Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Ulcerative Colitis. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Disease Pathophysiology Research Report: Ulcerative Colitis (UC)
Target Disease - Disease Name: Ulcerative Colitis - MONDO ID: (not specified) - Category: Complex
Overview and core concepts Ulcerative colitis is a chronic, relapsing inflammatory disease of the colonic mucosa characterized by a breakdown of epithelial barrier integrity, dysregulated mucosal immune responses to luminal antigens, and perturbations of the gut microbial ecosystem. Recent single-cell and spatial multi-omic studies in 2023–2024 refine this model, linking interferon-rich immune niches, epithelial injury, and myeloid–stromal networks to treatment response and resistance, and highlighting actionable axes such as IL-23/Th17, epithelial alarmins, pyroptosis, and microbiome-derived metabolites. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3, jairath2024il23inhibitionfor pages 1-2)
1) Core Pathophysiology - Barrier failure and epithelial injury - Loss of mucus barrier and goblet cell dysfunction with altered mucin biochemistry are hallmarks in UC, weakening physical segregation of microbes and epithelium and amplifying inflammatory signaling. “Mucus layer loss in UC, with reduced number/size of goblet cells and decreased MUC2 glycosylation” has been emphasized in recent syntheses. (calvez2025novelinsightsinto pages 2-4) URL: https://doi.org/10.3390/biomedicines13020305 (2025; review synthesizing recent primary findings) - Advanced endo-microscopy and spatial tools underscore barrier healing as a key endpoint; barrier assessment predicts outcomes and therapeutic response, and integrates tight junction abnormalities (ZO-1, claudins) with epithelial ultrastructure in vivo. (thomas2024alongitudinalsinglecell pages 1-2) URL: https://doi.org/10.1038/s41590-024-01994-8 (Oct 2024) - Immune network dysfunction and IFN signaling niches - A 1-million-cell single-cell atlas of adalimumab-treated IBD localized “interferon (IFN)-response signatures … to T cell aggregates and epithelial damage in both CD and UC,” and in non-remission, UC exhibited “increased multi-cellular IFN signalling,” implicating IFN-programmed multicellular niches in ongoing epithelial injury. (thomas2024alongitudinalsinglecell pages 1-2) URL: https://doi.org/10.1038/s41590-024-01994-8 (Oct 2024) - In checkpoint inhibitor colitis (mechanistically overlapping with UC at the tissue level), single-cell multi-omics identified neutrophil-rich infiltrates, epithelial apoptosis, and endothelial hypoxia programs as components of barrier dysfunction, supporting generalizable injury pathways. (thomas2024singlecelltranscriptomicanalyses pages 1-3) URL: https://doi.org/10.1038/s41591-024-02895-x (May 2024) - Cytokine axes - IL‑23/Th17 axis: IL‑23 is a hierarchically dominant cytokine in IMIDs; it expands and stabilizes Th17 cells, driving IL‑17A/F, IL‑22, TNF, IFN‑γ, and IL‑26 and engaging ILC3/γδ T cells. Selective IL‑23p19 inhibitors show strong efficacy in IBD. (jairath2024il23inhibitionfor pages 1-2) URL: https://doi.org/10.1016/S0140-6736(24)01750-1 (Oct 2024) - Type 2 alarmins (IL‑33/TSLP/IL‑25) and innate circuits contribute to epithelial–immune crosstalk and can promote repair or inflammation context‑dependently; these are enriched in epithelial compartments and interact with ILC2s and T cells in inflamed mucosa (supported by 2024–2025 scRNA‑seq and reviews). (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Programmed cell death (PCD) - Inflammasome–pyroptosis: UC tissues show inflammasome activation and epithelial pyroptosis; 2024 work links SLC6A14 upregulation to NLRP3-mediated pyroptosis in epithelial cells, and numerous translational efforts target NLRP3–GSDMD. (gu2024slc6a14promotesulcerative pages 16-17) URL: https://doi.org/10.3748/wjg.v30.i3.252 (Jan 2024) - Microbiome–metabolite axes - SCFA deficiency and compositional dysbiosis (e.g., Bacteroides-dominant “Bact2” enterotype) correlate with impaired barrier function and proinflammatory programming; reduced butyrate is repeatedly observed and mechanistically linked to epithelial and immune modulation. (zhang2025fucoidanasa pages 5-7) URL: https://doi.org/10.3389/fcimb.2025.1626614 (2025 review summarizing 2013–2024 evidence)
