MICROBIAL METABOLITES AS REGULATORS OF HOST IMMUNITY: MOLECULAR PATHWAYS, IMMUNE HOMEOSTASIS, AND DISEASE PROGRESSION
Keywords:
microbial metabolites, host immunity, immune homeostasis, microbiota–immune signaling, precision immunomodulation
Abstract
Microbial metabolites have become a key mediator of host-microbial dialogue, connecting microbial activity to the regulation of the immune system, maintenance of tissue integrity, and disease pathogenesis. This review synthesizes current evidence on the major immunoregulatory metabolite classes, including short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines, vitamins, and microbial lipids, and examines the molecular pathways through which they influence host immunity. Special emphasis is placed on G-protein-coupled receptor signaling, signaling of aryl hydrocarbon receptors, bile acid receptors, inflammasome pathways, epigenetic regulation and immunometabolic reprogramming. The review also examines the impact of microbial metabolites on the regulation of macrophage, neutrophil, natural killer, T-cell and B-cell function, as well as supporting epithelial barrier function, mucosal tolerance, colonization resistance and immune balance in the periphery. Dysregulated metabolite profiles are associated with diseases of the intestine, autoimmune, respiratory, cardiometabolic, neurological, infectious and malignant diseases, but effects are highly receptor- and tissue-dependent and dose- and host physiology-dependent. The following are examples of translation opportunities: metabolites as biomarkers, postbiotic approaches, receptor-targeted interventions, and modulation of immunotherapy responses. The next steps will rely on causal validation, standardisation of multi-omics, mechanistic precision and personalised microbiome-directed immunomodulation.
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References
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3.Ansaldo, E., Farley, T. K., & Belkaid, Y. (2021). Control of immunity by the microbiota. Annual review of immunology, 39(1), 449-479.
4.Brown, E. M., Clardy, J., & Xavier, R. J. (2023). Gut microbiome lipid metabolism and its impact on host physiology. Cell host & microbe, 31(2), 173-186.
5.Budden, K. F., Shukla, S. D., Rehman, S. F., Bowerman, K. L., Keely, S., Hugenholtz, P., ... & Hansbro, P. M. (2019). Functional effects of the microbiota in chronic respiratory disease. The Lancet Respiratory Medicine, 7(10), 907-920.
6.Cai, J., Sun, L., & Gonzalez, F. J. (2022). Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell host & microbe, 30(3), 289-300.
7.Calvo-Barreiro, L., Zhang, L., Abdel-Rahman, S. A., Naik, S. P., & Gabr, M. (2023). Gut microbial-derived metabolites as immune modulators of T helper 17 and regulatory T cells. International Journal of Molecular Sciences, 24(2), 1806.
8.Chen, Y. Y., Lu, Y. T., Wang, Y. D., Ding, N. N., Huang, Z. X., Hu, J. B., ... & Chen, J. X. (2025). Xiaoyaosan improves depression-like behaviours in mice with post-stroke depression by modulating gut microbiota and microbial metabolism and regulating P2X7R/NLRP3 inflammasome. Phytomedicine, 145, 157078.
9.Daliri, E. B. M., Ofosu, F. K., Chelliah, R., Lee, B. H., & Oh, D. H. (2021). Challenges and perspective in integrated multi-omics in gut microbiota studies. Biomolecules, 11(2), 300.
10.Eshleman, E. M., & Alenghat, T. (2021). Epithelial sensing of microbiota-derived signals. Genes & Immunity, 22(5), 237-246.
11.Gasaly, N., De Vos, P., & Hermoso, M. A. (2021). Impact of bacterial metabolites on gut barrier function and host immunity: a focus on bacterial metabolism and its relevance for intestinal inflammation. Frontiers in immunology, 12, 658354.
12.Hajjo, R., Sabbah, D. A., & Al Bawab, A. Q. (2022). Unlocking the potential of the human microbiome for identifying disease diagnostic biomarkers. Diagnostics, 12(7), 1742.
