Ulcerative colitis causes
Jump to navigation
Jump to search
|
Ulcerative colitis Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Ulcerative colitis causes On the Web |
|
American Roentgen Ray Society Images of Ulcerative colitis causes |
|
Risk calculators and risk factors for Ulcerative colitis causes |
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
No single cause of ulcerative colitis (UC) has been identified. The current model is that UC results from a dysregulated innate and adaptive mucosal immune response against the commensal gut microbiota. This response occurs in genetically susceptible individuals and is triggered or shaped by environmental exposures and a defective epithelial barrier.[1][2][3] Genetic risk is polygenic and explains only a small fraction of disease variance. Family history is the strongest individual risk factor. Environmental associations include an inverse association with current smoking and appendectomy, and positive associations with former smoking, enteric infection, antibiotic exposure, and Westernized diet. Dysbiosis is consistently present, but it is both a cause and a consequence of inflammation.
Causes
Genetic susceptibility
- Polygenic, low-penetrance architecture: Genome-wide association studies have identified more than 240 inflammatory bowel disease (IBD) risk loci. Most loci are shared between UC and Crohn's disease.[3][2] Known loci explain only about 4–7.5% of disease variance in UC (vs. about 8–13% in Crohn's disease), so genetic testing has no predictive or diagnostic role in routine adult practice.[3]
- Family history: About 8–14% of patients with UC report a family history of IBD. First-degree relatives have an approximately 4-fold increased risk.[4][5]
- UC-predominant barrier genes: Loci involved in epithelial barrier and cell-adhesion function are characteristic of UC. Examples are HNF4A, CDH1 (E-cadherin), LAMB1, and ECM1.[4][3]
- HLA region: The strongest UC association is in the MHC class II (HLA-DR) region. The HLA-DRB1*0103 allele is associated with extensive disease and a higher risk of colectomy.[6]
- Shared immune pathways: Genes in the IL-23/Th17 pathway (IL23R, IL12B, STAT3, JAK2, TYK2) and IL-10 signaling are implicated in both UC and Crohn's disease. Several of these pathways are now direct drug targets.[3]
- Disease-divergent loci: Some variants have opposite effects in the two diseases. NOD2 and PTPN22 variants increase Crohn's disease risk but appear protective in UC. For this reason, Crohn's-centric genetics should not be applied to UC.[7]
- Ancestry: Most GWAS data come from European and East Asian cohorts. Studies in African American populations have replicated HLA-DRB1 and identified ancestry-specific UC loci (ZNF649, LSAMP). Trans-ancestry meta-analysis has added further novel IBD loci.[8][9]
- Very-early-onset IBD: This is the main exception to polygenic risk. Monogenic defects, most notably in IL-10 and IL-10 receptor signaling, can be causative and clinically actionable.[3]
Environmental factors
The rising global incidence of UC suggests a dominant environmental contribution, as does the convergence of risk in immigrants toward that of high-incidence host countries.[1] Most associations come from observational, often retrospective studies.
