The gut microbiome–immune axis in inflammatory bowel disease: Microbial mechanisms and therapeutic implications
The human gut microbiome makes up a highly diverse microbial ecosystem that is crucial for host metabolism, immunological modulation, and intestinal barrier integrity. The bacteria phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria dominate the intestinal microbiota, contributing to metabolic processes such as dietary polysaccharide fermentation and the synthesis of bioactive microbial metabolites. Dysbiosis, or disruptions in microbial composition and function, has been linked to the development of autoimmune disorders. Microbial mechanisms that relate dysbiosis to disease include the growth of pro-inflammatory microbial taxa, decreased synthesis of short-chain fatty acids (SCFAs), altered microbial metabolic pathways, and loss of epithelial barrier integrity. Among autoimmune disorders, inflammatory bowel disease (IBD), which encompasses Crohn’s disease and ulcerative colitis, is one of the best-studied cases of microbiome-associated pathology. In this review, we focus on the role of gut microbiome alterations in the pathogenesis of IBD, highlighting microbial dysbiosis, changes in microbial metabolites, and host–microbiome interactions that contribute to intestinal inflammation. This review also examines microbiome-targeted therapeutic strategies, including probiotics, prebiotics, fecal microbiota transplantation, and postbiotics, alongside emerging artificial intelligence–based approaches to personalized treatment, and consider how comorbid systemic conditions may shape microbial homeostasis in IBD patients. Understanding these microbial pathways may open new possibilities for microbiome-based diagnostics and therapeutic approaches in IBD.
- Ouyang H, Yang Y, Zhang X, Cui Y, Zhang Y. Microbial orchestration of neuroimmune crosstalk: from homeostasis to disease. Front Immunol. 2025;16:1679286. doi: 10.3389/fimmu.2025.1679286
- Cortés M, Olate P, Rodriguez R, et al. Human microbiome as an immunoregulatory axis: mechanisms, dysbiosis, and therapeutic modulation. Microorganisms. 2025;13(9):2147. doi: 10.3390/microorganisms13092147
- Han EJ, Ahn JS, Chae YJ, Chung HJ. Immunomodulatory roles of Faecalibacterium prausnitzii and Akkermansia muciniphila in autoimmune diseases: mechanistic insights and therapeutic potential. Clin Rev Allergy Immunol. 2025;68(1):77. doi: 10.1007/s12016-025-09093-8
- Shan Y, Lee M, Chang EB. The gut microbiome and inflammatory bowel diseases. Annu Rev Med. 2022;73(1):455-468. doi: 10.1146/annurev-med-042320-021020
- Nazir A, Hussain FHN, Nadeem Hussain TH, Al Dweik R, Raza A. Therapeutic targeting of the host-microbiota-immune axis: implications for precision health. Front Immunol. 2025;16:1570233. doi: 10.3389/fimmu.2025.1570233
- Abavisani M, Faraji N, Ebadpour N, Kesharwani P, Sahebkar A. Beyond digestion: Exploring how the gut microbiota modulates human social behaviors. Neuroscience. 2025;565:52-62. doi: 10.1016/j.neuroscience.2024.11.068
- Hays KE, Pfaffinger JM, Ryznar R. The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease. Gut Microbes. 2024;16(1):2393270. doi: 10.1080/19490976.2024.2393270
- Zhao Y, Chen J, Qin Y, et al. Linking Short-Chain Fatty Acids to Systemic Homeostasis: Mechanisms, Therapeutic Potential, and Future Directions. J Nutr Metab. 2025;2025:8870958. doi: 10.1155/jnme/8870958
- Zhao L. Guild-Level Response of the Gut Microbiome to Nutritional Signals: Advancing Precision Nutrition for Metabolic Health. Annu Rev Nutr. 2025;45(1):197-221. doi: 10.1146/annurev-nutr-122424-022254
- Park B, Kim JY, Riffey OF, Walsh TJ, Johnson J, Donohoe DR. Crosstalk between butyrate oxidation in colonocyte and butyrate-producing bacteria. iScience. 2024;27(9):110853. doi: 10.1016/j.isci.2024.110853
- Shaheen WA, Quraishi MN, Iqbal TH. Gut microbiome and autoimmune disorders. Clin Exp Immunol. 2022;209(2):161-174. doi: 10.1093/cei/uxac057
- Tao M, Wu T, Zhou X, et al. Butyrate enhances gut dysbiosis by activating the cAMP/PKA/CREB signaling pathway to inhibit the progression of endometrial carcinoma. BMC Microbiol. 2025;25(1):516. doi: 10.1186/s12866-025-04190-2
- Ventura I, Chomon-García M, Tomás-Aguirre F, et al. Therapeutic and Immunologic Effects of Short-Chain Fatty Acids in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci. 2024;25(20):10879. doi: 10.3390/ijms252010879
- Li Q. The gut microbiota as an actor in immunometabolism: impact in inflammatory bowel diseases. Halscience. 2025. doi: 10.70675/f8e4bb82z869cz4996zaec0z0e1ab6c0a7d3.
