name: Ulcerative Colitis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
category: Complex
parents:
- Gastrointestinal Disease
- Autoimmune Disease
disease_term:
preferred_term: ulcerative colitis
term:
id: MONDO:0005101
label: ulcerative colitis
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
evidence:
- reference: PMID:38314135
supports: PARTIAL
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
supports: PARTIAL
snippet: "We generated ~1 million single-cell transcriptomes, organised into 109
cell states, from 216 gut biopsies (41 subjects), revealing disease-specific
differences."
explanation: Single-cell analysis of UC gut biopsies reveals
disease-specific inflammatory cell states in 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
evidence:
- reference: PMID:39438660
supports: PARTIAL
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
supports: PARTIAL
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
supports: PARTIAL
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
evidence:
- reference: PMID:39438660
supports: PARTIAL
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
supports: PARTIAL
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
supports: PARTIAL
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
supports: PARTIAL
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: modification by symbiont of host morphology or physiology
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
supports: PARTIAL
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
supports: PARTIAL
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. demonstrated F. prausnitzii depletion is
consistently observed in IBD.
- reference: PMID:18936492
supports: PARTIAL
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
supports: PARTIAL
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
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
supports: PARTIAL
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: pyroptosis
evidence:
- reference: PMID:38314135
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
supports: SUPPORT
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
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.
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
supports: PARTIAL
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
- name: Urgency
category: Gastrointestinal
frequency: VERY_FREQUENT
notes: Fecal urgency
phenotype_term:
preferred_term: Fecal Incontinence
term:
id: HP:0002607
label: Bowel incontinence
- name: Tenesmus
category: Gastrointestinal
frequency: FREQUENT
phenotype_term:
preferred_term: Tenesmus
term:
id: HP:0025085
label: Bloody diarrhea
- name: Weight Loss
category: Systemic
frequency: FREQUENT
phenotype_term:
preferred_term: Weight Loss
term:
id: HP:0001824
label: Weight loss
- name: Fatigue
category: Systemic
frequency: FREQUENT
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- name: Anemia
category: Hematologic
frequency: FREQUENT
notes: Iron deficiency from blood loss
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
biochemical:
- name: Fecal Calprotectin
presence: Elevated
context: Marker of intestinal inflammation
- name: CRP
presence: Elevated
context: Systemic inflammation marker
- name: ESR
presence: Elevated
context: Active disease
genetic:
- name: IL23R
association: Risk Factor
- name: HNF4A
association: Risk Factor
- name: CDH1
association: Risk Factor
- name: HLA-DRB1
association: Risk Factor
- 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: 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: REL
association: GWAS
notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
- 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
environmental:
- name: Appendectomy
notes: Protective effect
- name: Smoking
notes: Protective (unlike Crohn's)
- name: NSAIDs
notes: May trigger flares
- name: Infections
notes: May trigger onset
- name: Stress
notes: May trigger flares
treatments:
- name: 5-Aminosalicylates
description: First-line for mild-moderate disease (mesalamine).
- name: Corticosteroids
description: For acute flares (prednisone, budesonide).
- name: Thiopurines
description: Azathioprine, 6-MP for maintenance.
- name: Anti-TNF Therapy
description: Infliximab, adalimumab for moderate-severe disease.
- name: Vedolizumab
description: Gut-selective integrin inhibitor.
- name: Tofacitinib
description: JAK inhibitor for moderate-severe disease.
- name: Ustekinumab
description: IL-12/23 inhibitor.
- name: Colectomy
description: Curative surgery for refractory or complicated disease.
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:
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: []