Crohn Disease

name: Crohn Disease
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-06T00:00:00Z'
description: A chronic inflammatory bowel disease that affects the lining of the digestive tract, causing a wide range of gastrointestinal and systemic symptoms.
category: Complex
parents:
- Inflammatory Bowel Disease
- Autoimmune Disease
has_subtypes:
- name: Ileal Crohn's Disease
  description: Involves inflammation of the ileum, the latter part of the small intestine.
  evidence:
  - reference: PMID:37377591
    reference_title: "Crohn's disease: Why the ileum?"
    supports: SUPPORT
    snippet: In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type.
    explanation: This reference supports the statement that Crohn's disease involves inflammation of the ileum, and specifies this subtype as Ileal Crohn's Disease.
  - reference: PMID:30882291
    reference_title: "How dyspepsia led to the diagnosis of Morbus Crohn."
    supports: SUPPORT
    snippet: Gastroscopy revealed severe aphthous pangastritis with biopsies showing a focal active and chronic gastritis with presence of granulomas... coloscopy showing an aphthous terminal ileum... concordant with a slightly active, mildly chronic terminal ileitis typical for Crohn's disease.
    explanation: This reference supports the claim that Crohn's disease can involve the ileum, characterizing it distinctly as terminal ileitis which is a known feature of Ileal Crohn's Disease.
  - reference: PMID:31960900
    reference_title: "Imaging Findings of Ileal Inflammation at Computed Tomography and Magnetic Resonance Enterography: What do They Mean When Ileoscopy and Biopsy are Negative?"
    supports: SUPPORT
    snippet: Crohn''s disease patients with unequivocal imaging findings of ileal inflammation at enterography despite negative ileoscopy and biopsy are likely to have active inflammatory Crohn''s disease.
    explanation: This reference highlights that Crohn's disease can manifest as inflammation of the ileum, aligning with the subtype of Ileal Crohn's Disease.
- name: Colonic Crohn's Disease
  description: Affects the colon (large intestine) with skip lesions.
  evidence:
  - reference: PMID:38437854
    reference_title: "Crohn's disease."
    supports: PARTIAL
    snippet: Commonly affecting the terminal ileum and proximal colon, Crohn's disease inflammation is often discontinuous and patchy, segmental, and transmural.
    explanation: The literature indicates that Crohn's disease can affect the colon and often presents with discontinuous, patchy inflammation. However, it is typically not limited to the colon and often involves the terminal ileum.
  - reference: PMID:11271896
    reference_title: "Crohn's disease of aphthous type: serial changes in intestinal lesions."
    supports: SUPPORT
    snippet: The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient. Typical small intestinal CD occurred in four of seven patients with marked aphthous lesions of the small intestine, whereas colonic CD occurred in two of eight patients with such aphthous lesions of the colon.
    explanation: This study shows that Crohn's disease can indeed affect the colon specifically, supporting the subtype known as Colonic Crohn's Disease.
  - reference: PMID:26906301
    reference_title: "Terminal Ileitis as a Feature of Henoch-Schönlein Purpura Masquerading as Crohn Disease in Adults."
    supports: PARTIAL
    snippet: Although ileitis can be seen in HSP, terminal ileitis is virtually pathognomonic for Crohn disease.
    explanation: The focus is on terminal ileitis, commonly seen in Crohn’s disease. It suggests that Crohn's disease frequently involves the ileum, but does not refute that the colon can also be involved.
  - reference: PMID:33278326
    reference_title: "Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine."
    supports: PARTIAL
    snippet: Changes in absorptive capacity and first-pass metabolism in the small intestine affect oral drug bioavailability.
    explanation: This study focuses on small intestine involvement in Crohn's disease but does not refute colonic involvement with skip lesions.
  - reference: PMID:28379745
    reference_title: "Endoscopic Skipping of the Terminal Ileum in Pediatric Crohn Disease."
    supports: NO_EVIDENCE
    snippet: Nearly half (36/73, 49%) of the patients with normal or nonspecific findings at ileocolonoscopy had radiologically active disease with a median length of SB involvement of 20 cm (range, 1 to > 100 cm).
    explanation: Findings indicate that Crohn's Disease can have varying and discontinuous involvement, including potentially just the colon, thereby supporting the subtype.
- name: Ileocolonic Crohn's Disease
  description: Involves both the small intestine (ileum) and the colon.
  evidence:
  - reference: PMID:33712743
    reference_title: "Location is important: differentiation between ileal and colonic Crohn's disease."
    supports: PARTIAL
    snippet: Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment.
    explanation: Although the literature acknowledges different manifestations of Crohn's disease involving the ileum and colon, it primarily discusses the broader differentiation between small-intestinal and colonic Crohn's Disease without naming or detailing specific subtypes such as Ileocolonic Crohn's Disease.
  - reference: PMID:11271896
    reference_title: "Crohn's disease of aphthous type: serial changes in intestinal lesions."
    supports: PARTIAL
    snippet: The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient.
    explanation: This provides clinical evidence of Crohn's Disease affecting both the ileum and colon in patients but does not explicitly label it as Ileocolonic Crohn's Disease.
  - reference: PMID:38294885
    reference_title: "Biologics, small molecule therapies and surgery in small bowel Crohn's disease."
    supports: SUPPORT
    snippet: The terminal ileum and small bowel (SB) are involved in 30-45% of patients with Crohn's disease, while 20% have both small and large bowel involvement.
    explanation: This literature reference supports the statement by noting that 20% of Crohn's disease cases involve both the small and large intestines, which corresponds to the description of Ileocolonic Crohn's Disease.
prevalence:
- population: Global
  percentage: 0.2-0.3
  evidence:
  - reference: PMID:37137806
    reference_title: "The global, regional, and national burden of inflammatory bowel diseases, 1990-2019: A systematic analysis for the global burden of disease study 2019."
    supports: NO_EVIDENCE
    snippet: The crude prevalence of IBD increased by 47% in 2019 globally.
    explanation: The available literature does not provide specific data on the percentage prevalence of Crohn's Disease alone globally; it talks about the prevalence of IBD as a whole.
  - reference: PMID:35930087
    reference_title: "Characteristics of adult patients newly diagnosed with Crohn's disease: interim analysis of the nation-wide inception cohort registry study of patients with Crohn's disease in Japan (iCREST-CD)."
    supports: NO_EVIDENCE
    snippet: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn''s disease after June 2016 (age >/= 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020.
    explanation: This study focuses on the prevalence and characteristics of Crohn's Disease specifically in Japan, not globally.
progression:
- phase: Onset
  age_range: 15-35
  evidence:
  - reference: PMID:33587489
    reference_title: "Age at Diagnosis Is Determinant for the Outcome of Inflammatory Bowel Disease: Is It a Myth?"
    supports: PARTIAL
    snippet: Patients were divided into a derivation (80%) cohort and a validation (20%) cohort. The primary outcome was progressive disease... In our final model, age at diagnosis older than 60 years was significantly associated with a lower risk of developing progressive disease... In patients with CD.
    explanation: The study indicates that younger patients, particularly those aged less than 60 years, are at higher risk of developing progressive Crohn's disease.
  - reference: PMID:37384664
    reference_title: "Clinical course of new-onset Crohn's disease in children and adolescents in dependency of age, initial location, initial severity level and therapy over the period 2000-2014 based on the Saxon Pediatric IBD-Registry in Germany."
    supports: REFUTE
    snippet: Logistic regression analysis of the initial characteristics showed that the age at diagnosis, gender, initial location and initial extra-intestinal manifestation are not associated with the progression of the disease.
    explanation: This study states that the progression of Crohn's disease is not linked to the initial age of diagnosis among children and adolescents.
