Ulcerative colitis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Usama Talib, BSc, MD [3]
Overview
Ulcerative colitis (UC) arises from a gene–environment interaction. In a genetically susceptible host, environmental exposures lead to a defective epithelial barrier, gut microbial dysbiosis, and a dysregulated mucosal immune response. Together these start and sustain continuous mucosal inflammation of the colon.[1][2] There is no single causative agent. Genetics, barrier failure, dysbiosis, and immune dysregulation each contribute, but none is sufficient on its own.[3] The adaptive immune response in UC is classically an atypical Th2 response driven by NKT cells through IL-13. This contrasts with the Th1 pattern of Crohn's disease, and both diseases share a Th17/IL-23 axis.[4][5] Each mechanistic node maps to an approved drug class: anti-TNF, anti-integrin, anti-IL-12/23 or IL-23, JAK inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators. This mapping is the main clinical value of understanding UC pathogenesis.[1]
Pathophysiology
Pattern of Mucosal Inflammation
- Inflammation is confined to the mucosa. It begins in the rectum and extends proximally in a continuous pattern to a variable length of the colon.[6]
Pathogenic Model
UC is a multifactorial disorder with four interacting domains:[1][2][7]
- Genetic susceptibility
- Genome-wide association studies have identified more than 200 IBD risk loci. These loci are enriched for genes involved in intestinal barrier function and T-cell immunity.[1][2]
- Known risk variants explain only about 19–26% of IBD heritability.[8]
- Genotyping therefore does not predict disease onset or phenotype and has no routine clinical role.[2]
- Environmental triggers
- Smoking has a distinctive relationship with UC. Current smoking is associated with a lower risk, while former smokers and recent quitters have a higher risk.[6]
- Other modifiers include appendectomy, NSAIDs, antibiotics, enteric infections, and diet. Many of these act by reshaping the microbiome.[2][6]
- Epithelial barrier dysfunction is an early and possibly primary event (see below).
- Immune dysregulation consists of aberrant innate and adaptive responses to luminal microbial antigens.
Epithelial Barrier Dysfunction
Barrier failure is detectable early in the disease. It is increasingly viewed as a primary driver rather than only a consequence of inflammation.[7][6]
- Mucus layer defects: reduced mucin 2 (MUC2) synthesis and goblet cell depletion make the mucus barrier thinner and more permeable.[7][6]
- Tight junction disruption: downregulation of occludin, claudins, and tricellulin increases paracellular permeability.[7]
- Pre-clinical changes:
- Epithelial stress pathways: two mechanisms link genetic and environmental hits to epithelial inflammation.[7][6]
- Reduced colonocyte PPAR-γ expression. PPAR-γ normally restrains NF-κB.
- Unresolved endoplasmic reticulum stress, for example through the XBP1 pathway.
- Once the barrier fails, luminal microbial antigens reach immune cells in the lamina propria. This sets up a self-reinforcing cycle of inflammation and further barrier injury.[7][9]
Microbial Dysbiosis
- Characteristic changes in the UC microbiome:[6][8]
- Reduced microbial diversity.
- Depletion of commensals that produce short-chain fatty acids (SCFAs), such as Faecalibacterium prausnitzii.
- Expansion of facultative pathobionts, including Escherichia coli and other Enterobacteriaceae and Proteobacteria.
- No single causative organism: no pathogen reproducibly causes UC. Disease reflects altered proportions of normally resident taxa and opportunistic pathobionts.[3][8]
- Dysbiosis is both cause and consequence:[10][9]
- The inflamed mucosa is rich in oxygen and nitrate, which favors aerotolerant Proteobacteria and perpetuates inflammation.
- The direction of causality remains unresolved.
- Functional consequences: loss of SCFAs (colonocyte fuel and inducers of regulatory T cells) and activation of toll-like receptor–NF-κB signaling amplify release of pro-inflammatory cytokines.[6][10]
Dysregulated Immune Response
Innate Immunity
- After antigens cross the epithelium, dendritic cells, macrophages, and neutrophils are activated.[2]
- A hallmark of UC is mucosal neutrophil accumulation with neutrophil extracellular traps (NETs). NETs amplify TNF and IL-1β signaling.[2]
- Dendritic cells shift to a pro-inflammatory, less tolerogenic phenotype and induce fewer regulatory T cells.[2]
Adaptive Immunity
- Atypical Th2 response: non-classic NKT cells produce IL-5 and IL-13.[4][5]
- IL-13 is directly cytotoxic to epithelial cells.
- It induces apoptosis and disrupts tight junctions.
- Th9 cells: these PU.1⁺ cells are induced by epithelial IL-33 and produce IL-9.[5][11]
- They are more enriched in UC mucosa than in Crohn's disease.
- They impair epithelial proliferation and barrier function.
- Th17 cells: these RORγt⁺ cells are driven by IL-23 and produce IL-17, IL-21, and IL-22. They are present in both UC and Crohn's disease.[5][12]
- Effector:regulatory T-cell imbalance: impaired regulation by IL-10 and TGF-β sustains inflammation.[4]
- Loss-of-function mutations in IL-10 or its receptor cause severe early-onset colitis.
