THE ROLE OF SHORT-CHAIN FATTY ACIDS IN IMMUNE REGULATION AND INTESTINAL HOMEOSTASIS IN INFLAMMATORY BOWEL DISEASE
Abstract
Background: Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation driven by dysregulated immune responses and impaired epithelial barrier function. Increasing evidence highlights short-chain fatty acids (SCFAs)—particularly acetate, propionate, and butyrate—produced by gut microbiota as key mediators linking microbial composition to immune regulation and maintenance of intestinal homeostasis.
Methodology: This review was conducted through an extensive analysis of clinical, experimental, and translational studies indexed in PubMed, Google Scholar, and the Cochrane Library, focusing on gut microbiota composition, SCFA metabolism, epithelial barrier integrity, immune mechanisms, and SCFA-targeted therapeutic strategies in IBD.
Results: Patients with IBD consistently show reduced abundance of SCFA-producing bacteria, especially butyrate-generating taxa such as Faecalibacterium and Roseburia, accompanied by decreased fecal SCFA levels and impaired epithelial SCFA utilization. SCFAs exert potent anti-inflammatory effects via histone deacetylase inhibition and activation of SCFA-responsive G protein-coupled receptors, promoting regulatory immune phenotypes and suppressing pro-inflammatory signaling. Concurrently, they enhance intestinal barrier function by stimulating mucus production, reinforcing tight junctions, and supporting epithelial metabolic activity. Dietary fiber enrichment, prebiotics, probiotics, and microbiota-directed therapies demonstrate potential to restore SCFA availability and improve inflammatory and clinical outcomes, although responses remain heterogeneous.
Conclusions: SCFAs represent a crucial interface between gut microbiota, immune regulation, and epithelial barrier integrity, positioning SCFA-related mechanisms as promising therapeutic targets in IBD. Despite encouraging evidence, further well-designed, mechanistic, and personalized studies are needed to clarify causality, optimize SCFA-based interventions, and translate findings into effective clinical strategies.
References
Cai, Z., Wang, S., & Li, J. (2021). Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Frontiers in Medicine, 8, 765474. https://doi.org/10.3389/fmed.2021.765474
Caron, B., Honap, S., & Peyrin-Biroulet, L. (2024). Epidemiology of Inflammatory Bowel Disease across the Ages in the Era of Advanced Therapies. Journal of Crohn’s & Colitis, 18(Supplement_2), ii3–ii15. https://doi.org/10.1093/ecco-jcc/jjae082
Chen, Y., Zhou, J., & Wang, L. (2021). Role and Mechanism of Gut Microbiota in Human Disease. Frontiers in Cellular and Infection Microbiology, 11, 625913. https://doi.org/10.3389/fcimb.2021.625913
Cronin, P., Joyce, S. A., O’Toole, P. W., & O’Connor, E. M. (2021). Dietary Fibre Modulates the Gut Microbiota. Nutrients, 13(5), 1655. https://doi.org/10.3390/nu13051655
Damen, B., Cloetens, L., Broekaert, W. F., François, I., Lescroart, O., Trogh, I., Arnaut, F., Welling, G. W., Wijffels, J., Delcour, J. A., Verbeke, K., & Courtin, C. M. (2012). Consumption of breads containing in situ-produced arabinoxylan oligosaccharides alters gastrointestinal effects in healthy volunteers. The Journal of Nutrition, 142(3), 470–477. https://doi.org/10.3945/jn.111.146464
De Preter, V., Arijs, I., Windey, K., Vanhove, W., Vermeire, S., Schuit, F., Rutgeerts, P., & Verbeke, K. (2012). Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway. Inflammatory Bowel Diseases, 18(6), 1127–1136. https://doi.org/10.1002/ibd.21894
Deleu, S., Machiels, K., Raes, J., Verbeke, K., & Vermeire, S. (2021). Short chain fatty acids and its producing organisms: An overlooked therapy for IBD? EBioMedicine, 66, 103293. https://doi.org/10.1016/j.ebiom.2021.103293
Derrien, M., Vaughan, E. E., Plugge, C. M., & de Vos, W. M. (2004). Akkermansia muciniphila gen. Nov., sp. Nov., a human intestinal mucin-degrading bacterium. International Journal of Systematic and Evolutionary Microbiology, 54(Pt 5), 1469–1476. https://doi.org/10.1099/ijs.0.02873-0
Di Tommaso, N., Gasbarrini, A., & Ponziani, F. R. (2021). Intestinal Barrier in Human Health and Disease. International Journal of Environmental Research and Public Health, 18(23), 12836. https://doi.org/10.3390/ijerph182312836
