020 - enables personalized SCFA flux predictions from patient
    metagenomes
- name: Host-Microbiome Multi-Objective Optimization Model
  description: >
    Integrated metabolic model combining human colonic epithelial cell metabolism
    with
    gut microbiome community models. Predicts metabolic crosstalk disruption in UC,
    including butyrate deprivation effects on colonocyte beta-oxidation and tight
    junction
    maintenance.
  model_type: GENOME_SCALE_METABOLIC
  publication: PMID:38729159
  notes: iScience 2024 - models host-microbiome metabolic interactions at
    community scale
datasets:
# CELLxGENE - IBD single-cell atlas
- accession: "cellxgene:7c7bd6c2-925b-4034-baab-620ef1b760e1"
  title: Human inflammatory bowel disease (IBD) and healthy control 10x Single-cell transcriptomics data
  description: >-
    Single-cell transcriptomic atlas of human inflammatory bowel disease including
    ulcerative colitis and Crohn disease samples alongside healthy controls.
    Characterizes immune and epithelial cell populations in inflamed intestinal
    tissue.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: colon tissue
    tissue_term:
      preferred_term: colon
      term:
        id: UBERON:0001155
        label: colon
  conditions:
  - ulcerative colitis
  - Crohn disease
  - normal
  publication: PMID:37488103
  notes: CZI CELLxGENE collection. DOI 10.1038/s41467-023-40156-6. Covers both UC and CD for comparative analysis.

references:
- reference: DOI:10.1038/s41590-024-01994-8
  title: A longitudinal single-cell atlas of anti-tumour necrosis factor
    treatment in inflammatory bowel disease
  findings: []
- reference: DOI:10.1038/s41591-024-02895-x
  title: Single-cell transcriptomic analyses reveal distinct immune cell
    contributions to epithelial barrier dysfunction in checkpoint inhibitor
    colitis
  findings: []
- reference: DOI:10.3389/fcimb.2025.1626614
  title: 'Fucoidan as a therapeutic agent for ulcerative colitis: mechanisms of action
    and modulation of the gut microbiota'
  findings: []
- reference: DOI:10.3390/biomedicines13020305
  title: Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases
  findings: []
- reference: DOI:10.3748/wjg.v30.i3.252
  title: SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3
    inflammasome-mediated pyroptosis
  findings: []

📚

References & Deep Research

References

DOI:10.1038/s41590-024-01994-8

A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

No top-level findings curated for this source.

DOI:10.1038/s41591-024-02895-x

Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis

No top-level findings curated for this source.

DOI:10.3389/fcimb.2025.1626614

Fucoidan as a therapeutic agent for ulcerative colitis: mechanisms of action and modulation of the gut microbiota

No top-level findings curated for this source.

DOI:10.3390/biomedicines13020305

Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases

No top-level findings curated for this source.

DOI:10.3748/wjg.v30.i3.252

SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis

No top-level findings curated for this source.

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: Ulcerative Colitis
Category: Complex
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 24

Key Pathophysiology Nodes

Mucosal Inflammation
Dysregulated Immune Response
Epithelial Barrier Dysfunction
Loss of Microbial Diversity
Loss of Keystone SCFA Producers
Pathobiont Expansion
Decreased Butyrate Production
Impaired Colonocyte Energy Metabolism
Increased Microbial Community Instability
NLRP3 Inflammasome-Mediated Pyroptosis
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1016/s0140-6736(24
DOI:10.1038/s41590-024-01994-8
DOI:10.1038/s41591-024-02895-x
DOI:10.3389/fcimb.2025.1626614
DOI:10.3390/biomedicines13020305
DOI:10.3748/wjg.v30.i3.252

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 16 citations 2025-12-17T23:36:06.449854

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Ulcerative Colitis
MONDO ID: (if available)
Category: Complex

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Ulcerative Colitis. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Disease Pathophysiology Research Report: Ulcerative Colitis (UC)

Target Disease - Disease Name: Ulcerative Colitis - MONDO ID: (not specified) - Category: Complex

Overview and core concepts Ulcerative colitis is a chronic, relapsing inflammatory disease of the colonic mucosa characterized by a breakdown of epithelial barrier integrity, dysregulated mucosal immune responses to luminal antigens, and perturbations of the gut microbial ecosystem. Recent single-cell and spatial multi-omic studies in 2023–2024 refine this model, linking interferon-rich immune niches, epithelial injury, and myeloid–stromal networks to treatment response and resistance, and highlighting actionable axes such as IL-23/Th17, epithelial alarmins, pyroptosis, and microbiome-derived metabolites. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3, jairath2024il23inhibitionfor pages 1-2)