2) Key molecular players - Genes/proteins (HGNC) - IL23A/IL23R (IL‑23 axis), STAT3, JAK2/TYK2 (downstream IL‑23 signaling) (jairath2024il23inhibitionfor pages 1-2) - MUC2 (goblet cell mucin), MUC1; tight junction proteins OCLN (occludin), CLDN family, TJP1 (ZO‑1) (calvez2025novelinsightsinto pages 2-4) - NLRP3, CASP1, GSDMD (pyroptosis) (gu2024slc6a14promotesulcerative pages 16-17) - Chemical entities (ChEBI) - Short-chain fatty acids (butyrate, acetate, propionate) – barrier and immunomodulatory metabolites (zhang2025fucoidanasa pages 5-7) - Cell types (CL) - Secretory epithelial lineages (goblet cells), colonocytes; myeloid subsets (inflammatory monocytes/macrophages), neutrophils (NET‑forming); T cell aggregates (tissue-resident memory), ILC3/ILC2; endothelial and fibroblast stromal subsets (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Anatomical locations (UBERON) - Colonic mucosa, lamina propria, epithelial barrier, vascular endothelium; inflamed niches spatially adjacent to epithelial damage (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3)
3) Biological processes (GO annotations, representative) - Barrier and epithelial processes: “epithelial cell differentiation,” “mucin biosynthetic process,” “tight junction assembly,” “epithelial cell apoptotic process” (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Immune signaling: “response to interferon,” “IL‑23 signaling pathway,” “Th17 cell differentiation,” “neutrophil activation,” “NET formation,” “inflammatory response” (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2) - Inflammasome and PCD: “inflammasome complex assembly,” “pyroptosis” (GO:0070269), “caspase‑1 activation” (gu2024slc6a14promotesulcerative pages 16-17) - Metabolite–host: “response to short-chain fatty acid,” “regulation of intestinal epithelial cell proliferation by microbiome” (zhang2025fucoidanasa pages 5-7)
4) Cellular components (GO CC) - Apical junctional complex (tight junctions: occludin, claudins, ZO‑1); mucus layer (MUC2-rich), lamina propria immune aggregates; NLRP3 inflammasome (cytosolic); endothelial lining and perivascular stromal niches (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3)
5) Disease progression model - Initiation: genetic susceptibility and environmental triggers lead to barrier weakening (mucus depletion, TJ disruption) permitting microbial and metabolite translocation. - Amplification: APCs overproduce IL‑23, licensing Th17/ILC3 circuits; epithelial alarmins (IL‑33/TSLP/IL‑25) activate innate lymphoid and myeloid cells; neutrophils infiltrate and form NETs; IFN-programmed multicellular niches form around T cell aggregates adjacent to epithelial injury. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - Epithelial injury/death: IFN and TNF signaling, neutrophil proteases/ROS and pyroptosis (NLRP3–caspase‑1–GSDMD) drive epithelial apoptosis/pyroptosis and barrier loss. (thomas2024singlecelltranscriptomicanalyses pages 1-3, gu2024slc6a14promotesulcerative pages 16-17) - Chronicity: dysbiosis with SCFA depletion sustains inflammation and barrier dysfunction; stromal/endothelial remodeling and hypoxia stabilize inflammatory niches; outcomes (remission vs nonremission) track with persistence of IFN signaling and inflammatory myeloid/T cell states under therapy. (thomas2024alongitudinalsinglecell pages 1-2, zhang2025fucoidanasa pages 5-7, thomas2024singlecelltranscriptomicanalyses pages 1-3)
6) Phenotypic manifestations (HP terms, representative) - Bloody diarrhea, abdominal pain, urgency, weight loss; endoscopic mucosal friability and ulceration; histology: crypt abscesses, neutrophilic infiltration, goblet cell depletion, epithelial apoptosis. Mechanistically linked to epithelial barrier failure, neutrophil/NET activity, IFN and IL‑23-driven inflammation. (thomas2024singlecelltranscriptomicanalyses pages 1-3, jairath2024il23inhibitionfor pages 1-2)
Recent developments and latest research (2023–2024 priority) - Single-cell therapeutic atlas (anti‑TNF): “interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage” and “increased multi-cellular IFN signalling (UC)” predicted nonremission, connecting IFN niches to treatment dynamics. (thomas2024alongitudinalsinglecell pages 1-2) - Checkpoint inhibitor colitis single-cell: identified epithelial apoptosis, neutrophil enrichment, and endothelial hypoxia programs linked to barrier dysfunction; mechanistic pathways overlap with UC. (thomas2024singlecelltranscriptomicanalyses pages 1-3) - IL‑23 pathway synthesis and therapy: IL‑23 drives Th17 effectors across IMIDs; selective IL‑23p19 inhibitors demonstrate efficacy with rationale grounded in STAT3/JAK2–TYK2 signaling. (jairath2024il23inhibitionfor pages 1-2) - Pyroptosis evidence: UC epithelium exhibits NLRP3–caspase‑1–GSDMD activation; SLC6A14 promotes UC progression by facilitating NLRP3-mediated pyroptosis, pointing to epithelial metabolic–inflammasome crosstalk as a target. (gu2024slc6a14promotesulcerative pages 16-17) - Barrier biomarkers: serum occludin decreased, claudin‑2 and zonulin increased in IBD; anti‑TNF treatment improved these markers in UC, suggesting systemic readouts of barrier integrity. (thomas2024alongitudinalsinglecell pages 1-2)