  - reference: PMID:37266570
    reference_title: "A Novel 8-Predictors Signature to Predict Complicated Disease Course in Pediatric-onset Crohn's Disease: A Population-based Study."
    supports: PARTIAL
    snippet: The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination... Decision curve analysis confirmed the clinical utility of the model.
    explanation: Though the exact age range of 15-35 is not specifically discussed, the predictive model includes various factors that can affect disease progression, which might encompass age-related variations.
  - reference: PMID:28051217
    reference_title: "Changes of Crohn's disease phenotype over time."
    supports: NO_EVIDENCE
    snippet: Our aim was to identify the phenotype evolution of Crohn's disease over time according to the Montreal Classification and to precise predictive factors of the need for immunosuppressant treatment or surgery... without association with age, sex or smoking habits.
    explanation: This study did not find evidence associating age with the progression of Crohn's disease, focusing instead on phenotype and specific disease markers.
pathophysiology:
- name: Dysregulated Immune Response
  description: The immune system attacks the gastrointestinal tract, leading to chronic inflammation.
  downstream:
  - target: Intestinal Inflammation and Epithelial Injury
    description: Persistent immune activation sustains bowel-wall inflammation with epithelial and stromal injury in affected segments.
  - target: IL-23/Th17 Axis Dysregulation
    description: Chronic mucosal immune activation promotes sustained IL-23-driven Th17 polarization.
  evidence:
  - reference: PMID:32242028
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown.
    explanation: The statement is supported as one of the major factors causing Crohn's Disease is the dysregulated immune system attacking the gastrointestinal tract.
  - reference: PMID:36720220
    reference_title: "The landscape of immune dysregulation in Crohn's disease revealed through single-cell transcriptomic profiling in the ileum and colon."
    supports: PARTIAL
    snippet: Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors... we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications.
    explanation: This study supports the mechanism involving the immune system leading to inflammation and chronic disease in the gastrointestinal tract.
  - reference: PMID:21543977
    reference_title: "Role of the lymphatic system in the pathogenesis of Crohn's disease."
    supports: SUPPORT
    snippet: The lymphatic system is re-emerging as a critical player in inflammatory and immune processes... Recent studies reporting lymphangitis, lymphangiogenesis, bacterial infiltration and lymph node infection, immune cell trafficking, and fat-wrapping in Crohn's disease suggest altered lymph drainage and lymphatic pumping, implicating the lymphatic system as a likely player in inflammatory disorders and IBDs.
    explanation: The literature acknowledges the immune system's involvement in Crohn's Disease through various mechanisms, including lymphatic system dysfunction.
- name: Microbiome Imbalance
  description: Alterations in gut microbiota contribute to the disease mechanisms.
  downstream:
  - target: Intestinal Barrier Dysfunction
    description: Dysbiosis challenges epithelial barrier integrity and promotes abnormal host-microbiota interactions.
  - target: Dysregulated Immune Response
    description: Altered gut microbial communities shape a pathological mucosal immune response.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: This study details changes in microbial composition and reduction in species diversity as key factors in the dynamics of Crohn's Disease, thereby supporting the statement.
  - reference: PMID:18810765
    reference_title: "Crohn's disease--defect in innate defence."
    supports: SUPPORT
    snippet: This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta-defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation.
    explanation: This study indicates that defects in innate defense mechanisms allow microbial invasion, which triggers inflammation, supporting the involvement of microbiota alterations in Crohn's Disease.
  - reference: PMID:23971750
    reference_title: "Nutrigenetics, nutrigenomics and inflammatory bowel diseases."
    supports: SUPPORT
    snippet: Inflammatory bowel disease includes ulcerative colitis and Crohn's disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota.
    explanation: This article mentions the role of gut microbiota as an environmental factor in the etiology of Crohn's Disease, supporting the contribution of microbiome imbalance to disease mechanisms.
- name: Paneth Cell Autophagy Impairment
  description: Defective autophagy in Paneth cells due to mutations in autophagy genes (ATG16L1, ATG5) causes abnormal granule formation and impaired antimicrobial peptide secretion.
  cell_types:
  - preferred_term: Paneth cell
    term:
      id: CL:0000510
      label: paneth cell
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Antimicrobial Defense Deficiency
    description: Loss of Paneth cell granule secretion reduces antimicrobial peptide levels in intestinal lumen.
  evidence:
  - reference: PMID:18849966
    reference_title: "A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells."
    supports: SUPPORT
    snippet: ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway
    explanation: This study demonstrates that autophagy proteins ATG16L1 and ATG5 are essential for Paneth cell function and that defects cause granule abnormalities linked to Crohn's disease.
- name: Antimicrobial Defense Deficiency
  description: Reduced secretion of antimicrobial peptides (defensins, lysozyme) allows increased bacterial translocation across the intestinal epithelium.
  biological_processes:
  - preferred_term: Antimicrobial humoral response
    term:
      id: GO:0019730
      label: antimicrobial humoral response
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Intestinal Barrier Dysfunction
    description: Loss of antimicrobial peptide defense permits microbial encroachment at the epithelial surface and increased translocation.
- name: Intestinal Barrier Dysfunction
  description: Disrupted epithelial integrity and increased permeability permit microbial translocation and amplify mucosal immune activation.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Dysregulated Immune Response
    description: Increased microbial and luminal antigen exposure drives chronic mucosal immune activation.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: Supports epithelial barrier dysfunction as a mechanistic bridge between dysbiosis and pathological immune activation in Crohn disease.
- name: Intestinal Inflammation and Epithelial Injury
  description: Active intestinal inflammation produces epithelial and stromal injury that disrupts mucosal function in Crohn disease.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: Terminal ileum
    term:
      id: UBERON:0002116
      label: ileum
  downstream:
  - target: Diarrhea
    description: Inflamed intestinal mucosa and epithelial injury perturb absorptive and secretory function, contributing to diarrheal symptoms.
  - target: Abdominal Pain
    description: Active intestinal inflammation causes abdominal pain during Crohn flares.
  - target: Fibrosis and Stricture Formation
    description: Persistent inflammatory injury promotes fibroblast activation and progressive tissue remodeling.
  evidence:
  - reference: PMID:34313550
    reference_title: "Dysbiotic microbiota interactions in Crohn's disease."
    supports: SUPPORT
    snippet: Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects.
    explanation: Supports active intestinal inflammation as a proximal tissue-level step linking barrier and immune dysregulation to Crohn manifestations.
  - reference: PMID:36720220
    reference_title: "The landscape of immune dysregulation in Crohn's disease revealed through single-cell transcriptomic profiling in the ileum and colon."
    supports: SUPPORT
    snippet: Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells.
    explanation: Supports epithelial and stromal injury as a defining feature of active Crohn inflammation in affected intestinal tissue.
- name: Macrophage Autophagy Dysfunction
  description: Impaired autophagy in lamina propria macrophages leads to defective clearance of intracellular bacteria and inflammatory cytokine release.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: Intestinal lamina propria
    term:
      id: UBERON:0001238
      label: lamina propria of small intestine
  downstream:
  - target: Dysregulated Immune Response
    description: Defective bacterial clearance and cytokine release amplify chronic intestinal inflammation.
- name: IL-23/Th17 Axis Dysregulation
  description: Overactive IL-23 signaling drives pathogenic Th17 cell differentiation and chronic intestinal inflammation.
  cell_types:
  - preferred_term: Th17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: Dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: Th17 cell differentiation
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
  - preferred_term: IL-23 signaling
    term:
      id: GO:0038155
      label: interleukin-23-mediated signaling pathway
  locations:
  - preferred_term: Intestinal mucosa
    term:
      id: UBERON:0002116
      label: ileum
- name: Fibrosis and Stricture Formation
  description: Chronic inflammation leads to fibroblast activation, extracellular matrix deposition, and intestinal strictures.