- T-cell plasticity: T cells can change phenotype, for example Th17 cells converting to Th1 cells or mixed FOXP3⁺IL-17⁺ cells appearing. Together with redundancy in the cytokine network, this helps explain why blocking a single cytokine often fails.[13]
| T-cell subset | Inducing signal | Signature cytokines | Predominant disease |
|---|---|---|---|
| Atypical Th2 (NKT-driven) | — | IL-5, IL-13 | UC |
| Th9 | IL-33 | IL-9 | UC |
| Th1 | IL-12 | IFN-γ, TNF, IL-6 | Crohn's disease |
| Th17 | IL-23 | IL-17, IL-21, IL-22 | Both |
| Treg (reduced Treg:effector ratio) | — | IL-10, TGF-β | Both |
Adapted from Neurath 2017 and Neurath 2019.[12][5]
Pathogenic Targets of Approved Therapies
| Pathogenic target | Mechanism | Representative agents |
|---|---|---|
| TNF | Neutralizes a dominant pro-inflammatory cytokine | Infliximab, adalimumab, golimumab |
| α4β7 integrin–MAdCAM-1 | Blocks gut-selective lymphocyte trafficking | Vedolizumab |
| IL-12/IL-23 (p40); IL-23 (p19) | Inhibits the Th17/IL-23 axis | Ustekinumab; mirikizumab |
| JAK–STAT signaling | Oral inhibition of multiple cytokine pathways | Tofacitinib, filgotinib, upadacitinib |
| S1P receptor | Retains lymphocytes in lymph nodes | Ozanimod, etrasimod |
Table sources: Gros 2023, Le Berre 2023, Neurath 2019.[1][2][5]
Each agent blocks only one node of a redundant inflammatory network. As a result, only about 30–60% of patients respond to any given advanced therapy. This explains primary non-response and supports sequencing or combining mechanisms.[1][13]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Gros B, Kaplan GG (2023). "Ulcerative Colitis in Adults: A Review". JAMA. 330 (10): 951–965. doi:10.1001/jama.2023.15389. PMID 37698559 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Le Berre C, Honap S, Peyrin-Biroulet L (2023). "Ulcerative colitis". Lancet. 402 (10401): 571–584. doi:10.1016/S0140-6736(23)00966-2.
- ↑ 3.0 3.1 Kennedy MS, Chang EB (2025). "Emerging concepts and shifting paradigms for understanding the microbial basis of inflammatory bowel diseases". J Clin Invest. 135 (17): e193969. doi:10.1172/JCI193969. PMID 40892512 Check
|pmid=value (help). - ↑ 4.0 4.1 4.2 Ordás I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ (2012). "Ulcerative colitis". Lancet. 380 (9853): 1606–1619. doi:10.1016/S0140-6736(12)60150-0.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Neurath MF (2019). "Targeting immune cell circuits and trafficking in inflammatory bowel disease". Nat Immunol. 20 (8): 970–979. doi:10.1038/s41590-019-0415-0.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF (2017). "Ulcerative colitis". Lancet. 389 (10080): 1756–1770. doi:10.1016/S0140-6736(16)32126-2. PMID 27914657.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Kobayashi T, Siegmund B, Le Berre C, Wei SC, Ferrante M, Shen B, Bernstein CN, Danese S, Peyrin-Biroulet L, Hibi T (2020). "Ulcerative colitis". Nat Rev Dis Primers. 6 (1): 74. doi:10.1038/s41572-020-0205-x.
- ↑ 8.0 8.1 8.2 Gilliland A, Chan JJ, De Wolfe TJ, Yang H, Vallance BA (2024). "Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care". Gastroenterology. 166 (1): 44–58. doi:10.1053/j.gastro.2023.09.019. PMID 37734419 Check
|pmid=value (help). - ↑ 9.0 9.1 Rynikova M, Bojcukova V, Demeckova V (2026). "One therapy, many targets: redefining ulcerative colitis treatment through fecal microbiota transplantation". Ther Adv Gastroenterol. 19: 17562848261437918. doi:10.1177/17562848261437918.
- ↑ 10.0 10.1 Caruso R, Lo BC, Núñez G (2020). "Host–microbiota interactions in inflammatory bowel disease". Nat Rev Immunol. 20 (7): 411–426. doi:10.1038/s41577-019-0268-7.
- ↑ Kałużna A, Olczyk P, Komosińska-Vassev K (2022). "The Role of Innate and Adaptive Immune Cells in the Pathogenesis and Development of the Inflammatory Response in Ulcerative Colitis". J Clin Med. 11 (2): 400. doi:10.3390/jcm11020400.
- ↑ 12.0 12.1 Neurath MF (2017). "Current and emerging therapeutic targets for IBD". Nat Rev Gastroenterol Hepatol. 14 (5): 269–278. doi:10.1038/nrgastro.2016.208.
- ↑ 13.0 13.1 Neurath MF (2024). "Strategies for targeting cytokines in inflammatory bowel disease". Nat Rev Immunol. 24 (8): 559–576. doi:10.1038/s41577-024-01008-6.