Molecular and Immune Mechanisms in Ulcerative Colitis Pathophysiology
Article Sidebar
Main Article Content
Abstract
Ulcerative colitis is a chronic inflammatory bowel disease characterized by continuous, predominantly mucosal inflammation beginning in the rectum. This narrative review integrates epithelial, microbial, genetic, metabolic, and immune mechanisms that sustain colonic injury. Barrier disruption, altered mucus, and changes in sealing and pore-forming tight-junction proteins increase exposure of the lamina propria to luminal antigens. Pattern-recognition and inflammasome pathways can amplify tumour-necrosis-factor, interleukin-1, interleukin-6, and chemokine signalling, but their contribution varies by cell type, disease stage, and treatment. Adaptive immunity is heterogeneous: UC has classically been associated with an atypical Th2/IL-13 axis, while IL-23/Th17 pathways and defective regulatory networks contribute in subsets of patients. NOD2 and autophagy variants are central to Crohn disease genetics and should not be presented as defining abnormalities of UC. Dysbiosis and reduced short-chain-fatty-acid production may impair epithelial repair, although no universal microbial signature or single causal organism has been established. Neutrophil recruitment, oxidative injury, and incomplete resolution contribute to ulceration, bleeding, urgency, and diarrhoea; transmural dysfunction and toxic megacolon occur mainly in severe or fulminant disease. Persistent inflammation also increases dysplasia risk. These interacting mechanisms support phenotype-aware treatment while cautioning against universal pathway claims. Because the evidence was narratively selected, the conclusions require confirmation through a transparent and reproducible search strategy.
Article Details
References
Garza-Hernandez D, Sepulveda-Villegas M, Garcia-Pelaez J, Aguirre-Gamboa R, Lakatos PL, Estrada K, et al. A systematic review and functional bioinformatics analysis of genes associated with Crohn’s disease identify more than 120 related genes. BMC Genomics [Internet]. 2022;23(1):1–14. Available from: https://doi.org/10.1186/s12864-022-08491-y
2. Purnomo HD, Permatadewi CO, Prasetyo A, Indiarso D, Hutami HT, Puspasari D, et al. Colorectal cancer screening in Semarang, Indonesia: A multicenter primary health care based study. PLoS One [Internet]. 2023;18(1 January):1–12. Available from: http://dx.doi.org/10.1371/journal.pone.0279570
3. Okamoto R, Watanabe M. Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease. J Gastroenterol. 2016;51(1):11–21.
4. Lu ZK, Chen ZR, Zhu JY, Xu Y, Hua X. Analysis of the association of single nucleotide polymorphisms of interleukin-23 receptor (IL-23R) and inflammatory bowel disease in a Chinese Han cohort. Oncotarget. 2016;7(42):67851–6.
5. Cang X, Li N, Qi J, Chen H, Xing H, Qiu J, et al. Identification of immune-associated genes for the diagnosis of ulcerative colitis-associated carcinogenesis via integrated bioinformatics analysis. Front Oncol. 2024;14(November):1–16.
6. Gadjalova I, Heinze JM, Goess MC, Hofmann J, Buck A, Weber MC, et al. B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation. Mucosal Immunol [Internet]. 2024;17(1):67–80. Available from: https://doi.org/10.1016/j.mucimm.2023.10.005
7. Liu Z, Zhang Y, Jin T, Yi C, Ocansey DKW, Mao F. The role of NOD2 in intestinal immune response and microbiota modulation: A therapeutic target in inflammatory bowel disease. Int Immunopharmacol [Internet]. 2022;113(PB):109466. Available from: https://doi.org/10.1016/j.intimp.2022.109466
8. Jergens AE, Parvinroo S, Kopper J, Wannemuehler MJ. Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease. Front Med. 2021;8(August):1–17.
9. García-Miguel M, González MJ, Quera R, Hermoso MA. Innate immunity modulation by the IL-33/ST2 system in intestinal mucosa. Biomed Res Int. 2013;2013.
10. Lee J, Lozano-Ruiz B, Yang FM, Fan DD, Shen L, González-Navajas JM. The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy. Front Immunol. 2021;12(March):1–12.
11. Liu C, Zeng Y, Wen Y, Huang X, Liu Y. Natural Products Modulate Cell Apoptosis: A Promising Way for the Treatment of Ulcerative Colitis. Front Pharmacol. 2022;13(January):1–16.