Dostal, A., Lacroix, C., Bircher, L., Pham, V. T., Follador, R., Zimmermann, M. B., & Chassard, C. (2015). Iron Modulates Butyrate Production by a Child Gut Microbiota In Vitro. mBio, 6(6), e01453-01415. https://doi.org/10.1128/mBio.01453-15
Facchin, S., Vitulo, N., Calgaro, M., Buda, A., Romualdi, C., Pohl, D., Perini, B., Lorenzon, G., Marinelli, C., D’Incà, R., Sturniolo, G. C., & Savarino, E. V. (2020). Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterology and Motility, 32(10), e13914. https://doi.org/10.1111/nmo.13914
Guan, Q. (2019). A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. Journal of Immunology Research, 2019, 7247238. https://doi.org/10.1155/2019/7247238
Hays, K. E., Pfaffinger, J. M., & Ryznar, R. (2024). The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease. Gut Microbes, 16(1), 2393270. https://doi.org/10.1080/19490976.2024.2393270
Hou, H., Chen, D., Zhang, K., Zhang, W., Liu, T., Wang, S., Dai, X., Wang, B., Zhong, W., & Cao, H. (2022). Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation? Cancer Letters, 526, 225–235. https://doi.org/10.1016/j.canlet.2021.11.027
Kelly, C. J., Zheng, L., Campbell, E. L., Saeedi, B., Scholz, C. C., Bayless, A. J., Wilson, K. E., Glover, L. E., Kominsky, D. J., Magnuson, A., Weir, T. L., Ehrentraut, S. F., Pickel, C., Kuhn, K. A., Lanis, J. M., Nguyen, V., Taylor, C. T., & Colgan, S. P. (2015). Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host & Microbe, 17(5), 662–671. https://doi.org/10.1016/j.chom.2015.03.005
Khan, M. T., Duncan, S. H., Stams, A. J. M., van Dijl, J. M., Flint, H. J., & Harmsen, H. J. M. (2012). The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic-anoxic interphases. The ISME Journal, 6(8), 1578–1585. https://doi.org/10.1038/ismej.2012.5
Koleva, P. T., Valcheva, R. S., Sun, X., Gänzle, M. G., & Dieleman, L. A. (2012). Inulin and fructo-oligosaccharides have divergent effects on colitis and commensal microbiota in HLA-B27 transgenic rats. The British Journal of Nutrition, 108(9), 1633–1643. https://doi.org/10.1017/S0007114511007203
Lo Sasso, G., Khachatryan, L., Kondylis, A., Battey, J. N. D., Sierro, N., Danilova, N. A., Grigoryeva, T. V., Markelova, M. I., Khusnutdinova, D. R., Laikov, A. V., Salafutdinov, I. I., Romanova, Y. D., Siniagina, M. N., Vasiliev, I. Y., Boulygina, E. A., Solovyeva, V. V., Garanina, E. E., Kitaeva, K. V., Ivanov, K. Y., … Abdulkhakov, S. R. (2021). Inflammatory Bowel Disease-Associated Changes in the Gut: Focus on Kazan Patients. Inflammatory Bowel Diseases, 27(3), 418–433. https://doi.org/10.1093/ibd/izaa188
Louis, P., & Flint, H. J. (2009). Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiology Letters, 294(1), 1–8. https://doi.org/10.1111/j.1574-6968.2009.01514.x
Louis, P., & Flint, H. J. (2017). Formation of propionate and butyrate by the human colonic microbiota. Environmental Microbiology, 19(1), 29–41. https://doi.org/10.1111/1462-2920.13589
Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., Ballet, V., Claes, K., Van Immerseel, F., Verbeke, K., Ferrante, M., Verhaegen, J., Rutgeerts, P., & Vermeire, S. (2014). A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut, 63(8), 1275–1283. https://doi.org/10.1136/gutjnl-2013-304833
Miao, W., Wu, X., Wang, K., Wang, W., Wang, Y., Li, Z., Liu, J., Li, L., & Peng, L. (2016). Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2. International Journal of Molecular Sciences, 17(10), 1696. https://doi.org/10.3390/ijms17101696
Miller, T. L., & Wolin, M. J. (1996). Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Applied and Environmental Microbiology, 62(5), 1589–1592. https://doi.org/10.1128/aem.62.5.1589-1592.1996
Neurath, M. F., Artis, D., & Becker, C. (2025). The intestinal barrier: A pivotal role in health, inflammation, and cancer. The Lancet. Gastroenterology & Hepatology, 10(6), 573–592. https://doi.org/10.1016/S2468-1253(24)00390-X
O’Riordan, K. J., Collins, M. K., Moloney, G. M., Knox, E. G., Aburto, M. R., Fülling, C., Morley, S. J., Clarke, G., Schellekens, H., & Cryan, J. F. (2022). Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Molecular and Cellular Endocrinology, 546, 111572. https://doi.org/10.1016/j.mce.2022.111572