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: Tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
  locations:
  - preferred_term: Intestinal wall
    term:
      id: UBERON:0001262
      label: wall of intestine
  - preferred_term: Mesenteric adipose tissue
    term:
      id: UBERON:0015143
      label: mesenteric fat pad
  downstream:
  - target: Intestinal Obstruction
    description: Progressive stricture formation narrows the bowel lumen and produces obstructive symptoms.
- name: TL1A-Mediated T Cell Activation
  description: Tumor necrosis factor-like ligand 1A (TL1A) activates T cells through death receptor 3 (DR3), promoting inflammatory cytokine production and recruitment of myeloid cells to sites of tissue damage.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: T cell activation
    term:
      id: GO:0042110
      label: T cell activation
  locations:
  - preferred_term: Rectal mucosa
    term:
      id: UBERON:0003346
      label: mucosa of rectum
  downstream:
  - target: Dysregulated Immune Response
    description: TL1A-DR3 signaling amplifies pathogenic T-cell cytokine programs within the broader Crohn inflammatory network.
  - target: Myeloid Cell Recruitment to Perianal Tissue
    description: Activated T cells produce chemokines that recruit macrophages to perianal inflammatory sites.
- name: Myeloid Cell Recruitment to Perianal Tissue
  description: Chemokine-driven infiltration of macrophages and other myeloid cells into perianal tissues, establishing chronic inflammation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
  locations:
  - preferred_term: Perianal region
    term:
      id: UBERON:0012336
      label: perianal skin
  downstream:
  - target: Myeloid-Stromal Cell Crosstalk
    description: Recruited macrophages interact with resident fibroblasts, driving tissue remodeling.
- name: Myeloid-Stromal Cell Crosstalk
  description: Interferon-driven macrophage activation promotes fibroblast activation and matrix degradation, creating tissue disruption that leads to fistula tract formation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Type II interferon signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  locations:
  - preferred_term: Perianal region
    term:
      id: UBERON:0012336
      label: perianal skin
  downstream:
  - target: Perianal Disease
    description: Chronic myeloid-fibroblast crosstalk and tissue remodeling drive perianal fistula and abscess phenotypes.
phenotypes:
- category: Gastrointestinal
  name: Abdominal Pain
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29246562
    reference_title: "Crohn's disease."
    supports: SUPPORT
    snippet: The most frequent symptoms are abdominal pain and diarrhoea, which can seriously affect patients' quality of life.
  - reference: PMID:33946069
    reference_title: "Chronic Abdominal Pain: Gastroenterologist Approach."
    supports: SUPPORT
    snippet: In Crohn's disease, inflammation causes pain.
  - reference: PMID:35380673
    reference_title: "Pain Characteristics in Patients with Inflammatory Bowel Disease: A Monocentric Cross-Sectional Study."
    supports: SUPPORT
    snippet: The prevalence of pain was high in IBD patients ... and higher in CD patients.
  - reference: PMID:33836648
    reference_title: "Distinct clinical phenotypes for Crohn's disease derived from patient surveys."
    supports: NO_EVIDENCE
    snippet: Using the patients'' self-reported information, we identified two subpopulations of Crohn's disease; these subpopulations differ in disease severity, associations with smoking, and genetic transmission patterns.
    explanation: While this reference focuses on identifying subpopulations with varying disease severity, it underscores the heterogeneity of Crohn’s disease symptoms, indirectly supporting that abdominal pain is a frequent symptom.
  diagnostic: true
  notes: Often occurs in the right lower quadrant
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- category: Gastrointestinal
  name: Diarrhea
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: Weight Loss
  - target: Malnutrition
  - target: Dehydration
  evidence:
  - reference: PMID:22230271
    reference_title: "Diagnosis and management of Crohn's disease."
    supports: PARTIAL
    snippet: Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia.
    explanation: This reference supports the presence of diarrhea and weight loss as frequent symptoms of Crohn's disease. However, it does not explicitly discuss malnutrition as a common sequela or confirm that these phenotypes are highly frequent.
  - reference: PMID:38036713
    reference_title: "Weight loss from diagnosis of Crohn's disease to one year post-diagnosis results in earlier surgery."
    supports: PARTIAL
    snippet: Malnutrition might play a key role in the prognosis of patients with Crohn's disease (CD) ... Forty-one patients (24.8%) had body weight loss whereas 124 patients (75.2%) had no body weight loss.
    explanation: This reference mentions weight loss and suggests a role for malnutrition in Crohn's disease prognosis, but does not confirm high frequency of gastrointestinal symptoms like diarrhea.
  notes: Can be bloody or non-bloody
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
- category: Systemic
  name: Fatigue
  frequency: FREQUENT
  evidence:
  - reference: PMID:23111414
    reference_title: "Determinants of fatigue in Crohn's disease patients."
    supports: SUPPORT
    snippet: A high percentage of CD patients suffer from fatigue.
    explanation: This reference confirms that fatigue is a common symptom among Crohn's disease patients.
  - reference: PMID:37569413
    reference_title: "Fatigue in Inflammatory Joint Diseases."
    supports: SUPPORT
    snippet: Despite high prevalence and importance, the symptom is often underestimated in clinical practice.
    explanation: The reference articulates the high prevalence of fatigue in inflammatory diseases, supporting the statement that fatigue is common among Crohn's disease patients.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Gastrointestinal
  frequency: OCCASIONAL
  name: Perianal Disease
  notes: Fistulas, abscesses, skin tags
  evidence:
  - reference: PMID:15227686
    reference_title: "Perianal Crohn's disease."
    supports: PARTIAL
    snippet: Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses.
    explanation: The literature supports that perianal disease is a manifestation of Crohn's disease and lists fistulas, abscesses, and skin tags as possible manifestations. However, it does not specifically address the frequency as 'occasional'.
  - reference: PMID:15711045
    reference_title: "Fistulizing Crohn's disease."
    supports: PARTIAL
    snippet: Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%).
    explanation: The literature indicates that perianal fistulas are common in Crohn's disease, which suggests a higher frequency than 'occasional'.
  - reference: PMID:33280851
    reference_title: "A child presents with perianal symptoms - how often is this Crohn's disease?"
    supports: PARTIAL
    snippet: Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula.
    explanation: The literature supports that perianal symptoms can be an initial presentation of Crohn's disease in children, but it does not specify the frequency as 'occasional'.
- category: Gastrointestinal
  frequency: OCCASIONAL
  name: Intestinal Obstruction
  notes: Due to stricturing disease
  evidence:
  - reference: PMID:29043578
    reference_title: "Duodenal Crohn's Disease-a Diagnostic Conundrum."
    supports: SUPPORT
    snippet: The most common phenotype is stricturing disease which can lead to obstructive-like symptoms.
    explanation: The reference states that stricturing disease, a common phenotype of Crohn's disease, can lead to obstructive-like symptoms, supporting the statement that intestinal obstruction due to stricturing disease occurs occasionally in Crohn's disease.
  - reference: PMID:34014617
    reference_title: "Intestinal stricture in Crohn's disease: A 2020 update."
    supports: SUPPORT
    snippet: Approximately 70% of patients inevitably develop fibrosis-associated intestinal stricture after 10 years of CD diagnosis, which seriously affects their quality of life.
    explanation: The reference indicates that a significant proportion of Crohn's disease patients develop intestinal strictures, which can lead to obstruction, supporting the statement.