- Chen C, Wang GQ, Li D, Zhang F. Microbiota-gut-brain axis in neurodegenerative diseases: molecular mechanisms and therapeutic targets. Mol Biomed. 2025;6(1). doi: 10.1186/s43556-025-00307-1
- Ge Z, Chen C, Chen J, et al. Gut Microbiota-Derived 3-Hydroxybutyrate Blocks GPR43-Mediated IL6 Signaling to Ameliorate Radiation Proctopathy. Adv Sci. 2024;11(28):e2306217. doi: 10.1002/advs.202306217
- Yoon KN, Choi YH, Keum GB, et al. Lactiplantibacillus argentoratensis AGMB00912 alleviates diarrhea and promotes the growth performance of piglets during the weaning transition. BMC Microbiol. 2024;24(1):404. doi: 10.1186/s12866-024-03536-6
- Yu Y, Ding Y, Wang S, Jiang L. Gut Microbiota Dysbiosis and Its Impact on Type 2 Diabetes: From Pathogenesis to Therapeutic Strategies. Metabolites. 2025;15(6):397. doi: 10.3390/metabo15060397
- Neagu AI, Bostan M, Ionescu VA, et al. The Impact of the Microbiota on the Immune Response Modulation in Colorectal Cancer. Biomolecules. 2025;15(7):1005. doi: 10.3390/biom15071005
- Lan T, Hou Q, Zhao H, et al. Gut microbiota dysbiosis impairs TGF-β/Smad4 signaling to drive postoperative metastasis in colorectal cancer. Front Microbiol. 2025;16:1654227. doi: 10.3389/fmicb.2025.1654227
- Yoo JY, Sniffen S, McGill Percy KC, Pallaval VB, Chidipi B. Gut Dysbiosis and Immune System in Atherosclerotic Cardiovascular Disease (ACVD). Microorganisms. 2022;10(1):108. doi: 10.3390/microorganisms10010108
- Motte LRD, Giarritiello F, Sala LL, et al. A systematic review of TMAO, microRNAs, and the oral/gut microbiomes in atherosclerosis and myocardial infarction: mechanistic insights and translational opportunities. J Transl Med. 2025. doi: 10.1186/s12967-025-07224-5
- Ni FX, Wang HX, Hu J, et al. The gut-lung axis in COPD: immunomodulatory roles of gut microbiota and novel therapeutic strategies. Front Immunol. 2026;17:1733726. doi: 10.3389/fimmu.2026.1733726
- Lv J, Zhang Y, Liu S, Wang R, Zhao J. Gut-lung axis in allergic asthma: microbiota-driven immune dysregulation and therapeutic strategies. Front Pharmacol. 2025;16:1617546. doi: 10.3389/fphar.2025.1617546
- Wang W, Dernst A, Martin B, et al. Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation. Cell Rep. 2024;43(9):114736. doi: 10.1016/j.celrep.2024.114736
- Kou R, Guo Y, Qin Z, et al. Systemic dysregulation of the gut microenvironment plays a pivotal role in the onset and progression of inflammatory bowel disease. Front Immunol. 2025;16:1661386. doi: 10.3389/fimmu.2025.1661386
- Wang X, Yuan W, Yang C, et al. Emerging role of gut microbiota in autoimmune diseases. Front Immunol. 2024;15:1365554. doi: 10.3389/fimmu.2024.1365554
- Yu S, Zhang M, Dou Z, Tian B, Lu J. Gut microbiota metabolites in the immunoregulation of enteritis: research progress. Front Immunol. 2025;16:1706472. doi: 10.3389/fimmu.2025.1706472
- Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024;15:1386607. doi: 10.3389/fimmu.2024.1386607
- Andoh A, Nishida A. Alteration of the Gut Microbiome in Inflammatory Bowel Disease. Digestion. 2023;104(1):16-23. doi: 10.1159/000525925
- Duan H, Xu B, Luo P, Chen T, Zou J. Microbial metabolites and their influence on the tumor microenvironment. Front Immunol. 2025;16:1675677. doi: 10.3389/fimmu.2025.1675677