12. Liu T, Li Q, Jin Q, Yang L, Mao H, Qu P, et al. Targeting HMGB1: A Potential Therapeutic Strategy for Chronic Kidney Disease. Int J Biol Sci. 2023;19(15):5020–35.
13. Tang R, Li L. Modulation of Short-Chain Fatty Acids as Potential Therapy Method for Type 2 Diabetes Mellitus. Can J Infect Dis Med Microbiol. 2021;2021.
14. Abbas AK, Litchman A h., Pillai S. Cellular and Molecular Immunology. Ninth Edit. Abbas AK, editor. Elsevier. Elsevier; 2018. 1–514 p.
15. Agraib LM, Yamani MI, Tayyem R, Abu-Sneineh AT, Rayyan YM. Probiotic supplementation induces remission and changes in the immunoglobulins and inflammatory response in active ulcerative colitis patients: A pilot, randomized, double-blind, placebo-controlled study. Clin Nutr ESPEN [Internet]. 2022;51:83–91. Available from: https://doi.org/10.1016/j.clnesp.2022.08.020
16. Démaris A, Widigson ESK, Ilvemark JFKF, Steenholdt C, Seidelin JB, Huisinga W, et al. Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review. Pharmaceutics. 2022;14(10).
17. Park SC, Jeen YT. Genetic studies of inflammatory bowel disease-focusing on Asian patients. Cells. 2019;8(5):1–22.
18. Winkelmann P, Unterweger AL, Khullar D, Beigel F, Koletzko L, Siebeck M, et al. The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease. Immunity, Inflamm Dis. 2021;9(3):804–18.
19. Zhang Y, George J, Li Y, Olufade R, Zhao X. Matrix metalloproteinase-9 expression is enhanced in renal parietal epithelial cells of Zucker diabetic fatty rats and is induced by albumin in in vitro primary parietal cell culture. PLoS One. 2015;10(4):1–20.
20. Mao L, Kitani A, Strober W, Fuss IJ. The role of NLRP3 and IL-1β in the pathogenesis of inflammatory bowel disease. Front Immunol. 2018;9(NOV):1–9.
21. Hidalgo A, Libby P, Soehnlein O, Aramburu IV, Papayannopoulos V, Silvestre-Roig C. Neutrophil extracellular traps: from physiology to pathology. Cardiovasc Res. 2022;118(13):2737–53.
22. Yeshi K, Ruscher R, Hunter L, Daly NL, Loukas A, Wangchuk P. Revisiting inflammatory bowel disease: Pathology, treatments, challenges and emerging therapeutics including drug leads from natural products. J Clin Med. 2020;9(5):1–39.
23. Dutra IL, Araújo LG, Assunção RG, Lima YA, Nascimento JR, Vale AAM, et al. Pic-producing escherichia coli induces high production of proinflammatory mediators by the host leading to death by sepsis. Int J Mol Sci. 2020;21(6).
24. Redsted M, Grønhøj M, Brøchner LD, Fassov JL, Svart MV, Andersen JR, et al. Metabolic stress in patients with acute severe ulcerative colitis - A single-center cohort study. Clin Nutr ESPEN. 2023;58(November):603.
25. Herrador-López M, Martín-Masot R, Navas-López VM. Dietary Interventions in Ulcerative Colitis: A Systematic Review of the Evidence with Meta-Analysis. Nutrients. 2023;15(19):1–20.
26. Carreras J. Artificial Intelligence Analysis of Ulcerative Colitis Using an Autoimmune Discovery Transcriptomic Panel. Healthc. 2022;10(8).
27. Morita M, Takedatsu H, Yoshioka S, Mitsuyama K, Tsuruta K, Kuwaki K, et al. Utility of Diagnostic Colonoscopy in Pediatric Intestinal Disease. J Clin Med. 2022;11(19):1–9.
28. Bertram G. Katzung, Masters SB, Trevor AJ. Farmakologi Dasar & Klinik Edisi 12, Katzung. 12th ed. Katzung BG, Masters SB, Trevor AJ, editors. Vol. 1, McGraw-Hill Medical. New York: McGraw-Hill Medical Lange; 2015. 1–1245 p.