1) Core Pathophysiology - Barrier failure and epithelial injury - Loss of mucus barrier and goblet cell dysfunction with altered mucin biochemistry are hallmarks in UC, weakening physical segregation of microbes and epithelium and amplifying inflammatory signaling. “Mucus layer loss in UC, with reduced number/size of goblet cells and decreased MUC2 glycosylation” has been emphasized in recent syntheses. (calvez2025novelinsightsinto pages 2-4) URL: https://doi.org/10.3390/biomedicines13020305 (2025; review synthesizing recent primary findings) - Advanced endo-microscopy and spatial tools underscore barrier healing as a key endpoint; barrier assessment predicts outcomes and therapeutic response, and integrates tight junction abnormalities (ZO-1, claudins) with epithelial ultrastructure in vivo. (thomas2024alongitudinalsinglecell pages 1-2) URL: https://doi.org/10.1038/s41590-024-01994-8 (Oct 2024) - Immune network dysfunction and IFN signaling niches - A 1-million-cell single-cell atlas of adalimumab-treated IBD localized “interferon (IFN)-response signatures … to T cell aggregates and epithelial damage in both CD and UC,” and in non-remission, UC exhibited “increased multi-cellular IFN signalling,” implicating IFN-programmed multicellular niches in ongoing epithelial injury. (thomas2024alongitudinalsinglecell pages 1-2) URL: https://doi.org/10.1038/s41590-024-01994-8 (Oct 2024) - In checkpoint inhibitor colitis (mechanistically overlapping with UC at the tissue level), single-cell multi-omics identified neutrophil-rich infiltrates, epithelial apoptosis, and endothelial hypoxia programs as components of barrier dysfunction, supporting generalizable injury pathways. (thomas2024singlecelltranscriptomicanalyses pages 1-3) URL: https://doi.org/10.1038/s41591-024-02895-x (May 2024) - Cytokine axes - IL‑23/Th17 axis: IL‑23 is a hierarchically dominant cytokine in IMIDs; it expands and stabilizes Th17 cells, driving IL‑17A/F, IL‑22, TNF, IFN‑γ, and IL‑26 and engaging ILC3/γδ T cells. Selective IL‑23p19 inhibitors show strong efficacy in IBD. (jairath2024il23inhibitionfor pages 1-2) URL: https://doi.org/10.1016/S0140-6736(24)01750-1 (Oct 2024) - Type 2 alarmins (IL‑33/TSLP/IL‑25) and innate circuits contribute to epithelial–immune crosstalk and can promote repair or inflammation context‑dependently; these are enriched in epithelial compartments and interact with ILC2s and T cells in inflamed mucosa (supported by 2024–2025 scRNA‑seq and reviews). (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Programmed cell death (PCD) - Inflammasome–pyroptosis: UC tissues show inflammasome activation and epithelial pyroptosis; 2024 work links SLC6A14 upregulation to NLRP3-mediated pyroptosis in epithelial cells, and numerous translational efforts target NLRP3–GSDMD. (gu2024slc6a14promotesulcerative pages 16-17) URL: https://doi.org/10.3748/wjg.v30.i3.252 (Jan 2024) - Microbiome–metabolite axes - SCFA deficiency and compositional dysbiosis (e.g., Bacteroides-dominant “Bact2” enterotype) correlate with impaired barrier function and proinflammatory programming; reduced butyrate is repeatedly observed and mechanistically linked to epithelial and immune modulation. (zhang2025fucoidanasa pages 5-7) URL: https://doi.org/10.3389/fcimb.2025.1626614 (2025 review summarizing 2013–2024 evidence)