- Kaur N, Chen CC, Luther J, Kao JY. Intestinal dysbiosis in inflammatory bowel disease. Gut Microbes. 2011;2(4):211-216. doi: 10.4161/gmic.2.4.17863
- Sultan S, El-Mowafy M, Elgaml A, Ahmed TAE, Hassan H, Mottawea W. Metabolic Influences of Gut Microbiota Dysbiosis on Inflammatory Bowel Disease. Front Physiol. 2021;12:715506. doi: 10.3389/fphys.2021.715506
- Zheng J, Sun Q, Zhang J, Ng SC. The role of gut microbiome in inflammatory bowel disease diagnosis and prognosis. United Eur Gastroenterol J. 2022;10(10):1091-1102. doi: 10.1002/ueg2.12338
- Bernardi F, D’Amico F, Bencardino S, et al. Gut Microbiota Metabolites: Unveiling Their Role in Inflammatory Bowel Diseases and Fibrosis. Pharmaceuticals. 2024;17(3):347. doi: 10.3390/ph17030347
- Iliev ID, Ananthakrishnan AN, Guo CJ. Publisher Correction: Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities. Nat Rev Microbiol. 2025;23(8):541. doi: 10.1038/s41579-025-01175-w
- Bajaj A, Markandey M, Kedia S, Ahuja V. Gut bacteriome in inflammatory bowel disease: An update on recent advances. Indian J Gastroenterol. 2024;43(1):103-111. doi: 10.1007/s12664-024-01541-1
- Cui Y, Huang Y. The Gut-Brain Axis in Comorbidity of Inflammatory Bowel Disease and Anxiety/Depression: Mechanisms, Controversies, and Future Directions. Int J Gen Med. 2026;19:612029. doi: 10.2147/IJGM.S612029
- Zhai J, Li Y, Liu J, Dai C. Neuroimmune interactions: The bridge between inflammatory bowel disease and the gut microbiota. Clin Transl Med. 2025;15(5):e70329. doi: 10.1002/ctm2.70329
- Alem M, Abtahi Froushani SM, Hajighahramani N, Hosseini-Asl S, Pourfarzi F, Nemati R. Immuno-informatics voyage through molecular mimicry of Heat Shock Proteins: Potential IBD immunopathogenesis. PLoS ONE. 2025;20(10):e0333618. doi: 10.1371/journal.pone.0333618
- Liu X, Lu B, Tang H, et al. Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors. eBioMedicine. 2024;109:105427. doi: 10.1016/j.ebiom.2024.105427
- Muruganandam A, Migliorini F, Jeyaraman N, et al. Molecular Mimicry Between Gut Microbiome and Rheumatoid Arthritis: Current Concepts. Med Sci. 2024;12(4):72. doi: 10.3390/medsci12040072
- Al-Habsi N, Al-Khalili M, Haque SA, Elias M, Olqi NA, Al Uraimi T. Health Benefits of Prebiotics, Probiotics, Synbiotics, and Postbiotics. Nutrients. 2024;16(22):3955. doi: 10.3390/nu16223955
- Haneishi Y, Furuya Y, Hasegawa M, Picarelli A, Rossi M, Miyamoto J. Inflammatory Bowel Diseases and Gut Microbiota. Int J Mol Sci. 2023;24(4):3817. doi: 10.3390/ijms24043817
- Ghouri YA, Richards DM, Rahimi EF, Krill JT, Jelinek KA, DuPont AW. Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. Clin Exp Gastroenterol. 2014;7:473-487. doi: 10.2147/CEG.S27530
- Yang X, Guo H, Zou M. Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives. Mol Biomed. 2026;7(1):2. doi: 10.1186/s43556-025-00395-z
- Saez-Lara MJ, Gomez-Llorente C, Plaza-Diaz J, Gil A. The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials. Biomed Res Int. 2015;2015:505878. doi: 10.1155/2015/505878
- Estevinho MM, Yuan Y, Rodríguez-Lago I, et al. Efficacy and safety of probiotics in IBD: An overview of systematic reviews and updated meta-analysis of randomized controlled trials. United Eur Gastroenterol J. 2024;12(7):960-981. doi: 10.1002/ueg2.12636
- Ng SC, Hart AL, Kamm MA, Stagg AJ, Knight SC. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis. 2009;15(2):300-310. doi: 10.1002/ibd.20602