- Enteric infection/antibiotics
- Westernized diet
- Urban living, oral contraceptives, vitaming D deficiency
- NSAIDs
Gut microbiome and dysbiosis
- UC is consistently associated with reduced microbial diversity. Butyrate-producing Firmicutes (e.g., Faecalibacterium prausnitzii, Lachnospiraceae) are depleted, and facultative pathobionts (e.g., Proteobacteria, Escherichia) are expanded.[10][11]
- No single causative organism has been identified. In the pathobiont model, otherwise-commensal microbes become pro-inflammatory under permissive host conditions.[12]
- Causality runs in both directions and is unresolved. Inflammation increases luminal oxygen and nitrate, which favors Proteobacteria. Cross-sectional microbiome signatures should therefore not be read as evidence of causation.[10]
Immune dysregulation and epithelial barrier dysfunction
- Adaptive immunity: UC shows an atypical Th2-skewed and Th17 effector response with regulatory T cell imbalance. Mediators include TNF, IL-13, IL-5, IL-17, IL-21, IL-22, and IL-23–regulated pathways.[1][6]
- Innate immunity: Contributors include neutrophil accumulation with extracellular-trap formation, pro-inflammatory dendritic cells and macrophages, and innate lymphoid cells.[1][13]
- Barrier failure: A defective mucus layer and impaired cell adhesion allow microbial antigens to penetrate the mucosa. This fits the UC-predominant barrier-gene associations described above.[3]
- Therapeutic relevance: These pathways are the basis of current targeted therapies: anti-TNF agents, anti-α4β7 integrin (vedolizumab), anti-IL-12/23 and anti-IL-23 agents (ustekinumab, mirikizumab), JAK inhibitors (tofacitinib), and S1P-receptor modulators (ozanimod). See the medical therapy microchapter for details.[2]
Clinical implications
- UC is not a single-gene or single-pathogen disease. Genetic or microbiome testing to "find the cause" is not indicated in routine adult UC because it does not change management.[3]
- First-degree relatives have about a 4-fold increased risk, which is relevant to counseling and diagnostic suspicion. No validated primary prevention strategy exists.[5][1]
- In new-onset or flaring disease, take a history of recent enteric infection, antibiotic use, and smoking cessation. These are associations rather than proven causes.[4][12]
Areas of uncertainty
- Whether dysbiosis is a cause or a consequence of inflammation remains unresolved.[10]
- Most heritability is still unexplained. Rare variants, epigenetics, and gene–environment interactions are active research areas.[1]
- Environmental associations are mostly retrospective and prone to recall bias and reverse causation. Some, such as the smoking and appendectomy effects, may differ by region.[4][5]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Le Berre C, Honap S, Peyrin-Biroulet L (2023). "Ulcerative colitis". Lancet. 402 (10401): 571–584. doi:10.1016/S0140-6736(23)00966-2. PMID 37573077 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 Gros B, Kaplan GG (2023). "Ulcerative colitis in adults: a review". JAMA. 330 (10): 951–965. doi:10.1001/jama.2023.15389. PMID 37698557 Check
|pmid=value (help). - ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Chang JT (2020). "Pathophysiology of inflammatory bowel diseases". N Engl J Med. 383 (27): 2652–2664. doi:10.1056/NEJMra2002697. PMID 33382932 Check
|pmid=value (help). - ↑ 4.0 4.1 4.2 4.3 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.
- ↑ 5.0 5.1 5.2 Bouhuys M, Lexmond WS, van Rheenen PF (2023). "Pediatric inflammatory bowel disease". Pediatrics. 151 (1): e2022058037. doi:10.1542/peds.2022-058037. PMID 36545774 Check
|pmid=value (help). - ↑ 6.0 6.1 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. PMID 22914296.
- ↑ Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY; et al. (2012). "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease". Nature. 491 (7422): 119–124. doi:10.1038/nature11582. PMID 23128233.
- ↑ Brant SR, Okou DT, Simpson CL; et al. (2017). "Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease". Gastroenterology. 152 (1): 206–217.e2.
- ↑ Cordero RY, Cordero JB, Stiemke AB, Datta LW, Buyske S, Kugathasan S, McGovern DPB, Brant SR, Simpson CL (2023). "Trans-ancestry, Bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian and European cohort". Hum Mol Genet. PMC 9941836 Check
|pmc=value (help). - ↑ 10.0 10.1 10.2 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. PMID 32005980 Check
|pmid=value (help). - ↑ Jamal F, Odeh NB, Alatout MHI, Khan MA, Pasha SB; et al. (2026). "Diet in ulcerative colitis: a narrative review of its role in pathogenesis and treatment". Dig Dis Sci. PMID 40982139 Check
|pmid=value (help). - ↑ 12.0 12.1 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). - ↑ 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. PMID 35054093 Check
|pmid=value (help).