2) Key molecular players - Genes/proteins (HGNC) - IL23A/IL23R (IL‑23 axis), STAT3, JAK2/TYK2 (downstream IL‑23 signaling) (jairath2024il23inhibitionfor pages 1-2) - MUC2 (goblet cell mucin), MUC1; tight junction proteins OCLN (occludin), CLDN family, TJP1 (ZO‑1) (calvez2025novelinsightsinto pages 2-4) - NLRP3, CASP1, GSDMD (pyroptosis) (gu2024slc6a14promotesulcerative pages 16-17) - Chemical entities (ChEBI) - Short-chain fatty acids (butyrate, acetate, propionate) – barrier and immunomodulatory metabolites (zhang2025fucoidanasa pages 5-7) - Cell types (CL) - Secretory epithelial lineages (goblet cells), colonocytes; myeloid subsets (inflammatory monocytes/macrophages), neutrophils (NET‑forming); T cell aggregates (tissue-resident memory), ILC3/ILC2; endothelial and fibroblast stromal subsets (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Anatomical locations (UBERON) - Colonic mucosa, lamina propria, epithelial barrier, vascular endothelium; inflamed niches spatially adjacent to epithelial damage (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3)

3) Biological processes (GO annotations, representative) - Barrier and epithelial processes: “epithelial cell differentiation,” “mucin biosynthetic process,” “tight junction assembly,” “epithelial cell apoptotic process” (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Immune signaling: “response to interferon,” “IL‑23 signaling pathway,” “Th17 cell differentiation,” “neutrophil activation,” “NET formation,” “inflammatory response” (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2) - Inflammasome and PCD: “inflammasome complex assembly,” “pyroptosis” (GO:0070269), “caspase‑1 activation” (gu2024slc6a14promotesulcerative pages 16-17) - Metabolite–host: “response to short-chain fatty acid,” “regulation of intestinal epithelial cell proliferation by microbiome” (zhang2025fucoidanasa pages 5-7)

4) Cellular components (GO CC) - Apical junctional complex (tight junctions: occludin, claudins, ZO‑1); mucus layer (MUC2-rich), lamina propria immune aggregates; NLRP3 inflammasome (cytosolic); endothelial lining and perivascular stromal niches (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3)

5) Disease progression model - Initiation: genetic susceptibility and environmental triggers lead to barrier weakening (mucus depletion, TJ disruption) permitting microbial and metabolite translocation. - Amplification: APCs overproduce IL‑23, licensing Th17/ILC3 circuits; epithelial alarmins (IL‑33/TSLP/IL‑25) activate innate lymphoid and myeloid cells; neutrophils infiltrate and form NETs; IFN-programmed multicellular niches form around T cell aggregates adjacent to epithelial injury. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Epithelial injury/death: IFN and TNF signaling, neutrophil proteases/ROS and pyroptosis (NLRP3–caspase‑1–GSDMD) drive epithelial apoptosis/pyroptosis and barrier loss. (thomas2024singlecelltranscriptomicanalyses pages 1-3, gu2024slc6a14promotesulcerative pages 16-17) - Chronicity: dysbiosis with SCFA depletion sustains inflammation and barrier dysfunction; stromal/endothelial remodeling and hypoxia stabilize inflammatory niches; outcomes (remission vs nonremission) track with persistence of IFN signaling and inflammatory myeloid/T cell states under therapy. (thomas2024alongitudinalsinglecell pages 1-2, zhang2025fucoidanasa pages 5-7, thomas2024singlecelltranscriptomicanalyses pages 1-3)

6) Phenotypic manifestations (HP terms, representative) - Bloody diarrhea, abdominal pain, urgency, weight loss; endoscopic mucosal friability and ulceration; histology: crypt abscesses, neutrophilic infiltration, goblet cell depletion, epithelial apoptosis. Mechanistically linked to epithelial barrier failure, neutrophil/NET activity, IFN and IL‑23-driven inflammation. (thomas2024singlecelltranscriptomicanalyses pages 1-3, jairath2024il23inhibitionfor pages 1-2)

Recent developments and latest research (2023–2024 priority) - Single-cell therapeutic atlas (anti‑TNF): “interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage” and “increased multi-cellular IFN signalling (UC)” predicted nonremission, connecting IFN niches to treatment dynamics. (thomas2024alongitudinalsinglecell pages 1-2) - Checkpoint inhibitor colitis single-cell: identified epithelial apoptosis, neutrophil enrichment, and endothelial hypoxia programs linked to barrier dysfunction; mechanistic pathways overlap with UC. (thomas2024singlecelltranscriptomicanalyses pages 1-3) - IL‑23 pathway synthesis and therapy: IL‑23 drives Th17 effectors across IMIDs; selective IL‑23p19 inhibitors demonstrate efficacy with rationale grounded in STAT3/JAK2–TYK2 signaling. (jairath2024il23inhibitionfor pages 1-2) - Pyroptosis evidence: UC epithelium exhibits NLRP3–caspase‑1–GSDMD activation; SLC6A14 promotes UC progression by facilitating NLRP3-mediated pyroptosis, pointing to epithelial metabolic–inflammasome crosstalk as a target. (gu2024slc6a14promotesulcerative pages 16-17) - Barrier biomarkers: serum occludin decreased, claudin‑2 and zonulin increased in IBD; anti‑TNF treatment improved these markers in UC, suggesting systemic readouts of barrier integrity. (thomas2024alongitudinalsinglecell pages 1-2)