- Roy S, Dhaneshwar S. Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: Current perspectives. World J Gastroenterol. 2023;29(14):2078-2100. doi: 10.3748/wjg.v29.i14.2078
- Alvarez CS, Badia J, Bosch M, Giménez R, Baldomà L. Outer Membrane Vesicles and Soluble Factors Released by Probiotic Escherichia coli Nissle 1917 and Commensal ECOR63 Enhance Barrier Function by Regulating Expression of Tight Junction Proteins in Intestinal Epithelial Cells. Front Microbiol. 2016;7:1981. doi: 10.3389/fmicb.2016.01981
- Yao S, Zhao Z, Wang W, Liu X. Bifidobacterium Longum: Protection against Inflammatory Bowel Disease. J Immunol Res. 2021;2021:1-11. doi: 10.1155/2021/8030297
- Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53(11):1617-1623. doi: 10.1136/gut.2003.037747
- Schultz M. Clinical use of E. coli Nissle 1917 in inflammatory bowel disease. Inflamm Bowel Dis. 2008;14(7):1012-1018. doi: 10.1002/ibd.20377
- Akutko K, Stawarski A. Probiotics, Prebiotics and Synbiotics in Inflammatory Bowel Diseases. J Clin Med. 2021;10(11):2466. doi: 10.3390/jcm10112466
- Khan I, Ullah N, Zha L, et al. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens. 2019;8(3):126. doi: 10.3390/pathogens8030126
- Costa RL, Moreira J, Lorenzo A, Lamas CC. Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series. BMC Complement Altern Med. 2018;18(1):329. doi: 10.1186/s12906-018-2394-3
- Orel R, Kamhi Trop T. Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease. World J Gastroenterol. 2014;20(33):11505-11524. doi: 10.3748/wjg.v20.i33.11505
- Bashir Yahya E, Abdulsamad AA, Suliman Aburowais MA, Abogmaza AF. Insights into microbiome-based therapeutics: engineered probiotics, bacteriophages, and microbiome-derived metabolites. Biomed Res Ther. 2025;12(12):8062-8071. doi: 10.15419/35b1xn36
- Wang X, Peng J, Cai P, et al. The emerging role of the gut microbiota and its application in inflammatory bowel disease. Biomed Pharmacother. 2024;179:117302. doi: 10.1016/j.biopha.2024.117302
- Parada Venegas D, De la Fuente MK, Landskron G, et al. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front Immunol. 2019;10:277. doi: 10.3389/fimmu.2019.00277
- Zhou J, Li M, Chen Q, et al. Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective oral delivery. Nat Commun. 2022;13(1):3432. doi: 10.1038/s41467-022-31171-0
- Martyniak A, Medyńska-Przęczek A, Wędrychowicz A, Skoczeń S, Tomasik PJ. Prebiotics, Probiotics, Synbiotics, Paraprobiotics and Postbiotic Compounds in IBD. Biomolecules. 2021;11(12):1903. doi: 10.3390/biom11121903
- Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Muir JG, Gibson PR. Consistent Prebiotic Effect on Gut Microbiota With Altered FODMAP Intake in Patients with Crohn’s Disease: A Randomised, Controlled Cross-Over Trial of Well-Defined Diets. Clin Transl Gastroenterol. 2016;7(4):e164. doi: 10.1038/ctg.2016.22
- Furrie E, Macfarlane S, Kennedy A, et al. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut. 2005;54(2):242-249. doi: 10.1136/gut.2004.044834
- Looijer-van Langen MA, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflamm Bowel Dis. 2009;15(3):454-462. doi: 10.1002/ibd.20737
- Butterworth AD, Thomas AG, Akobeng AK. Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008. doi: 10.1002/14651858.CD006634.pub2.