  - reference: PMID:37973225
    reference_title: "Endoscopic Management of Colonic Obstruction."
    supports: SUPPORT
    snippet: Benign etiologies of colonic obstructions include...inflammatory processes such as Crohn's disease.
    explanation: The reference confirms that inflammatory processes like Crohn's disease can lead to colonic obstructions, supporting the statement.
  phenotype_term:
    preferred_term: Intestinal Obstruction
    term:
      id: HP:0004796
      label: Gastrointestinal obstruction
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Arthritis
  notes: Can affect both large and small joints
  evidence:
  - reference: PMID:21122514
    reference_title: "The joint-gut axis in inflammatory bowel diseases."
    supports: SUPPORT
    snippet: The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies.
    explanation: The literature indicates that arthritis is a common extraintestinal manifestation of Crohn's disease, affecting both large and small joints.
  - reference: PMID:36730654
    reference_title: "The Influence of Coexisting Familial Mediterranean Fever on Crohn's Disease: Data From an FMF Endemic Area."
    supports: SUPPORT
    snippet: The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04).
    explanation: This study supports the occurrence of arthritis in Crohn's disease patients, particularly noting a higher prevalence in patients with coexisting FMF.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
- category: Dermatologic
  frequency: OCCASIONAL
  name: Erythema Nodosum
  notes: Painful nodules on shins
  evidence:
  - reference: PMID:16143688
    reference_title: "Important cutaneous manifestations of inflammatory bowel disease."
    supports: SUPPORT
    snippet: Erythema nodosum is a common cause of tender red nodules of the shins. Management includes leg elevation, NSAIDs, and potassium iodide.
    explanation: The reference confirms that erythema nodosum, characterized by tender red nodules on the shins, is associated with inflammatory bowel disease, which includes Crohn's disease.
  - reference: PMID:24746312
    reference_title: "Erythema nodosum - a review of an uncommon panniculitis."
    supports: SUPPORT
    snippet: Erythema nodosum (EN) is clinically the most frequent form of panniculitis and is considered a reactive process that may be triggered by a wide variety of stimuli. Whilst up to 55% of EN is considered idiopathic, the most common causes include infections, drugs, systemic illnesses such as sarcoidosis and inflammatory bowel disease, pregnancy, and malignancy.
    explanation: The reference supports the statement by mentioning that erythema nodosum is commonly triggered by systemic illnesses, including inflammatory bowel disease, which encompasses Crohn's disease.
  phenotype_term:
    preferred_term: Erythema Nodosum
    term:
      id: HP:0012219
      label: Erythema nodosum
- category: Ocular
  frequency: OCCASIONAL
  name: Uveitis
  notes: Inflammation of the eye
  evidence:
  - reference: PMID:2052301
    reference_title: "Ocular inflammation in Crohn's disease."
    supports: PARTIAL
    snippet: Seven patients had uveitis, eight had episcleritis, and four had anterior scleritis.
    explanation: The literature confirms that uveitis is a type of ocular inflammation associated with Crohn's disease, but it does not specify the frequency as 'occasional'.
  - reference: PMID:29102673
    reference_title: "Amblyopia due to intermediate uveitis as the presenting symptom of Crohn's disease in a 6-year-old boy."
    supports: PARTIAL
    snippet: This case of Crohn's disease and uveitis is unusual in that ocular inflammation preceded intestinal involvement, with the atypical feature of chronic intermediate uveitis.
    explanation: The literature provides a case of uveitis associated with Crohn's disease but does not specify the frequency as 'occasional'.
  phenotype_term:
    preferred_term: Uveitis
    term:
      id: HP:0000554
      label: Uveitis
- category: Systemic
  frequency: FREQUENT
  name: Fatigue
  notes: Often worsened during disease flares
  evidence:
  - reference: PMID:20456309
    reference_title: "Systematic review: fatigue in inflammatory bowel disease."
    supports: SUPPORT
    snippet: Fatigue is common, disabling yet underappreciated, in patients with chronic diseases, including inflammatory bowel disease (IBD).
    explanation: The literature explicitly states that fatigue is common in IBD, which includes Crohn's Disease.
  - reference: PMID:17560419
    reference_title: "Extra-intestinal manifestations of Crohn's disease."
    supports: PARTIAL
    snippet: Pain and depression are associated with inflammatory bowel disease, and their control benefits patients.
    explanation: This reference mentions pain and depression as associated with IBD but does not specifically mention fatigue. However, the association with other systemic symptoms suggests a partial support.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Systemic
  frequency: OCCASIONAL
  name: Fever
  notes: More common during acute flares
  evidence:
  - reference: PMID:30244270
    reference_title: "Acute febrile neutrophilic dermatosis in a patient with Crohn's disease: case report and review of the literature."
    supports: SUPPORT
    snippet: Crohn's disease is a chronic inflammatory bowel disease. The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss.
    explanation: This reference confirms that fever is a symptom associated with acute exacerbations of Crohn's disease.
  - reference: PMID:921308
    reference_title: "Crohn's disease in childhood."
    supports: SUPPORT
    snippet: In 32 patients with Crohn's disease which started in childhood, abdominal pain, diarrhoea, and weight loss were the common presenting symptoms, but unexplained fever and failure to grow were also prominent.
    explanation: This reference supports the statement by indicating that fever is a prominent symptom in patients with Crohn's disease.
  - reference: PMID:27743896
    reference_title: "Procalcitonin in Crohn's disease with fever episodes, a variable to differentiate intra-abdominal abscess from disease flares."
    supports: SUPPORT
    snippet: A frequent problem in CD is the discrimination of fever caused by exacerbated bowel inflammation or IAA.
    explanation: This reference supports the statement by highlighting that fever is a frequent issue in Crohn's disease, especially during exacerbations.
  - reference: PMID:31347993
    reference_title: "Unexplained fever in a young man with Crohn's disease: a case report and review of literature."
    supports: SUPPORT
    snippet: A 23-year-old man with a known history of Crohn's disease (CD), who underwent an ileocaecal resection for localized disease activity three months ago, suffered from persistent fever with chills since 10 days.
    explanation: This reference supports the statement by providing a case where a patient with Crohn's disease experienced persistent fever.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- category: Systemic
  name: Weight Loss
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Weight Loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Systemic
  name: Malnutrition
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Malnutrition
    term:
      id: HP:0004395
      label: Malnutrition
- category: Systemic
  name: Dehydration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Gastrointestinal
  name: Intestinal Stricture
  frequency: FREQUENT
  notes: Approximately 35% of patients develop intestinal strictures; complications requiring surgery occur in up to 70% within 10 years. Fibrostenotic disease manifestation.
- category: Gastrointestinal
  name: Perianal Fistula
  frequency: FREQUENT
  notes: Occurs in approximately 20-50% of Crohn's disease patients; often requires surgical intervention. Related to perianal abscess formation.
  phenotype_term:
    preferred_term: Perianal abscess
    term:
      id: HP:0009789
      label: Perianal abscess
- category: Gastrointestinal
  name: Transmural Inflammation
  frequency: VERY_FREQUENT
  notes: Characteristic feature of Crohn's disease affecting all layers of the intestinal wall.
  diagnostic: true
  phenotype_term:
    preferred_term: Intestinal inflammation
    term:
      id: HP:4000055
      label: Intestinal inflammation
biochemical:
- name: C-Reactive Protein (CRP)
  presence: Elevated
  evidence:
  - reference: PMID:24635486
    reference_title: "C-reactive protein in Crohn's disease: how informative is it?"
    supports: SUPPORT
    snippet: C-reactive protein (CRP) is an important acute-phase marker, produced mainly in the liver. Its production by mesenteric adipocytes has been recently stressed in Crohn's disease (CD).
    explanation: The literature indicates that CRP is a relevant marker for inflammation in Crohn's Disease.