Current applications and implementations - Biologics and small molecules - Anti‑TNF (e.g., adalimumab): cellular remission associates with dampened IFN multicellular signaling in UC; nonresponders show persistent IFN niches. (thomas2024alongitudinalsinglecell pages 1-2) - Anti‑integrin (vedolizumab): targets lymphocyte trafficking; single-cell/spatial analyses reveal broader effects on myeloid and stromal subsets contributing to epithelial injury and may correlate with response signatures. (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Anti‑IL‑23 (p19) agents: strong clinical efficacy with mechanistic rationale in UC; ongoing head-to-head and biomarker discovery efforts. (jairath2024il23inhibitionfor pages 1-2) - Biomarkers and imaging - Barrier-focused biomarkers (occludin, claudin‑2, zonulin) and advanced endoscopic/spatial imaging to quantify junctional integrity and epithelial healing are emerging to guide therapy. (thomas2024alongitudinalsinglecell pages 1-2)
Expert opinions and authoritative analysis - The Lancet 2024 perspective on IL‑23 positions p19 blockade as mechanistically superior to p40 for UC and related IMIDs, arguing IL‑23’s centrality in Th17‑driven mucosal inflammation and outlining JAK–STAT signaling dependencies and cell targets beyond Th17, such as ILC3s. (jairath2024il23inhibitionfor pages 1-2) - Single-cell therapeutic atlases (Nature Immunology 2024) reframe resistance to anti‑TNF around persistent IFN niches and pretreatment epithelial/myeloid states, underscoring the need for biomarkers capturing epithelial–immune–stromal crosstalk. (thomas2024alongitudinalsinglecell pages 1-2)
Relevant statistics and recent data - Cell atlas scale: ~1,000,000 gut single-cell transcriptomes, 216 biopsies, 41 subjects; pretreatment epithelial and myeloid differences correlated with remission; nonremission in UC linked to increased multicellular IFN signaling. (thomas2024alongitudinalsinglecell pages 1-2) - Barrier biomarkers: occludin (AUC ~0.96), claudin‑2 (AUC ~0.86–0.90), zonulin (AUC ~0.74 for CD) in distinguishing IBD from controls; improvement after anti‑TNF in UC (study details summarized alongside the anti‑TNF atlas context). (thomas2024alongitudinalsinglecell pages 1-2)
Ontology-aligned annotations (examples) - HGNC: IL23A, IL23R, STAT3, MUC2, OCLN, CLDN2, TJP1, NLRP3, CASP1, GSDMD. (jairath2024il23inhibitionfor pages 1-2, calvez2025novelinsightsinto pages 2-4, gu2024slc6a14promotesulcerative pages 16-17) - GO BP: response to interferon; Th17 cell differentiation; mucin biosynthetic process; tight junction assembly; inflammasome complex assembly; pyroptosis. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, calvez2025novelinsightsinto pages 2-4, gu2024slc6a14promotesulcerative pages 16-17) - GO CC: apical junction complex; mucus layer; NLRP3 inflammasome; endothelial cell of vasculature. (calvez2025novelinsightsinto pages 2-4, thomas2024singlecelltranscriptomicanalyses pages 1-3) - CL: goblet cell, colonocyte, neutrophil, monocyte/macrophage, CD4+ and CD8+ tissue-resident T cells, ILC2/ILC3, endothelial cell, fibroblast. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - UBERON: colon mucosa (UBERON:0001155), lamina propria, intestinal epithelium, colonic endothelium. (thomas2024alongitudinalsinglecell pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3) - CHEBI: butyrate (CHEBI:30089), acetate (CHEBI:15343), propionate (CHEBI:17295). (zhang2025fucoidanasa pages 5-7)
Embedded evidence quotes
"spatial/system-level analyses identified interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in both CD and UC." (thomas2024alongitudinalsinglecell pages 1-2)
"nonremitters displayed disease progression ... increased multi-cellular IFN signalling (UC)." (thomas2024alongitudinalsinglecell pages 1-2)
"neutrophilic infiltrates and increased intraepithelial lymphocytes and epithelial apoptosis." (thomas2024singlecelltranscriptomicanalyses pages 1-3)
"IL-23 (a p19-containing heterodimer sharing p40 with IL-12) promotes expansion and stabilization of Th17 cells that secrete IL-17A/F, IL-22, TNFα, IFNγ, and IL-26." (jairath2024il23inhibitionfor pages 1-2)
"promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis." (gu2024slc6a14promotesulcerative pages 16-17)
"mucus layer loss in UC, with reduced number/size of goblet cells and decreased MUC2 glycosylation." (calvez2025novelinsightsinto pages 2-4)
"reduced butyrate and other SCFAs in disease." (zhang2025fucoidanasa pages 5-7)
Blockquote: Concise, directly quoted findings from recent single-cell and review studies highlighting IFN signatures and epithelial damage, neutrophil/epithelial injury, IL-23/Th17 biology, NLRP3‑pyroptosis, mucus/goblet cell loss, and SCFA depletion in UC (context citations included).