Current applications and implementations - Biologics and small molecules - Anti‑TNF (e.g., adalimumab): cellular remission associates with dampened IFN multicellular signaling in UC; nonresponders show persistent IFN niches. (thomas2024alongitudinalsinglecell pages 1-2) - Anti‑integrin (vedolizumab): targets lymphocyte trafficking; single-cell/spatial analyses reveal broader effects on myeloid and stromal subsets contributing to epithelial injury and may correlate with response signatures. (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Anti‑IL‑23 (p19) agents: strong clinical efficacy with mechanistic rationale in UC; ongoing head-to-head and biomarker discovery efforts. (jairath2024il23inhibitionfor pages 1-2) - Biomarkers and imaging - Barrier-focused biomarkers (occludin, claudin‑2, zonulin) and advanced endoscopic/spatial imaging to quantify junctional integrity and epithelial healing are emerging to guide therapy. (thomas2024alongitudinalsinglecell pages 1-2)

Expert opinions and authoritative analysis - The Lancet 2024 perspective on IL‑23 positions p19 blockade as mechanistically superior to p40 for UC and related IMIDs, arguing IL‑23’s centrality in Th17‑driven mucosal inflammation and outlining JAK–STAT signaling dependencies and cell targets beyond Th17, such as ILC3s. (jairath2024il23inhibitionfor pages 1-2) - Single-cell therapeutic atlases (Nature Immunology 2024) reframe resistance to anti‑TNF around persistent IFN niches and pretreatment epithelial/myeloid states, underscoring the need for biomarkers capturing epithelial–immune–stromal crosstalk. (thomas2024alongitudinalsinglecell pages 1-2)

Relevant statistics and recent data - Cell atlas scale: ~1,000,000 gut single-cell transcriptomes, 216 biopsies, 41 subjects; pretreatment epithelial and myeloid differences correlated with remission; nonremission in UC linked to increased multicellular IFN signaling. (thomas2024alongitudinalsinglecell pages 1-2) - Barrier biomarkers: occludin (AUC ~0.96), claudin‑2 (AUC ~0.86–0.90), zonulin (AUC ~0.74 for CD) in distinguishing IBD from controls; improvement after anti‑TNF in UC (study details summarized alongside the anti‑TNF atlas context). (thomas2024alongitudinalsinglecell pages 1-2)

Ontology-aligned annotations (examples) - HGNC: IL23A, IL23R, STAT3, MUC2, OCLN, CLDN2, TJP1, NLRP3, CASP1, GSDMD. (jairath2024il23inhibitionfor pages 1-2, calvez2025novelinsightsinto pages 2-4, gu2024slc6a14promotesulcerative pages 16-17) - GO BP: response to interferon; Th17 cell differentiation; mucin biosynthetic process; tight junction assembly; inflammasome complex assembly; pyroptosis. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, calvez2025novelinsightsinto pages 2-4, gu2024slc6a14promotesulcerative pages 16-17) - GO CC: apical junction complex; mucus layer; NLRP3 inflammasome; endothelial cell of vasculature. (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3) - CL: goblet cell, colonocyte, neutrophil, monocyte/macrophage, CD4+ and CD8+ tissue-resident T cells, ILC2/ILC3, endothelial cell, fibroblast. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - UBERON: colon mucosa (UBERON:0001155), lamina propria, intestinal epithelium, colonic endothelium. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - CHEBI: butyrate (CHEBI:30089), acetate (CHEBI:15343), propionate (CHEBI:17295). (zhang2025fucoidanasa pages 5-7)

Embedded evidence quotes

"spatial/system-level analyses identified interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in both CD and UC." (thomas2024alongitudinalsinglecell pages 1-2)

"nonremitters displayed disease progression ... increased multi-cellular IFN signalling (UC)." (thomas2024alongitudinalsinglecell pages 1-2)