  - reference: PMID:22868800
    reference_title: "Lipid peroxidation markers in Crohn's disease: the associations and diagnostic value."
    supports: SUPPORT
    snippet: 'MDA/TBARS were the best predictor of CD, comparable to CRP, with high specificity (MDA/TBARS sensitivity and specificity: 75% and 90%; CRP: 76% and 93%). Combined assessment of MDA/TBARS and CRP improved sensitivity (94%) corresponding with acceptable specificity (81%).'
    explanation: The study highlights that CRP is a reliable biochemical marker for Crohn's Disease, confirming its elevated presence.
  - reference: PMID:36550821
    reference_title: "An assessment of serum vitamin B12 and folate in patients with Crohn's disease."
    supports: SUPPORT
    snippet: C-reactive protein, vitamin B12, folate levels were studied along with hemogram analyses.
    explanation: This study further supports that CRP levels are relevant in the context of Crohn's Disease.
  context: General inflammation
- name: Fecal Calprotectin
  presence: Elevated
  context: Intestinal inflammation
  evidence:
  - reference: PMID:31088326
    reference_title: "Clinical value of fecal calprotectin."
    supports: SUPPORT
    snippet: Calprotectin, a cytosolic protein derived predominantly from neutrophils, is now widely used in this capacity. Calprotectin is found in various bodily fluids at concentrations proportional to the degree of inflammation, including in feces at levels roughly six times higher than in the blood. Fecal calprotectin (FCP) therefore reflects intestinal inflammation.
    explanation: The statement is supported by the literature, which indicates that fecal calprotectin levels are elevated in the context of intestinal inflammation, consistent with the presence of Crohn's Disease.
genetic:
- name: NOD2
  association: Risk Factor
  evidence:
  - reference: PMID:29358789
    reference_title: "Crohn's disease - genetic factors and progress of the disease."
    supports: SUPPORT
    snippet: 'BACKGROUND AND OBJECTIVES: Crohn''s disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC).'
    explanation: This reference states that NOD2 mutations are involved in Crohn's disease, supporting the association as a risk factor.
  - reference: PMID:23352252
    reference_title: "Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases."
    supports: SUPPORT
    snippet: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID... The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease.
    explanation: This reference confirms the association of NOD2 gene mutations with Crohn's disease.
  - reference: PMID:16773683
    reference_title: "NOD2: ethnic and geographic differences."
    supports: SUPPORT
    snippet: Investigations into the inheritance of the three risk alleles R702W, G908R and 1007fsInsC in NOD2 associated with susceptibility to Crohn's disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations.
    explanation: This reference clearly establishes the association of specific NOD2 mutations with susceptibility to Crohn's disease.
  - reference: PMID:12851870
    reference_title: "Crohn's disease and the NOD2 gene: a role for paneth cells."
    supports: SUPPORT
    snippet: The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation.
    explanation: This study supports the role of NOD2 as a genetic risk factor for Crohn's disease.
  - reference: PMID:32476786
    reference_title: "Genetic association analysis of CLEC5A and CLEC7A gene single-nucleotide polymorphisms and Crohn's disease."
    supports: SUPPORT
    snippet: While NOD2 mutations represent well established risk factors of CD, the role of other genes is incompletely understood.
    explanation: This confirms that NOD2 is a well-established genetic risk factor for Crohn's disease.
  - reference: PMID:11385577
    reference_title: "A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease."
    supports: SUPPORT
    snippet: Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease.
    explanation: This study provides evidence of a specific NOD2 mutation associated with Crohn's disease.
  - reference: PMID:17206682
    reference_title: "NOD2/CARD15 disease associations other than Crohn's disease."
    supports: SUPPORT
    snippet: The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases.
    explanation: This statement supports the association of NOD2 with Crohn's disease (CD).
  - reference: PMID:16987083
    reference_title: "Inflammatory bowel disease genetics: Nod2."
    supports: SUPPORT
    snippet: The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders.
    explanation: This reference emphasizes that the NOD2 association with Crohn's disease is well-established.
  - reference: PMID:27076762
    reference_title: "Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population."
    supports: SUPPORT
    snippet: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively.
    explanation: This study confirms the role of genetic risk scores including multiple SNP variants for predicting Crohn's disease.
- name: ATG16L1
  association: Risk Factor
  evidence:
  - reference: PMID:27698206
    reference_title: "Association between ATG16L1 gene polymorphism and the risk of Crohn's disease."
    supports: SUPPORT
    snippet: Conclusion In this meta-analysis, the ATG16L1 genotype was significantly associated with the risk of developing Crohn''s disease.
  - reference: PMID:25906181
    reference_title: "ATG16L1: A multifunctional susceptibility factor in Crohn disease."
    supports: SUPPORT
    snippet: single-nucleotide polymorphisms in ATG16L1 ... a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease.
  - reference: PMID:12840668
    reference_title: "Lessons to be learned from the NOD2 gene in Crohn's disease."
    supports: NO_EVIDENCE
    snippet: CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. Interestingly, CD patients often carry mutations on their two chromosomes suggesting a mutation dose effect.
    explanation: The reference focuses on the association between CARD15 mutations and Crohn’s Disease, with no information regarding ATG16L1.
  - reference: PMID:29795570
    reference_title: "Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population."
    supports: NO_EVIDENCE
    snippet: ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD.
    explanation: The reference highlights genetic risk factors in NOD2 and LRRK2 for Crohn's Disease, not ATG16L1.
  - reference: PMID:27076762
    reference_title: "Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population."
    supports: PARTIAL
    snippet: We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC)....The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively.
    explanation: The study involves identification of SNPs for risk prediction, however ATG16L1 is not mentioned explicitly. Thus, it only partially supports the statement.
- name: IL23R
  association: Risk Factor
  evidence:
  - reference: PMID:17068223
    reference_title: "A genome-wide association study identifies IL23R as an inflammatory bowel disease gene."
    supports: SUPPORT
    snippet: We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23.
    explanation: This study identifies IL23R as a gene significantly associated with Crohn's disease, supporting the statement that IL23R is a genetic risk factor for the condition.
  - reference: PMID:24989722
    reference_title: "Smoking behaviour modifies IL23r-associated disease risk in patients with Crohn's disease."
    supports: SUPPORT
    snippet: We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking.
    explanation: This study supports the association between IL23R and Crohn's disease, while also highlighting the interaction between IL23R variants and environmental factors like smoking.
- name: LRRK2
  association: Risk Factor
  notes: Hyperactive LRRK2 variants (e.g., G2019S, N2081D) impair autophagy and drive Paneth-cell dysfunction, leading to intestinal inflammation.
- name: TNFSF15
  association: Risk Factor
  notes: Encodes TL1A, a TNF superfamily cytokine involved in T-cell costimulation and fibroblast activation in fistulizing disease.
- name: CARD9
  association: Risk Factor
  notes: Involved in antifungal immunity; variants associated with fungal dysbiosis and impaired pathogen clearance.
- name: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: STAT3
  association: GWAS
  notes: Signal transducer mediating Th17 differentiation via JAK-STAT pathway
- name: IL10
  association: GWAS
  notes: Anti-inflammatory cytokine critical for immune tolerance
- name: CD28
  association: GWAS
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: IRF8
  association: GWAS
  notes: Interferon regulatory factor controlling myeloid cell development and type I interferon response
- name: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage commitment
- name: IKZF1
  association: GWAS
  notes: Ikaros transcription factor essential for lymphocyte development and differentiation
- name: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: PRDM1
  association: GWAS
  notes: Blimp-1 transcription factor regulating T cell and B cell terminal differentiation
- name: PTPN22
  association: GWAS
  notes: Protein tyrosine phosphatase modulating T cell receptor signaling threshold
- name: IL21R
  association: GWAS
  notes: IL-21 receptor mediating T and B cell activation and differentiation
environmental:
- name: Smoking
  notes: Increases the risk and severity of Crohn's disease.
  evidence:
  - reference: PMID:27016849
    reference_title: "[Smoking, smoking cessation and Crohn's disease]."
    supports: SUPPORT
    snippet: Smoking increases the risk of complications, recurrences and resort of surgery, corticosteroids or immunosuppressants.
    explanation: The provided literature clearly states that smoking increases the risk and severity of Crohn's disease, aligning with the statement.