Evidence items (with links) - Thomas et al., Nature Immunology 2024: single-cell anti‑TNF atlas in IBD; IFN-response niches adjacent to epithelial damage; increased IFN signaling in UC nonremission. DOI: 10.1038/s41590-024-01994-8; Published Oct 22, 2024. URL: https://doi.org/10.1038/s41590-024-01994-8 (thomas2024alongitudinalsinglecell pages 1-2) - Thomas et al., Nature Medicine 2024: checkpoint inhibitor colitis scRNA‑seq; neutrophils, epithelial apoptosis, endothelial hypoxia signature linked to barrier dysfunction. DOI: 10.1038/s41591-024-02895-x; May 2024. URL: https://doi.org/10.1038/s41591-024-02895-x (thomas2024singlecelltranscriptomicanalyses pages 1-3) - Jairath et al., The Lancet 2024: IL‑23 inhibition across chronic inflammatory diseases; mechanistic grounding of UC efficacy via Th17/ILC3 and STAT3 signaling. DOI: 10.1016/S0140-6736(24)01750-1; Oct 2024. URL: https://doi.org/10.1016/S0140-6736(24)01750-1 (jairath2024il23inhibitionfor pages 1-2) - Gu et al., World Journal of Gastroenterology 2024: SLC6A14 promotes NLRP3‑mediated pyroptosis in UC epithelial cells. DOI: 10.3748/wjg.v30.i3.252; Jan 2024. URL: https://doi.org/10.3748/wjg.v30.i3.252 (gu2024slc6a14promotesulcerative pages 16-17) - Calvez et al., Biomedicines 2025: review synthesizing mucus/goblet cell defects in UC and innate immune roles. DOI: 10.3390/biomedicines13020305; Jan 2025. URL: https://doi.org/10.3390/biomedicines13020305 (calvez2025novelinsightsinto pages 2-4) - Zhang, Frontiers in Cellular and Infection Microbiology 2025: review summarizing 2013–2024 evidence of dysbiosis, pathobionts, and SCFA depletion in UC. DOI: 10.3389/fcimb.2025.1626614; Jul 2025. URL: https://doi.org/10.3389/fcimb.2025.1626614 (zhang2025fucoidanasa pages 5-7)
Limitations and notes - While we prioritized 2023–2024 primary sources, several synthesized statements on mucus/goblet cell and SCFA biology derive from high-level reviews that consolidate earlier primary studies. Future iterations may add more 2023–2024 primary metabolomics studies as they become available.
Conclusions Modern single-cell and spatial analyses in 2024 demonstrate that UC pathophysiology emerges from integrated epithelial barrier failure, IFN‑rich immune niches, IL‑23/Th17 and alarmin circuits, neutrophil effector pathways (including pyroptosis), and dysbiotic metabolite milieus. These insights map onto therapeutic mechanisms and resistance—anti‑TNF response tracks with resolution of IFN multicellular programs, while IL‑23 pathway blockade is mechanistically validated. Barrier-centric biomarkers and advanced imaging are moving toward clinical implementation to better align therapy with disease biology. (thomas2024alongitudinalsinglecell pages 1-2, jairath2024il23inhibitionfor pages 1-2, thomas2024singlecelltranscriptomicanalyses pages 1-3)
References
(thomas2024alongitudinalsinglecell pages 1-2): Tom Thomas, Matthias Friedrich, Charlotte Rich-Griffin, Mathilde Pohin, Devika Agarwal, Julia Pakpoor, Carl Lee, Ruchi Tandon, Aniko Rendek, Dominik Aschenbrenner, Ashwin Jainarayanan, Alexandru Voda, Jacqueline H. Y. Siu, Raphael Sanches-Peres, Eloise Nee, Dharshan Sathananthan, Dylan Kotliar, Peter Todd, Maria Kiourlappou, Lisa Gartner, Nicholas Ilott, Fadi Issa, Joanna Hester, Jason Turner, Saba Nayar, Jonas Mackerodt, Fan Zhang, Anna Jonsson, Michael Brenner, Soumya Raychaudhuri, Ruth Kulicke, Danielle Ramsdell, Nicolas Stransky, Ray Pagliarini, Piotr Bielecki, Noah Spies, Brian Marsden, Stephen Taylor, Allon Wagner, Paul Klenerman, Alissa Walsh, Mark Coles, Luke Jostins-Dean, Fiona M. Powrie, Andrew Filer, Simon Travis, Holm H. Uhlig, Calliope A. Dendrou, and Christopher D. Buckley. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nature Immunology, 25:2152-2165, Oct 2024. URL: https://doi.org/10.1038/s41590-024-01994-8, doi:10.1038/s41590-024-01994-8. This article has 47 citations and is from a highest quality peer-reviewed journal.
(thomas2024singlecelltranscriptomicanalyses pages 1-3): Molly Fisher Thomas, Kamil Slowikowski, Kasidet Manakongtreecheep, Pritha Sen, Nandini Samanta, Jessica Tantivit, Mazen Nasrallah, Leyre Zubiri, Neal P. Smith, Alice Tirard, Swetha Ramesh, Benjamin Y. Arnold, Linda T. Nieman, Jonathan H. Chen, Thomas Eisenhaure, Karin Pelka, Yuhui Song, Katherine H. Xu, Vjola Jorgji, Christopher J. Pinto, Tatyana Sharova, Rachel Glasser, PuiYee Chan, Ryan J. Sullivan, Hamed Khalili, Dejan Juric, Genevieve M. Boland, Michael Dougan, Nir Hacohen, Bo Li, Kerry L. Reynolds, and Alexandra-Chloé Villani. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nature medicine, 30:1349-1362, May 2024. URL: https://doi.org/10.1038/s41591-024-02895-x, doi:10.1038/s41591-024-02895-x. This article has 45 citations and is from a highest quality peer-reviewed journal.
(jairath2024il23inhibitionfor pages 1-2): Vipul Jairath, Maria Laura Acosta Felquer, and Raymond Jaihyun Cho. Il-23 inhibition for chronic inflammatory disease. The Lancet, 404:1679-1692, Oct 2024. URL: https://doi.org/10.1016/s0140-6736(24)01750-1, doi:10.1016/s0140-6736(24)01750-1. This article has 25 citations and is from a highest quality peer-reviewed journal.