"neutrophilic infiltrates and increased intraepithelial lymphocytes and epithelial apoptosis." (thomas2024singlecelltranscriptomicanalyses pages 1-3)

"IL-23 (a p19-containing heterodimer sharing p40 with IL-12) promotes expansion and stabilization of Th17 cells that secrete IL-17A/F, IL-22, TNFα, IFNγ, and IL-26." (jairath2024il23inhibitionfor pages 1-2)

"promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis." (gu2024slc6a14promotesulcerative pages 16-17)

"mucus layer loss in UC, with reduced number/size of goblet cells and decreased MUC2 glycosylation." (calvez2025novelinsightsinto pages 2-4)

"reduced butyrate and other SCFAs in disease." (zhang2025fucoidanasa pages 5-7)

Blockquote: Concise, directly quoted findings from recent single-cell and review studies highlighting IFN signatures and epithelial damage, neutrophil/epithelial injury, IL-23/Th17 biology, NLRP3‑pyroptosis, mucus/goblet cell loss, and SCFA depletion in UC (context citations included).

Evidence items (with links) - Thomas et al., Nature Immunology 2024: single-cell anti‑TNF atlas in IBD; IFN-response niches adjacent to epithelial damage; increased IFN signaling in UC nonremission. DOI: 10.1038/s41590-024-01994-8; Published Oct 22, 2024. URL: https://doi.org/10.1038/s41590-024-01994-8 (thomas2024alongitudinalsinglecell pages 1-2) - Thomas et al., Nature Medicine 2024: checkpoint inhibitor colitis scRNA‑seq; neutrophils, epithelial apoptosis, endothelial hypoxia signature linked to barrier dysfunction. DOI: 10.1038/s41591-024-02895-x; May 2024. URL: https://doi.org/10.1038/s41591-024-02895-x (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Jairath et al., The Lancet 2024: IL‑23 inhibition across chronic inflammatory diseases; mechanistic grounding of UC efficacy via Th17/ILC3 and STAT3 signaling. DOI: 10.1016/S0140-6736(24)01750-1; Oct 2024. URL: https://doi.org/10.1016/S0140-6736(24)01750-1 (jairath2024il23inhibitionfor pages 1-2) - Gu et al., World Journal of Gastroenterology 2024: SLC6A14 promotes NLRP3‑mediated pyroptosis in UC epithelial cells. DOI: 10.3748/wjg.v30.i3.252; Jan 2024. URL: https://doi.org/10.3748/wjg.v30.i3.252 (gu2024slc6a14promotesulcerative pages 16-17) - Calvez et al., Biomedicines 2025: review synthesizing mucus/goblet cell defects in UC and innate immune roles. DOI: 10.3390/biomedicines13020305; Jan 2025. URL: https://doi.org/10.3390/biomedicines13020305 (calvez2025novelinsightsinto pages 2-4) - Zhang, Frontiers in Cellular and Infection Microbiology 2025: review summarizing 2013–2024 evidence of dysbiosis, pathobionts, and SCFA depletion in UC. DOI: 10.3389/fcimb.2025.1626614; Jul 2025. URL: https://doi.org/10.3389/fcimb.2025.1626614 (zhang2025fucoidanasa pages 5-7)

Limitations and notes - While we prioritized 2023–2024 primary sources, several synthesized statements on mucus/goblet cell and SCFA biology derive from high-level reviews that consolidate earlier primary studies. Future iterations may add more 2023–2024 primary metabolomics studies as they become available.

Conclusions Modern single-cell and spatial analyses in 2024 demonstrate that UC pathophysiology emerges from integrated epithelial barrier failure, IFN‑rich immune niches, IL‑23/Th17 and alarmin circuits, neutrophil effector pathways (including pyroptosis), and dysbiotic metabolite milieus. These insights map onto therapeutic mechanisms and resistance—anti‑TNF response tracks with resolution of IFN multicellular programs, while IL‑23 pathway blockade is mechanistically validated. Barrier-centric biomarkers and advanced imaging are moving toward clinical implementation to better align therapy with disease biology. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3)