Parada Venegas, D., De la Fuente, M. K., Landskron, G., González, M. J., Quera, R., Dijkstra, G., Harmsen, H. J. M., Faber, K. N., & Hermoso, M. A. (2019). Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Frontiers in Immunology, 10, 277. https://doi.org/10.3389/fimmu.2019.00277
Pral, L. P., Fachi, J. L., Corrêa, R. O., Colonna, M., & Vinolo, M. A. R. (2021). Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends in Immunology, 42(7), 604–621. https://doi.org/10.1016/j.it.2021.05.004
Qiu, P., Ishimoto, T., Fu, L., Zhang, J., Zhang, Z., & Liu, Y. (2022). The Gut Microbiota in Inflammatory Bowel Disease. Frontiers in Cellular and Infection Microbiology, 12, 733992. https://doi.org/10.3389/fcimb.2022.733992
Rauch, C. E., Mika, A. S., McCubbin, A. J., Huschtscha, Z., & Costa, R. J. S. (2022). Effect of prebiotics, probiotics, and synbiotics on gastrointestinal outcomes in healthy adults and active adults at rest and in response to exercise-A systematic literature review. Frontiers in Nutrition, 9, 1003620. https://doi.org/10.3389/fnut.2022.1003620
Rooks, M. G., & Garrett, W. S. (2016). Gut microbiota, metabolites and host immunity. Nature Reviews. Immunology, 16(6), 341–352. https://doi.org/10.1038/nri.2016.42
Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P. D., Manicassamy, S., Munn, D. H., Lee, J. R., Offermanns, S., & Ganapathy, V. (2014). Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity, 40(1), 128–139. https://doi.org/10.1016/j.immuni.2013.12.007
Sun, M., Wu, W., Liu, Z., & Cong, Y. (2017). Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. Journal of Gastroenterology, 52(1), 1–8. https://doi.org/10.1007/s00535-016-1242-9
Tao, R., de Zoeten, E. F., Ozkaynak, E., Chen, C., Wang, L., Porrett, P. M., Li, B., Turka, L. A., Olson, E. N., Greene, M. I., Wells, A. D., & Hancock, W. W. (2007). Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Medicine, 13(11), 1299–1307. https://doi.org/10.1038/nm1652
Trompette, A., Gollwitzer, E. S., Yadava, K., Sichelstiel, A. K., Sprenger, N., Ngom-Bru, C., Blanchard, C., Junt, T., Nicod, L. P., Harris, N. L., & Marsland, B. J. (2014). Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nature Medicine, 20(2), 159–166. https://doi.org/10.1038/nm.3444
Vinolo, M. A. R., Rodrigues, H. G., Hatanaka, E., Sato, F. T., Sampaio, S. C., & Curi, R. (2011). Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. The Journal of Nutritional Biochemistry, 22(9), 849–855. https://doi.org/10.1016/j.jnutbio.2010.07.009
Wagenaar, C. A., van de Put, M., Bisschops, M., Walrabenstein, W., de Jonge, C. S., Herrema, H., & van Schaardenburg, D. (2021). The Effect of Dietary Interventions on Chronic Inflammatory Diseases in Relation to the Microbiome: A Systematic Review. Nutrients, 13(9), 3208. https://doi.org/10.3390/nu13093208
Walker, A. W., Duncan, S. H., McWilliam Leitch, E. C., Child, M. W., & Flint, H. J. (2005). pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon. Applied and Environmental Microbiology, 71(7), 3692–3700. https://doi.org/10.1128/AEM.71.7.3692-3700.2005
Wan, J., Zhou, J., Wang, Z., Liu, D., Zhang, H., Xie, S., & Wu, K. (2025). Epidemiology, pathogenesis, diagnosis, and treatment of inflammatory bowel disease: Insights from the past two years. Chinese Medical Journal, 138(7), 763–776. https://doi.org/10.1097/CM9.0000000000003542
Wang, L., Zhang, J., Guo, Z., Kwok, L., Ma, C., Zhang, W., Lv, Q., Huang, W., & Zhang, H. (2014). Effect of oral consumption of probiotic Lactobacillus planatarum P-8 on fecal microbiota, SIgA, SCFAs, and TBAs of adults of different ages. Nutrition (Burbank, Los Angeles County, Calif.), 30(7–8), 776-783.e1. https://doi.org/10.1016/j.nut.2013.11.018
Yan, H., & Ajuwon, K. M. (2017). Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. PloS One, 12(6), e0179586. https://doi.org/10.1371/journal.pone.0179586
Zhang, D., Jian, Y.-P., Zhang, Y.-N., Li, Y., Gu, L.-T., Sun, H.-H., Liu, M.-D., Zhou, H.-L., Wang, Y.-S., & Xu, Z.-X. (2023). Short-chain fatty acids in diseases. Cell Communication and Signaling: CCS, 21(1), 212. https://doi.org/10.1186/s12964-023-01219-9
Zhang, Z., Zhang, H., Chen, T., Shi, L., Wang, D., & Tang, D. (2022). Regulatory role of short-chain fatty acids in inflammatory bowel disease. Cell Communication and Signaling: CCS, 20(1), 64. https://doi.org/10.1186/s12964-022-00869-5
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