(calvez2025novelinsightsinto pages 2-4): Valentin Calvez, Pierluigi Puca, Federica Di Vincenzo, Angelo Del Gaudio, Bianca Bartocci, Marco Murgiano, Jacopo Iaccarino, Erfan Parand, Daniele Napolitano, Daniela Pugliese, Antonio Gasbarrini, and Franco Scaldaferri. Novel insights into the pathogenesis of inflammatory bowel diseases. Biomedicines, 13:305, Jan 2025. URL: https://doi.org/10.3390/biomedicines13020305, doi:10.3390/biomedicines13020305. This article has 35 citations and is from a poor quality or predatory journal.
(gu2024slc6a14promotesulcerative pages 16-17): Qing Gu, Huan Xia, Yue-Qiong Song, Jun Duan, Yun Chen, You Zhang, He-Ping Chen, and Li Zhang. Slc6a14 promotes ulcerative colitis progression by facilitating nlrp3 inflammasome-mediated pyroptosis. World Journal of Gastroenterology, 30:252-267, Jan 2024. URL: https://doi.org/10.3748/wjg.v30.i3.252, doi:10.3748/wjg.v30.i3.252. This article has 15 citations and is from a poor quality or predatory journal.
(zhang2025fucoidanasa pages 5-7): Yating Zhang. Fucoidan as a therapeutic agent for ulcerative colitis: mechanisms of action and modulation of the gut microbiota. Frontiers in Cellular and Infection Microbiology, Jul 2025. URL: https://doi.org/10.3389/fcimb.2025.1626614, doi:10.3389/fcimb.2025.1626614. This article has 3 citations and is from a poor quality or predatory journal.
name: Ulcerative Colitis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-04-06T00:00:00Z'
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
reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
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
reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
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
reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
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
reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
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
reference_title: "IL-23 inhibition for chronic inflammatory disease."
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
reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
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
reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
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
reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
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
reference_title: "A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease."
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: symbiont-mediated perturbation of host process
downstream:
- target: Loss of Keystone SCFA Producers
description: Diversity loss disproportionately affects beneficial fermenters
- target: Increased Microbial Community Instability
description: Anna Karenina effect - dysbiotic communities become stochastic
evidence:
- reference: PMID:25307765
reference_title: "Meta-analyses of human gut microbes associated with obesity and IBD."
supports: 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
reference_title: "Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients."
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
reference_title: "Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients."
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
reference_title: "The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection."
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
reference_title: "A metagenome-wide association study of gut microbiota in type 2 diabetes."
supports: NO_EVIDENCE
snippet: "Patients with type 2 diabetes were characterized by a moderate degree
of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing
bacteria and an increase in various opportunistic pathogens."
explanation: While this study focused on T2D, it demonstrates the general
principle that dysbiosis involves loss of butyrate producers - a pattern
also seen in IBD.
- name: Impaired Colonocyte Energy Metabolism
description: >
Colonocytes deprived of butyrate shift from beta-oxidation to glycolysis,
causing energy deficit. This impairs tight junction maintenance, mucus
production by goblet cells, and epithelial renewal from crypt stem cells.
cell_types:
- preferred_term: Colonic Epithelial Cell
term:
id: CL:0011108
label: colon epithelial cell
downstream:
- target: Epithelial Barrier Dysfunction
description: Energy-deprived colonocytes cannot maintain barrier integrity
- name: Increased Microbial Community Instability
description: >
Anna Karenina effect - dysbiotic microbiomes show increased inter-individual
variability and temporal instability compared to healthy controls. The
community loses resilience and may occupy an alternative stable state that
resists therapeutic intervention.
notes: >
"All healthy microbiomes are alike; each dysbiotic microbiome is dysbiotic
in its own way." This increased stochasticity complicates biomarker discovery
and explains heterogeneous treatment responses.
downstream:
- target: Loss of Microbial Diversity
description: Feedback loop - community instability promotes further
diversity loss
evidence:
- reference: PMID:28836573
reference_title: "Stress and stability: applying the Anna Karenina principle to animal microbiomes."
supports: 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: pyroptotic inflammatory response
evidence:
- reference: PMID:38314135
reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
supports: SUPPORT
snippet: "SLC6A14 was increased and correlated with NLRP3 in UC tissues."
explanation: SLC6A14 expression is elevated and correlates with NLRP3 in UC
tissues, establishing a molecular link between this transporter and
inflammasome activation.
- reference: PMID:38314135
reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
supports: SUPPORT
snippet: "Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β,
IL-18, NLRP3)."
explanation: Experimental reduction of SLC6A14 decreases
pyroptosis-associated proteins including NLRP3, IL-1β, and IL-18,
demonstrating the causal role of this pathway in UC.
- reference: PMID:38314135
reference_title: "SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis."
supports: SUPPORT
snippet: "SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic
potential of modulating the SLC6A14/NLRP3 axis."
explanation: SLC6A14 promotes UC progression through NLRP3-mediated
pyroptosis, identifying this as a key pathophysiological mechanism and
potential therapeutic target.
phenotypes:
- name: Bloody Diarrhea
category: Gastrointestinal
frequency: VERY_FREQUENT
diagnostic: true
phenotype_term:
preferred_term: Bloody Diarrhea
term:
id: HP:0025085
label: Bloody diarrhea
evidence:
- reference: PMID:38724705
reference_title: "Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis."
supports: 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
evidence:
- reference: PMID:31272578
reference_title: "Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus."
explanation: Mayo Clinic Proceedings review confirms abdominal pain as a typical presenting symptom in UC.