- Russo E, Giudici F, Fiorindi C, Ficari F, Scaringi S, Amedei A. Immunomodulating Activity and Therapeutic Effects of Short Chain Fatty Acids and Tryptophan Post-biotics in Inflammatory Bowel Disease. Front Immunol. 2019;10:2754. doi: 10.3389/fimmu.2019.02754
- Wedlake L, Slack N, Andreyev HJ, Whelan K. Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel Dis. 2014;20(3):576-586. doi: 10.1097/01.MIB.0000437984.92565.31
- Imdad A, Nicholson MR, Tanner-Smith EE, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2018;2018(11):CD012774. doi: 10.1002/14651858.CD012774.pub2
- Zeng L, Deng Y, Yang K, Chen J, He Q, Chen H. Safety and efficacy of fecal microbiota transplantation for autoimmune diseases and autoinflammatory diseases: A systematic review and meta-analysis. Front Immunol. 2022;13:944387. doi: 10.3389/fimmu.2022.944387
- Rossen NG, Fuentes S, van der Spek MJ, et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology. 2015;149(1):110-118.e4. doi: 10.1053/j.gastro.2015.03.045
- Boicean A, Birlutiu V, Ichim C, Anderco P, Birsan S. Fecal Microbiota Transplantation in Inflammatory Bowel Disease. Biomedicines. 2023;11(4):1016. doi: 10.3390/biomedicines11041016
- Costello SP, Hughes PA, Waters O, et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA. 2019;321(2):156-164. doi: 10.1001/jama.2018.20046
- Sokol H, Landman C, Seksik P, et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome. 2020;8(1):12. doi: 10.1186/s40168-020-0792-5
- Vermeire S, Joossens M, Verbeke K, et al. Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease. J Crohns Colitis. 2016;10(4):387-394. doi: 10.1093/ecco-jcc/jjv203
- Tan P, Li X, Shen J, Feng Q. Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease: An Update. Front Pharmacol. 2020;11:574533. doi: 10.3389/fphar.2020.574533
- Cui B, Li P, Xu L, et al. Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis. J Transl Med. 2015;13:298. doi: 10.1186/s12967-015-0646-2
- Prajapati SK, Yadav D, Katiyar S, Jain S, Yadav H. Postbiotics as Mitochondrial Modulators in Inflammatory Bowel Disease: Mechanistic Insights and Therapeutic Potential. Biomolecules. 2025;15(7):954. doi: 10.3390/biom15070954
- Zhang T, Zhang W, Feng C, Kwok LY, He Q, Sun Z. Stronger gut microbiome modulatory effects by postbiotics than probiotics in a mouse colitis model. npj Sci Food. 2022;6(1):53. doi: 10.1038/s41538-022-00169-9
- Tsilingiri K, Barbosa T, Penna G, et al. Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model. Gut. 2012;61(7):1007-1015. doi: 10.1136/gutjnl-2011-300971
- Banfi D, Moro E, Bosi A, et al. Impact of Microbial Metabolites on Microbiota-Gut-Brain Axis in Inflammatory Bowel Disease. Int J Mol Sci. 2021;22(4):1623. doi: 10.3390/ijms22041623
- Štofilová J, Kvaková M, Kamlárová A, Hijová E, Bertková I, Guľašová Z. Probiotic-Based Intervention in the Treatment of Ulcerative Colitis: Conventional and New Approaches. Biomedicines. 2022;10(9):2236. doi: 10.3390/biomedicines10092236
- Kharb A, Zhu X. Unlocking therapeutic impacts of the gut microbiota with computational tools. Curr Opin Biotechnol. 2026;97:103431. doi: 10.1016/j.copbio.2025.103431
- Liu J, Zhao P, Jiang D, et al. Decoding the microbiome: artificial intelligence-targeted gut microenvironment breakthroughs in personalized cancer therapy. Gut Microbes. 2026;18(1):2672791. doi: 10.1080/19490976.2026.2672791