References

(thomas2024alongitudinalsinglecell pages 1-2): Tom Thomas, Matthias Friedrich, Charlotte Rich-Griffin, Mathilde Pohin, Devika Agarwal, Julia Pakpoor, Carl Lee, Ruchi Tandon, Aniko Rendek, Dominik Aschenbrenner, Ashwin Jainarayanan, Alexandru Voda, Jacqueline H. Y. Siu, Raphael Sanches-Peres, Eloise Nee, Dharshan Sathananthan, Dylan Kotliar, Peter Todd, Maria Kiourlappou, Lisa Gartner, Nicholas Ilott, Fadi Issa, Joanna Hester, Jason Turner, Saba Nayar, Jonas Mackerodt, Fan Zhang, Anna Jonsson, Michael Brenner, Soumya Raychaudhuri, Ruth Kulicke, Danielle Ramsdell, Nicolas Stransky, Ray Pagliarini, Piotr Bielecki, Noah Spies, Brian Marsden, Stephen Taylor, Allon Wagner, Paul Klenerman, Alissa Walsh, Mark Coles, Luke Jostins-Dean, Fiona M. Powrie, Andrew Filer, Simon Travis, Holm H. Uhlig, Calliope A. Dendrou, and Christopher D. Buckley. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nature Immunology, 25:2152-2165, Oct 2024. URL: https://doi.org/10.1038/s41590-024-01994-8, doi:10.1038/s41590-024-01994-8. This article has 47 citations and is from a highest quality peer-reviewed journal.
(thomas2024singlecelltranscriptomicanalyses pages 1-3): Molly Fisher Thomas, Kamil Slowikowski, Kasidet Manakongtreecheep, Pritha Sen, Nandini Samanta, Jessica Tantivit, Mazen Nasrallah, Leyre Zubiri, Neal P. Smith, Alice Tirard, Swetha Ramesh, Benjamin Y. Arnold, Linda T. Nieman, Jonathan H. Chen, Thomas Eisenhaure, Karin Pelka, Yuhui Song, Katherine H. Xu, Vjola Jorgji, Christopher J. Pinto, Tatyana Sharova, Rachel Glasser, PuiYee Chan, Ryan J. Sullivan, Hamed Khalili, Dejan Juric, Genevieve M. Boland, Michael Dougan, Nir Hacohen, Bo Li, Kerry L. Reynolds, and Alexandra-Chloé Villani. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nature medicine, 30:1349-1362, May 2024. URL: https://doi.org/10.1038/s41591-024-02895-x, doi:10.1038/s41591-024-02895-x. This article has 45 citations and is from a highest quality peer-reviewed journal.
(jairath2024il23inhibitionfor pages 1-2): Vipul Jairath, Maria Laura Acosta Felquer, and Raymond Jaihyun Cho. Il-23 inhibition for chronic inflammatory disease. The Lancet, 404:1679-1692, Oct 2024. URL: https://doi.org/10.1016/s0140-6736(24)01750-1, doi:10.1016/s0140-6736(24)01750-1. This article has 25 citations and is from a highest quality peer-reviewed journal.
(calvez2025novelinsightsinto pages 2-4): Valentin Calvez, Pierluigi Puca, Federica Di Vincenzo, Angelo Del Gaudio, Bianca Bartocci, Marco Murgiano, Jacopo Iaccarino, Erfan Parand, Daniele Napolitano, Daniela Pugliese, Antonio Gasbarrini, and Franco Scaldaferri. Novel insights into the pathogenesis of inflammatory bowel diseases. Biomedicines, 13:305, Jan 2025. URL: https://doi.org/10.3390/biomedicines13020305, doi:10.3390/biomedicines13020305. This article has 35 citations and is from a poor quality or predatory journal.
(gu2024slc6a14promotesulcerative pages 16-17): Qing Gu, Huan Xia, Yue-Qiong Song, Jun Duan, Yun Chen, You Zhang, He-Ping Chen, and Li Zhang. Slc6a14 promotes ulcerative colitis progression by facilitating nlrp3 inflammasome-mediated pyroptosis. World Journal of Gastroenterology, 30:252-267, Jan 2024. URL: https://doi.org/10.3748/wjg.v30.i3.252, doi:10.3748/wjg.v30.i3.252. This article has 15 citations and is from a poor quality or predatory journal.
(zhang2025fucoidanasa pages 5-7): Yating Zhang. Fucoidan as a therapeutic agent for ulcerative colitis: mechanisms of action and modulation of the gut microbiota. Frontiers in Cellular and Infection Microbiology, Jul 2025. URL: https://doi.org/10.3389/fcimb.2025.1626614, doi:10.3389/fcimb.2025.1626614. This article has 3 citations and is from a poor quality or predatory journal.

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