- name: Urgency
category: Gastrointestinal
frequency: VERY_FREQUENT
notes: Fecal urgency
phenotype_term:
preferred_term: Fecal Urgency
term:
id: HP:0012701
label: Bowel urgency
evidence:
- reference: PMID:30837080
reference_title: "A comprehensive review and update on ulcerative colitis()."
supports: SUPPORT
snippet: "The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."
explanation: Rectal urgency is described as a classic presenting symptom of ulcerative colitis.
- name: Tenesmus
category: Gastrointestinal
frequency: FREQUENT
phenotype_term:
preferred_term: Tenesmus
term:
id: HP:0012702
label: Tenesmus
evidence:
- reference: PMID:30837080
reference_title: "A comprehensive review and update on ulcerative colitis()."
supports: SUPPORT
snippet: "The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation."
explanation: Tenesmus is described as a classic presenting symptom of ulcerative colitis.
- name: Weight Loss
category: Systemic
frequency: FREQUENT
phenotype_term:
preferred_term: Weight Loss
term:
id: HP:0001824
label: Weight loss
evidence:
- reference: PMID:25506359
reference_title: "Determinants of Weight Loss prior to Diagnosis in Inflammatory Bowel Disease: A Retrospective Observational Study."
supports: SUPPORT
snippet: "51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss)."
explanation: Weight loss is a significant and common symptom in ulcerative colitis patients, with over half experiencing significant weight loss prior to diagnosis.
- name: Fatigue
category: Systemic
frequency: FREQUENT
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
evidence:
- reference: PMID:27310658
reference_title: "Conventional treatment regimens for ulcerative colitis alleviate fatigue - an observational cohort study."
supports: SUPPORT
snippet: "more severe fatigue was associated with more ulcerative colitis symptoms"
explanation: Fatigue is a common symptom in ulcerative colitis patients that correlates with disease activity and symptom severity.
- name: Anemia
category: Hematologic
frequency: FREQUENT
notes: Iron deficiency from blood loss
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: PMID:25646159
reference_title: "Anemia in inflammatory bowel disease: an under-estimated problem?"
supports: SUPPORT
snippet: "Anemia is one of the most frequent complications and/or extraintestinal manifestations of inflammatory bowel disease (IBD). Iron deficiency is the most important cause of anemia in Crohn's disease and ulcerative colitis patients."
explanation: Anemia, particularly iron deficiency anemia, is one of the most frequent complications of ulcerative colitis due to chronic blood loss from the inflamed colonic mucosa.
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).
treatment_term:
preferred_term: 5-aminosalicylate therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:21407188
reference_title: "Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥ 2.0 g/day have greater efficacy"
explanation: Systematic review and meta-analysis confirming 5-ASA efficacy in UC remission induction and relapse prevention.
- name: Corticosteroids
description: For acute flares (prednisone, budesonide).
treatment_term:
preferred_term: Corticosteroid therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:31272578
reference_title: "Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission."
explanation: Review confirms corticosteroids are used to induce remission with goal of achieving corticosteroid-free maintenance.
- name: Thiopurines
description: Azathioprine, 6-MP for maintenance.
treatment_term:
preferred_term: Thiopurine therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:31272578
reference_title: "Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."
explanation: Review confirms thiopurines as a treatment class for moderate-severe UC.
- name: Anti-TNF Therapy
description: Infliximab, adalimumab for moderate-severe disease.
treatment_term:
preferred_term: Anti-TNF therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:26902011
reference_title: "Anti-TNF-A Therapy about Infliximab and Adalimamab for the Effectiveness in Ulcerative Colitis Compared with Conventional Therapy: A Meta-Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy"
explanation: Meta-analysis demonstrating significant efficacy of anti-TNF agents in UC clinical response induction.
- name: Vedolizumab
description: Gut-selective integrin inhibitor.
treatment_term:
preferred_term: Vedolizumab therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:31470005
reference_title: "Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively"
explanation: Phase 3 RCT demonstrating vedolizumab efficacy with 46% clinical remission vs 14% placebo at week 52.
- name: Tofacitinib
description: JAK inhibitor for moderate-severe disease.
treatment_term:
preferred_term: JAK inhibitor therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:31272578
reference_title: "Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors."
explanation: Review confirms JAK inhibitors as approved treatment for moderate-severe UC.
- name: Ustekinumab
description: IL-12/23 inhibitor.
treatment_term:
preferred_term: IL-12/23 inhibitor therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:39461795
reference_title: "IL-23 inhibition for chronic inflammatory disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response"
explanation: IL-23 inhibitors demonstrate high efficacy in UC by targeting upstream pathological mechanisms.