13.Hou, K., Wu, Z. X., Chen, X. Y., Wang, J. Q., Zhang, D., Xiao, C., ... & Chen, Z. S. (2022). Microbiota in health and diseases. Signal transduction and targeted therapy, 7(1), 135.
14.Hou, Y., Li, J., & Ying, S. (2023). Tryptophan metabolism and gut microbiota: a novel regulatory axis integrating the microbiome, immunity, and cancer. Metabolites, 13(11), 1166.
15.Hu, Y., Chen, Z., Xu, C., Kan, S., & Chen, D. (2022). Disturbances of the gut microbiota and microbiota-derived metabolites in inflammatory bowel disease. Nutrients, 14(23), 5140.
16.Kayama, H., Okumura, R., & Takeda, K. (2020). Interaction between the microbiota, epithelia, and immune cells in the intestine. Annual review of immunology, 38(1), 23-48.
17.Kim, S., Seo, S. U., & Kweon, M. N. (2024, July). Gut microbiota-derived metabolites tune host homeostasis fate. In Seminars in immunopathology (Vol. 46, No. 1, p. 2). Berlin/Heidelberg: Springer Berlin Heidelberg.
18.Lee, M. H., Nuccio, S. P., Mohanty, I., Hagey, L. R., Dorrestein, P. C., Chu, H., & Raffatellu, M. (2024). How bile acids and the microbiota interact to shape host immunity. Nature Reviews Immunology, 24(11), 798-809.
19.Lei, J., Wang, X., & Liu, X. (2025). Microbiota-derived metabolites in the epigenetic regulation of the host. Science Bulletin.
20.Li, G., Lin, J., Zhang, C., Gao, H., Lu, H., Gao, X., ... & Liu, Z. (2021). Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut microbes, 13(1), 1968257.
21.Li, H. Y., Zhou, D. D., Gan, R. Y., Huang, S. Y., Zhao, C. N., Shang, A. O., ... & Li, H. B. (2021). Effects and mechanisms of probiotics, prebiotics, synbiotics, and postbiotics on metabolic diseases targeting gut microbiota: a narrative review. Nutrients, 13(9), 3211.
22.Liang, P., Chen, X., Su, Z., Luo, Y., Wang, T., Li, J., ... & Luo, T. (2025). The role of oral and gut microbiota in bone health: insights from bacterial extracellular vesicles. Microorganisms, 13(10), 2254.
23.Liu, H., Xiong, X., Zhu, W., Wang, S., Huang, W., Zhu, G., ... & Yang, L. (2025). Gut microbial metabolites in cancer immunomodulation. Molecular Cancer, 25(1), 8.
24.Liu, J., Tian, R., Sun, C., Guo, Y., Dong, L., Li, Y., & Song, X. (2023). Microbial metabolites are involved in tumorigenesis and development by regulating immune responses. Frontiers in immunology, 14, 1290414.
25.Lu, Y., Yuan, H., Liang, S., Li, D., Jiang, P., Wang, X., ... & Liu, D. (2025). Microbial metabolite-driven immune reprogramming in tumor immunotherapy: mechanisms and therapeutic perspectives. Frontiers in Immunology, 16, 1603658.
26.Lun, H., Li, P., Li, J., & Liu, F. (2024). The effect of intestinal flora metabolites on macrophage polarization. Heliyon, 10(15).
27.Ma, Z., Wang, Z., Cao, J., Dong, Y., & Chen, Y. (2025). Regulatory roles of intestinal CD4+ T cells in inflammation and their modulation by the intestinal microbiota. Gut microbes, 17(1), 2560019.
28.Mahalingam, S. S., & Pandiyan, P. (2024). Polyamines: key players in immunometabolism and immune regulation. Journal of cellular immunology, 6(5), 196.
29.Mann, E. R., Lam, Y. K., & Uhlig, H. H. (2024). Short-chain fatty acids: linking diet, the microbiome and immunity. Nature Reviews Immunology, 24(8), 577-595.