  - reference: PMID:31014995
    reference_title: "Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses."
    supports: SUPPORT
    snippet: 'We identified 9 factors that increase risk of IBD: smoking (CD)...'
    explanation: The review identifies smoking as a significant environmental risk factor that increases the risk of Crohn's disease.
  - reference: PMID:38238335
    reference_title: "Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease."
    supports: SUPPORT
    snippet: Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10-10) and UC (P < 2 × 10-16) risk, respectively.
    explanation: This prospective cohort study finds that both current and previous smoking habits are associated with increased risk of CD, which supports the statement.
  - reference: PMID:28838409
    reference_title: "Epidemiology, Natural History, and Risk Stratification of Crohn's Disease."
    supports: SUPPORT
    snippet: Understanding the potential environmental risk factors and natural history of CD in a given patient guides the physician when counseling the patient and selecting a treatment strategy.
    explanation: The review discusses smoking as an important environmental risk factor, thereby supporting the statement.
  exposure_term:
    preferred_term: Tobacco smoking exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
- name: Diet
  notes: Western diet with high-fat, low-fiber content may exacerbate symptoms.
  evidence:
  - reference: PMID:33574618
    reference_title: "Fiber-poor Western diets fuel inflammation."
    supports: SUPPORT
    snippet: Fiber-poor Western diets fuel inflammation.
    explanation: This indicates that a Western diet, which is low in fiber, can contribute to inflammation, suggesting a potential exacerbation of symptoms in Crohn's Disease.
  - reference: PMID:34010595
    reference_title: "Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation."
    supports: SUPPORT
    snippet: In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction.
    explanation: This study provides a direct mechanistic link between a Western diet and compromised gut immunity, which could exacerbate Crohn's disease symptoms.
  - reference: PMID:33159156
    reference_title: "Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study."
    supports: SUPPORT
    snippet: Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02).
    explanation: This Mendelian randomization study shows lifestyle factors including diet-related factors affect Crohn's disease risk.
  - reference: PMID:35595417
    reference_title: "Diet in the Pathogenesis and Management of Crohn's Disease."
    supports: PARTIAL
    snippet: most patients report minimal nutritional education from their provider, and providers report few nutritional resources to help them educate patients.
    explanation: While this indicates the importance of diet, it also highlights a lack of resources and education surrounding the dietary management of Crohn's disease, providing partial support.
  exposure_term:
    preferred_term: Dietary exposure
- name: Stress
  notes: Can trigger flare-ups and worsen symptoms.
  evidence:
  - reference: PMID:15288007
    reference_title: "Inflammatory bowel disease: the role of environmental factors."
    supports: NO_EVIDENCE
    snippet: Stress is also associated with IBD, but more as a modifier than an inducing factor, and its contribution is more obvious in IBD animal models than human IBD.
    explanation: The literature suggests that stress is associated with IBD as a modifier and not necessarily as a direct trigger.
  - reference: PMID:31574072
    reference_title: "Disease-Related Worries in Persons With Crohn Disease: An Interview Study."
    supports: SUPPORT
    snippet: The unpredictable course of the disease, impaired function due to fatigue, and lack of bowel control were the most prominent causes of worry. The worries created feelings of stress, guilt, and frustration. The participants expressed a need to talk about their worries, to make them visible and recognized, and to be understood.
    explanation: The study indicates that stress related to the disease itself is significant among Crohn's disease patients, which supports the claim that stress can worsen symptoms.
  exposure_term:
    preferred_term: Psychological stress exposure
treatments:
- name: Aminosalicylates
  description: Anti-inflammatory drugs used for mild to moderate disease.
  evidence:
  - reference: PMID:12786608
    reference_title: "Review article: medical treatment of mild to moderately active Crohn's disease."
    supports: SUPPORT
    snippet: The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators.
    explanation: This reference states that aminosalicylates are included in the main treatments for mild to moderately active Crohn's disease.
  - reference: PMID:34797442
    reference_title: "No Benefit of Continuing 5-Aminosalicylates in Patients with Crohn's Disease Treated with Anti-metabolite Therapy."
    supports: SUPPORT
    snippet: 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease.
    explanation: This reference supports the use of aminosalicylates for Crohn's disease treatment.
  - reference: PMID:17339853
    reference_title: "Drug insight: aminosalicylates for the treatment of IBD."
    supports: REFUTE
    snippet: Sulfasalazine and mesalazine are useful for the treatment of both active and quiescent ulcerative colitis, whereas they have no clinical effect on either active or inactive Crohn's disease.
    explanation: This reference explicitly states that aminosalicylates have no clinical effect on Crohn's disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Corticosteroids
  description: Used for short-term control during flare-ups to reduce inflammation.
  evidence:
  - reference: PMID:24532122
    reference_title: "Steroid use in Crohn's disease."
    supports: SUPPORT
    snippet: Corticosteroids have been used for decades to treat active Crohn's disease and remain the mainstay in the management of moderate-to-severe relapses in Crohn's disease.
    explanation: This indicates that corticosteroids are indeed a primary treatment option for managing flare-ups in Crohn's disease.
  - reference: PMID:32653651
    reference_title: "Inflammatory Bowel Disease - Non-biological treatment."
    supports: SUPPORT
    snippet: corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease.
    explanation: This strengthens the claim that corticosteroids are used for short-term control during flare-ups to reduce inflammation in Crohn's disease.
  - reference: PMID:18239408
    reference_title: "Drug safety in Crohn's disease therapy."
    supports: SUPPORT
    snippet: The management of Crohn's disease usually consists of a succession of short-term acute phase treatments followed by a long-term maintenance therapy.
    explanation: This reinforces that corticosteroids are part of the short-term treatment strategy to control flare-ups in Crohn's disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Immunomodulators
  description: Drugs like azathioprine and methotrexate to suppress the immune response.
  evidence:
  - reference: PMID:17105689
    reference_title: "Insights in immunomodulatory therapies for ulcerative colitis and Crohn's disease."
    supports: SUPPORT
    snippet: The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus.
    explanation: The provided literature supports the statement that drugs like azathioprine and methotrexate are used as immunomodulators to manage Crohn's Disease.
  - reference: PMID:35115294
    reference_title: "Parenteral Methotrexate Is Efficient in the Treatment of Azathioprine Refractory Crohn's Disease."
    supports: SUPPORT
    snippet: Our results show that parenteral use of methotrexate is efficacious in inducing and maintaining remission as a step-up agent in azathioprine refractory Crohn's disease patients.
    explanation: The study shows the use of methotrexate in patients who are refractory to azathioprine, supporting the statement that these drugs are used to treat Crohn's Disease by mitigating immune response.
  - reference: PMID:16245637
    reference_title: "[Crohn's disease--standards of treatment 2004]."
    supports: SUPPORT
    snippet: First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications.
    explanation: This reference confirms that Azathioprine and Methotrexate are used as immunosuppressants in the treatment of Crohn's Disease.