- name: Colectomy
description: Curative surgery for refractory or complicated disease.
treatment_term:
preferred_term: Colectomy
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:31272578
reference_title: "Ulcerative Colitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment."
explanation: Review confirms 15% of UC patients require colectomy for refractory disease or dysplasia.
experimental_models:
- name: Biopsy-derived UC colonoid air-liquid interface model
description: >
Biopsy-derived sigmoid colonoids differentiated as air-liquid interface
monolayers to model epithelial architecture, mucus production, and
pathobiont susceptibility in ulcerative colitis.
experimental_model_type: PRIMARY_CELL_CULTURE
namo_type: namo:TwoDCellCulture
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
tissue_term:
preferred_term: colon
term:
id: UBERON:0001155
label: colon
cell_types:
- preferred_term: Colonic Epithelial Cell
term:
id: CL:0011108
label: colon epithelial cell
conditions:
- ulcerative colitis
- non-IBD control
- pathobiont challenge
cell_source: Patient biopsy-derived sigmoid colonic epithelial crypts expanded
as colonoids
culture_system: Air-liquid interface colonoid monolayers with mucus and
pathobiont challenge assays
publication: PMID:41589595
findings:
- statement: UC biopsy-derived ALI colonoid monolayers retain persistent epithelial and mucus-barrier defects outside the inflamed tissue environment
evidence:
- reference: PMID:41589595
reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
explanation: Supports persistent epithelial barrier and mucus-layer defects relevant to Epithelial Barrier Dysfunction.
- reference: PMID:34418586
reference_title: "Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer."
explanation: Independently supports durable mucus-barrier defects in patient-derived UC colonoid monolayers.
- statement: UC colonoid monolayers provide a tractable epithelial system for linking mucus defects to pathobiont susceptibility
evidence:
- reference: PMID:41589595
reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "With the use of transcriptome analysis, we identified activated pathways associated with extracellular matrix formation and cell signaling, including numerous cancer-associated genes in UC ALI monolayers, which also proved significantly more susceptible to E. coli p19A."
explanation: Links epithelial remodeling and barrier compromise to increased susceptibility to bacterial challenge, consistent with mucosal inflammation and host-microbe dysfunction.
- reference: PMID:34418586
reference_title: "Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Chronic inflammation in UC causes long-term changes in GCs, leading to abnormal mucus secretion."
explanation: Supports a mechanistic connection between chronic inflammation and lasting goblet-cell secretory dysfunction in the model.
evidence:
- reference: PMID:41589595
reference_title: "Biopsy-derived colonoid air-liquid interface monolayers reveal persistent mucosal defects in ulcerative colitis patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "ALI monolayers from UC patients displayed a range of impairments, with classification ranging from a mild phenotype with distorted architecture and a thinner, more permeable mucus layer to a severe phenotype with defects in cellular differentiation and an inability to produce a mucus layer."
explanation: Supports this as a patient-derived UC epithelial model with direct relevance to mucosal inflammation and barrier dysfunction.
- name: Cytokine-conditioned hiPSC-derived colon organoid UC model
description: >
Human induced pluripotent stem cell-derived colon organoids exposed to
TNF-α, IFN-γ, and IL-1β to model UC-like epithelial injury and stromal
inflammatory signaling.
experimental_model_type: IPSC_DERIVED_MODEL
namo_type: namo:Organoid
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
tissue_term:
preferred_term: colon
term:
id: UBERON:0001155
label: colon
conditions:
- ulcerative colitis-like cytokine exposure
- TNF-α/IFN-γ/IL-1β stimulation
- tofacitinib response testing
cell_source: Human induced pluripotent stem cell-derived colon organoids
culture_system: Three-dimensional colon organoid culture with pro-inflammatory
cytokine conditioning
publication: PMID:39435148
findings:
- statement: Cytokine-conditioned hiPSC colon organoids reproduce epithelial injury and inflammatory stromal responses that resemble UC tissue
evidence:
- reference: PMID:39435148
reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Inflammatory responses in stromal cells and damage to intestinal epithelial cells were observed in the 3CK-treated hiPSC-COs."
explanation: Supports alignment with Dysregulated Immune Response and Epithelial Barrier Dysfunction in a human stem-cell-derived system.
- reference: PMID:39435148
reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."
explanation: Supports molecular resemblance of the model to UC tissue rather than generic cytokine injury alone.
- statement: The model can be used to test whether cytokine-driven inflammatory outputs are pharmacologically reversible
evidence:
- reference: PMID:39435148
reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, the elevated production of inflammatory cytokines observed in 3CK-treated hiPSC-COs was attenuated by treatment with tofacitinib."
explanation: Supports translational use of the model for pathway-focused drug testing in a UC-like inflammatory state.
evidence:
- reference: PMID:39435148
reference_title: "Establishment of an ulcerative colitis model using colon organoids derived from human induced pluripotent stem cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Comparison of molecular signatures of 3CK-treated hiPSC-COs with those of ulcerative colitis (UC) patient's colon revealed that 3CK-treated hiPSC-COs resemble UC patient's colon."
explanation: Supports this as a human iPSC-derived organoid model with molecular similarity to UC tissue.
- name: Human colon-on-chip mucus barrier model
description: >
Microfluidic human colon chip lined by primary patient-derived colonic
epithelial cells to model mucus bilayer formation and inflammatory control
of mucus hydration.
experimental_model_type: ORGAN_ON_CHIP
namo_type: namo:OrganOnChip
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
tissue_term:
preferred_term: colon
term:
id: UBERON:0001155
label: colon
cell_types:
- preferred_term: Colonic Epithelial Cell
term:
id: CL:0011108
label: colon epithelial cell
conditions:
- mucus barrier physiology
- prostaglandin E2 stimulation
- ulcerative colitis-relevant mucus barrier dysfunction
cell_source: Primary patient-derived colonic epithelial cells
culture_system: Microfluidic colon-on-chip device with live imaging of mucus
layer formation
publication: PMID:31778828
findings:
- statement: The colon chip reproduces human colonic mucus bilayer structure, making it useful for mechanistic study of mucus-barrier defects relevant to UC
evidence:
- reference: PMID:31778828
reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "The Colon Chip supports spontaneous goblet cell differentiation and accumulation of a mucus bilayer with impenetrable and penetrable layers, and a thickness similar to that observed in the human colon, while maintaining a subpopulation of proliferative epithelial cells."
explanation: Supports physiologic mucus-barrier fidelity in a human colon microphysiological system relevant to UC barrier biology.
- reference: PMID:31778828
reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "The Colon Chip may offer a new preclinical tool to analyze the role of mucus in human intestinal homeostasis as well as diseases, such as ulcerative colitis and cancer."
explanation: Supports inclusion as a restrained UC-adjacent organ-on-chip bridge rather than a direct disease-specific UC model.
- statement: The chip captures inflammatory mediator effects on mucus hydration without requiring animal models
evidence:
- reference: PMID:31778828
reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "Live imaging of the mucus layer formation on-chip showed that stimulation of the colonic epithelium with prostaglandin E2, which is increased during inflammation, causes rapid mucus volume expansion via an Na-K-Cl cotransporter 1 ion channel-dependent increase in its hydration state, but no increase in de novo mucus secretion."
explanation: Connects the platform to inflammatory mediator responses relevant to mucosal inflammation and mucus-layer physiology in UC.
evidence:
- reference: PMID:31778828
reference_title: "Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology."
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "A human colon-on-a-chip (Colon Chip) microfluidic device lined by primary patient-derived colonic epithelial cells was used to recapitulate mucus bilayer formation, and to visualize mucus accumulation in living cultures noninvasively."
explanation: Supports this as a human colon organ-on-chip platform for studying mucus-barrier mechanisms relevant to UC.
computational_models:
- name: AGORA2 Gut Microbiome Metabolic Models
description: >
Collection of 7,302 strain-resolved genome-scale metabolic reconstructions of
human
gut microorganisms. Enables modeling of UC-associated dysbiosis including loss
of
keystone SCFA producers (F. prausnitzii, Roseburia, Eubacterium rectale) and expansion
of pathobionts (Fusobacterium, Enterobacteriaceae). Supports colonocyte energy
metabolism
modeling.
model_type: GENOME_SCALE_METABOLIC
repository_url: https://www.vmh.life/
publication: PMID:36543475
notes: Nature Biotechnology 2022 - strain-level resolution for butyrate
producer depletion studies
- name: MICOM Community Metabolic Model
description: >
Metagenome-scale modeling framework for simulating metabolic interactions in the
gut microbiota. Models decreased butyrate production, impaired colonocyte energy
metabolism, and Anna Karenina effect (increased community instability) observed
in
UC. Integrates with dietary intervention modeling.
model_type: GENOME_SCALE_METABOLIC
model_software: COBRApy
publication: PMID:31964767
notes: mSystems 2020 - enables personalized SCFA flux predictions from patient
metagenomes
- name: Host-Microbiome Multi-Objective Optimization Model
description: >
Integrated metabolic model combining human colonic epithelial cell metabolism
with
gut microbiome community models. Predicts metabolic crosstalk disruption in UC,
including butyrate deprivation effects on colonocyte beta-oxidation and tight
junction
maintenance.
model_type: GENOME_SCALE_METABOLIC
publication: PMID:38729159
notes: iScience 2024 - models host-microbiome metabolic interactions at
community scale
datasets:
# CELLxGENE - IBD single-cell atlas
- accession: "cellxgene:7c7bd6c2-925b-4034-baab-620ef1b760e1"
title: Human inflammatory bowel disease (IBD) and healthy control 10x Single-cell transcriptomics data
description: >-
Single-cell transcriptomic atlas of human inflammatory bowel disease including
ulcerative colitis and Crohn disease samples alongside healthy controls.
Characterizes immune and epithelial cell populations in inflamed intestinal
tissue.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_types:
- preferred_term: colon tissue
tissue_term:
preferred_term: colon
term:
id: UBERON:0001155
label: colon
conditions:
- ulcerative colitis
- Crohn disease
- normal
publication: PMID:37488103
notes: CZI CELLxGENE collection. DOI 10.1038/s41467-023-40156-6. Covers both UC and CD for comparative analysis.
references:
- reference: DOI:10.1038/s41590-024-01994-8
title: A longitudinal single-cell atlas of anti-tumour necrosis factor
treatment in inflammatory bowel disease
findings: []
- reference: DOI:10.1038/s41591-024-02895-x
title: Single-cell transcriptomic analyses reveal distinct immune cell
contributions to epithelial barrier dysfunction in checkpoint inhibitor
colitis
findings: []
- reference: DOI:10.3389/fcimb.2025.1626614
title: 'Fucoidan as a therapeutic agent for ulcerative colitis: mechanisms of action
and modulation of the gut microbiota'
findings: []
- reference: DOI:10.3390/biomedicines13020305
title: Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases
findings: []
- reference: DOI:10.3748/wjg.v30.i3.252
title: SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3
inflammasome-mediated pyroptosis
findings: []