  - reference: PMID:24913384
    reference_title: "Can we get more from our current treatments?"
    supports: SUPPORT
    snippet: The only other long term disease-modifying options are the immunomodulators, methotrexate, azathioprine and mercaptopurine.
    explanation: This review supports the use of methotrexate and azathioprine as immunomodulators for long-term management of Crohn's Disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Biologics
  description: Anti-TNF agents (infliximab, adalimumab) and integrin inhibitors (vedolizumab) for moderate to severe disease.
  evidence:
  - reference: PMID:18034589
    reference_title: "Crohn's disease: a review of current treatment with a focus on biologics."
    supports: PARTIAL
    snippet: Infliximab and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults (infliximab and adalimumab) and children (infliximab) with Crohn's disease.
    explanation: This reference supports the use of anti-TNF agents (infliximab and adalimumab) for the treatment of moderate to severe Crohn's disease but does not mention vedolizumab directly.
  - reference: PMID:26195652
    reference_title: "Vedolizumab: An integrin-receptor antagonist for treatment of Crohn's disease and ulcerative colitis."
    supports: PARTIAL
    snippet: Vedolizumab is an integrin-receptor antagonist for the treatment of CD and UC in adults with moderately to severely active disease.
    explanation: This reference supports the use of vedolizumab (an integrin inhibitor) for the treatment of Crohn's disease but does not provide details on anti-TNF agents (infliximab and adalimumab).
  - reference: PMID:26616476
    reference_title: "Anti-TNF-α therapies for the treatment of Crohn's disease: the past, present and future."
    supports: SUPPORT
    snippet: Anti-TNF-alpha therapy is a novel approach that has transformed the way moderate-to-severe Crohn's disease (CD) is treated and has significantly improved clinical outcomes of patients.
    explanation: This reference supports the use of anti-TNF agents for moderate to severe Crohn's disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Nutritional Therapy
  description: Dietary modifications and enteral nutrition to manage symptoms and maintain nutrition.
  evidence:
  - reference: PMID:19244154
    reference_title: "Enteral nutrition as a primary therapy of Crohn's disease: the pediatric perspective."
    supports: SUPPORT
    snippet: Nutrition therapy of Crohn's disease is considered the first-line of treatment for Crohn's disease in children, especially in Europe.
    explanation: This article supports the use of nutrition therapy as a treatment for managing symptoms and maintaining nutrition in Crohn’s disease.
  - reference: PMID:38276922
    reference_title: "AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review."
    supports: SUPPORT
    snippet: New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery.
    explanation: This article supports the use of enteral nutrition as an effective therapy to induce remission and manage malnutrition in Crohn's disease.
  - reference: PMID:36558412
    reference_title: "Assessment of Dietary Adequacy and Quality in a Sample of Patients with Crohn's Disease."
    supports: SUPPORT
    snippet: Both under-and over-nutrition are prevalent in patients with Crohn's Disease (CD).
    explanation: The study highlights the importance of dietary modifications to manage nutritional status in Crohn's disease patients.
  - reference: PMID:35595414
    reference_title: "Conventional Therapies for Crohn's Disease."
    supports: SUPPORT
    snippet: The primary agents used in the treatment of Crohn's disease are aminosalicylates, corticosteroids, immunomodulators, and biologics. Each agent has different roles in the induction and maintenance of remission of disease.
    explanation: While this primarily focuses on pharmacologic therapy, it does acknowledge the role of different agents in maintaining remission.
  - reference: PMID:22410431
    reference_title: "Potential value of nutrigenomics in Crohn's disease."
    supports: SUPPORT
    snippet: Although an elemental diet might lead to disease remission, reintroducing real foods and sustainable diets in patients with Crohn's disease is currently difficult, and would benefit from the sensitivity and rapid feedback provided by the field of nutrigenomics.
    explanation: This reference suggests that dietary modifications can lead to remission and maintenance of Crohn's disease, validating the role of nutritional therapy.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
- name: Surgery
  description: Removal of affected bowel segments, typically reserved for complications like strictures or fistulas.
  evidence:
  - reference: PMID:21901520
    reference_title: "Emergency and elective surgery for small bowel Crohn's disease."
    supports: SUPPORT
    snippet: The indications for surgery include the failure of medical management, especially the persistence or worsening of symptoms in spite of proper treatment and complications of the disease process. These complications include intestinal obstruction, intestinal perforation with fistula formation or abscess, free perforation, gastrointestinal bleeding, urologic complications, cancer, and perianal disease.
    explanation: The excerpt indicates that surgery is reserved for complications such as strictures or fistulas among others, thus supporting the statement.
  - reference: PMID:32279173
    reference_title: "Strictures in Crohn's Disease: From Pathophysiology to Treatment."
    supports: SUPPORT
    snippet: Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures.
    explanation: The statement mentions surgery for complications like strictures, which is supported by the snippet indicating that fibrotic strictures rely on surgical procedures for treatment.
  - reference: PMID:21975159
    reference_title: "Diagnosis and treatment of fistulising Crohn's disease."
    supports: SUPPORT
    snippet: Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas.
    explanation: The statement links surgery to the complication of fistulas, which is supported by the snippet explaining the need for intestinal resection to manage symptomatic non-perianal fistulas.
  - reference: PMID:29462390
    reference_title: "Segmental Resection versus Total Proctocolectomy for Crohn's Colitis: What is the Best Operation in the Setting of Medically Refractory Disease or Dysplasia?"
    supports: SUPPORT
    snippet: When isolated to the colon, and patients become medically refractory, there are several surgical options - segmental resection, subtotal colectomy with ileorectal anastomosis, or a total proctocolectomy and end ileostomy. Unfortunately, surgery does not cure CD, and, regardless of the extent of bowel removed, recurrence may be seen in the small bowel.
    explanation: The snippet supports the statement by discussing various surgical options for patients who are medically refractory, involving the removal of affected bowel segments.
  - reference: PMID:36926950
    reference_title: "Duodenal stenosis surgical treatment in Crohn's disease."
    supports: SUPPORT
    snippet: A partial resection of 3rd and 4th portion of the duodenum and the first loop of jejunum was performed, with duodenojejunal anastomosis.
    explanation: The provided case demonstrates a scenario where surgery was performed due to refractory disease and complications, supporting the statement.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Anti-IL-23 Biologics
  description: Biologics targeting IL-23 (e.g., ustekinumab, risankizumab) for moderate to severe Crohn's disease refractory to anti-TNF therapy.
  notes: Reflects the central role of the IL-23/Th17 axis in CD pathogenesis.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: TL1A Inhibitors
  description: Emerging precision therapy targeting TL1A-DR3 signaling for fistulizing and fibrostenotic disease.
  notes: Under clinical investigation; addresses TNF-independent inflammatory pathways in perianal disease.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: JAK Inhibitors
  description: Small molecule inhibitors targeting JAK-STAT pathway for moderate to severe disease.
  notes: Addresses interferon-driven inflammation and may benefit refractory cases.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
review_notes: Crohn disease is a type of inflammatory bowel disease that can affect any part of the GI tract but most commonly the terminal ileum and colon. Extraintestinal manifestations involving the joints, skin and eyes occur in a subset of patients. The disease is characterized by periods of remission interspersed with flares.
disease_term:
  preferred_term: Crohn disease
  term:
    id: MONDO:0005011
    label: Crohn disease
experimental_models:
- name: Primary human small-intestinal monolayer barrier model
  description: >-
    Polarized primary human small-intestinal epithelial monolayers cultured on
    Transwells to study barrier integrity, permeability, and host-microbiota
    interface biology relevant to inflammatory bowel disease.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - intestinal barrier dysfunction
  - host-microbiota interaction modeling
  - gut barrier dysfunction (IBD-adjacent)
  cell_source: Primary human small-intestinal epithelial cells
  culture_system: Polarized two-dimensional Transwell monolayer
  publication: PMID:29094594
  modeled_mechanisms:
  - target: Intestinal Barrier Dysfunction
    description: Supports permeability and barrier-integrity readouts relevant to epithelial dysfunction in Crohn disease.
  - target: Microbiome Imbalance
    description: Supports controlled host-microbiota interface experiments relevant to dysbiosis-linked epithelial dysfunction in Crohn disease.
  findings:
  - statement: Primary human small-intestinal epithelial monolayers support barrier and host-microbiota assays relevant to Crohn disease
    evidence:
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment."
      explanation: Validates the primary human intestinal model, but the cited study is not Crohn-specific.
    - reference: PMID:29094594
      reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions."
      explanation: Supports relevance to barrier and host-microbiota questions central to Crohn disease, while remaining an indirect bridge rather than direct disease evidence.
  evidence:
  - reference: PMID:29094594
    reference_title: "Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions."
    explanation: Supports inclusion as a Crohn-relevant translational model but not as a Crohn-specific organoid or disease model.
- name: Enteroendocrine-deficient intestinal enteroid barrier model
  description: >-
    Human intestinal enteroid monolayers derived from pluripotent stem
    cell-derived organoids with NEUROG3 loss, cultured on Transwell filters to
    quantify permeability and inflammatory-cytokine-sensitive epithelial
    barrier responses.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  conditions:
  - enteroendocrine-cell deficiency
  - TNF exposure
  - epithelial barrier dysfunction
  cell_source: Crypt-derived enteroids isolated from wild-type and NEUROG3-null human intestinal organoids generated from pluripotent stem cells
  culture_system: Polarized two-dimensional Transwell enteroid monolayer
  publication: PMID:40095977
  modeled_mechanisms:
  - target: Intestinal Barrier Dysfunction
    description: Directly measures transepithelial resistance and paracellular permeability in cytokine-sensitive intestinal epithelial monolayers.
  - target: Intestinal Inflammation and Epithelial Injury
    description: Models inflammatory-cytokine-associated epithelial barrier injury in a Crohn-relevant gut epithelium context.
  findings:
  - statement: Enteroendocrine-deficient intestinal enteroid monolayers show impaired barrier function that persists under inflammatory cytokine exposure
    evidence:
    - reference: PMID:40095977
      reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like \"stem\" and villus-like differentiated cultures."
      explanation: Supports the baseline barrier-defect phenotype in the enteroid model.
    - reference: PMID:40095977
      reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine-tyrosine (PYY), and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor."
      explanation: Supports cytokine-sensitive perturbation and rescue of the barrier phenotype in this model.
  evidence:
  - reference: PMID:40095977
    reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins."
    explanation: Supports inclusion as a human intestinal enteroid Transwell model that directly assays epithelial barrier dysfunction.
  - reference: PMID:40095977
    reference_title: "Enteroendocrine cells regulate intestinal barrier permeability."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier."
    explanation: Supports Crohn-relevant use as an inflammatory barrier model, while remaining broader than Crohn-specific patient tissue.
- name: PSC-derived intestinal organoid-macrophage coculture model
  description: >-
    Human pluripotent stem cell-derived intestinal organoids combined with
    matched PSC-derived macrophages to model resident myeloid-epithelial
    interactions and inflammatory cytokine responses in intestinal tissue.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: intestine
    term:
      id: UBERON:0000160
      label: intestine
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - tissue-resident macrophage coculture
  - proinflammatory signaling
  - bacterial challenge
  cell_source: Human pluripotent stem cell-derived intestinal organoids and macrophages combined in coculture
  culture_system: Three-dimensional intestinal organoid coculture with PSC-derived tissue-resident macrophages
  publication: PMID:39701210
  modeled_mechanisms:
  - target: Dysregulated Immune Response
    description: Captures macrophage cytokine responses to proinflammatory signals within a human intestinal tissue context.
  findings:
  - statement: PSC-derived intestinal organoid-macrophage cocultures provide a human immune-epithelial system for inflammatory and bacterial-response studies relevant to Crohn disease
    evidence:
    - reference: PMID:39701210
      reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "HIO macrophages could phagocytose bacteria and produced inflammatory cytokines in response to proinflammatory signals, such as lipopolysaccharide, which could be reversed with interleukin-10."
      explanation: Supports functional immune-response readouts in the coculture model.
    - reference: PMID:39701210
      reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."
      explanation: Supports Crohn-relevant use as an IBD mechanism model, while remaining broader than Crohn-specific disease tissue.
  evidence:
  - reference: PMID:39701210
    reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HIOs and macrophages were generated separately through the directed differentiation of human pluripotent stem cells and combined in vitro."
    explanation: Supports model identity as a PSC-derived intestinal organoid-macrophage coculture system.
  - reference: PMID:39701210
    reference_title: "Deriving Human Intestinal Organoids with Functional Tissue-Resident Macrophages All From Pluripotent Stem Cells."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "This new organoid system can be used to investigate the molecular mechanisms involved in inflammatory bowel disease."
    explanation: Supports inclusion as a Crohn-relevant intestinal immune-epithelial model without overstating disease specificity.
computational_models:
- name: AGORA2 Gut Microbiome Metabolic Models
  description: >
    Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of human
    gut microorganisms. Enables modeling of dysbiosis-associated metabolic shifts in CD,
    including depletion of butyrate-producing Firmicutes (F. prausnitzii, Roseburia) and
    expansion of Enterobacteriaceae. Supports integration with host intestinal epithelial
    cell models.
  model_type: GENOME_SCALE_METABOLIC
  repository_url: https://www.vmh.life/
  publication: PMID:36543475
  notes: Nature Biotechnology 2022 - includes strain-level resolution for studying CD-associated dysbiosis patterns
- name: MICOM Community Metabolic Model
  description: >
    Metagenome-scale modeling framework for simulating metabolic interactions in the
    gut microbiota. Integrates dietary constraints and taxon abundances from metagenomic
    data to predict SCFA production deficits, cross-feeding network disruption, and
    pathobiont metabolic niches characteristic of CD dysbiosis.
  model_type: GENOME_SCALE_METABOLIC
  model_software: COBRApy
  publication: PMID:31964767
  findings:
  - statement: Community-level SCFA production is heterogeneous and highly individual-specific
    evidence:
    - reference: PMID:31964767
      reference_title: "MICOM: Metagenome-Scale Modeling To Infer Metabolic Interactions in the Gut Microbiota."
      supports: SUPPORT
      snippet: "the community-level production of short-chain fatty acids (SCFAs) was heterogeneous and highly individual specific"
      explanation: MICOM reveals personalized SCFA flux profiles relevant to understanding IBD heterogeneity.
  - statement: Model output reveals complex cross-feeding interactions that would be difficult to measure in vivo
    evidence:
    - reference: PMID:31964767
      reference_title: "MICOM: Metagenome-Scale Modeling To Infer Metabolic Interactions in the Gut Microbiota."
      supports: SUPPORT
      snippet: "Model output revealed complex cross-feeding interactions that would be difficult to measure in vivo"
      explanation: Enables mechanistic understanding of metabolic networks disrupted in CD dysbiosis.
  notes: mSystems 2020 - enables personalized microbiome metabolic modeling; applied to IBD cohorts
- name: Host-Microbiome Multi-Objective Optimization Model
  description: >
    Integrated metabolic model combining human intestinal epithelial cell (IEC) metabolism
    with gut microbiome community models. Uses multi-objective optimization to predict
    competition, mutualism, and neutralism between host and microbial metabolism. Models
    SCFA exchange, amino acid cross-feeding, and metabolic interactions disrupted in CD.
  model_type: GENOME_SCALE_METABOLIC
  publication: PMID:38729159
  notes: iScience 2024 - framework for quantifying host-microbiome metabolic crosstalk
classifications:
  harrisons_chapter:
  - classification_value: digestive system disorder
  - classification_value: inflammatory bowel disease
  - classification_value: autoimmune disease