30.McCarville, J. L., Chen, G. Y., Cuevas, V. D., Troha, K., & Ayres, J. S. (2020). Microbiota metabolites in health and disease. Annual review of immunology, 38(1), 147-170.
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32.Mostafavi Abdolmaleky, H., & Zhou, J. R. (2024). Gut microbiota dysbiosis, oxidative stress, inflammation, and epigenetic alterations in metabolic diseases. Antioxidants, 13(8), 985.
33.Mousa, W. K., Chehadeh, F., & Husband, S. (2022). Microbial dysbiosis in the gut drives systemic autoimmune diseases. Frontiers in immunology, 13, 906258.
34.Muttiah, B., & Hanafiah, A. (2025). Gut microbiota and cardiovascular diseases: unraveling the role of dysbiosis and microbial metabolites. International Journal of Molecular Sciences, 26(9), 4264.
35.Nemet, I., Saha, P. P., Gupta, N., Zhu, W., Romano, K. A., Skye, S. M., ... & Hazen, S. L. (2020). A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell, 180(5), 862-877.
36.O'Donnell, J. A., Zheng, T., Meric, G., & Marques, F. Z. (2023). The gut microbiome and hypertension. Nature reviews. Nephrology, 19(3), 153–167. https://doi.org/10.1038/s41581-022-00654-0
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38.Perl, M., Fante, M. A., Herfeld, K., Scherer, J. N., Poeck, H., & Orberg, E. T. (2025). Microbiota-derived metabolites: Key modulators of cancer immunotherapies. Med, 6(8).
39.Pernas, L. (2021). Cellular metabolism in the defense against microbes. Journal of Cell Science, 134(5), jcs252023.
40.Réka, F., Zsófia, B., Ádám, B., & Péter, F. (2025). The gut–muscle–immune axis in motion: Mechanistic synergies of SCFA metabolism, exercise, and microbial cross-feeding. Nutrients, 17(23), 3786.
41.Rosser, E. C., Piper, C. J., Matei, D. E., Blair, P. A., Rendeiro, A. F., Orford, M., ... & Mauri, C. (2020). Microbiota-derived metabolites suppress arthritis by amplifying aryl-hydrocarbon receptor activation in regulatory B cells. Cell metabolism, 31(4), 837-851.
42.Rothhammer, V., & Quintana, F. J. (2019). The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nature Reviews Immunology, 19(3), 184-197.
43.Saravanan, C., Gopinath, N. K., Ganesan, R., & Thirumurugan, D. (2025). Challenges and limitations in using bacterial metabolites as immunomodulators. Frontiers in Cellular and Infection Microbiology, 15, 1535394.
44.Scott, S. A., Fu, J., & Chang, P. V. (2020). Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences, 117(32), 19376-19387.
45.Singh, B. P., Rateb, M. E., Rodriguez-Couto, S., Polizeli, M. D. L. T. D. M., & Li, W. J. (2019). Microbial secondary metabolites: Recent developments and technological challenges. Frontiers in microbiology, 10, 914.
46.Sittipo, P., Shim, J. W., & Lee, Y. K. (2019). Microbial metabolites determine host health and the status of some diseases. International journal of molecular sciences, 20(21), 5296.
47.Tilg, H., Zmora, N., Adolph, T. E., & Elinav, E. (2020). The intestinal microbiota fuelling metabolic inflammation. Nature Reviews Immunology, 20(1), 40-54.
48.Tran, M., Huh, J. R., & Devlin, A. S. (2025). The role of gut microbial metabolites in the T cell lifecycle. Nature immunology, 26(8), 1246–1257. https://doi.org/10.1038/s41590-025-02227-2
49.Ullah, S., Wu, C., Zou, X., Zhong, Y., Ahmad, A., Jan, A. U., ... & Li, L. (2025). Understanding microbiota-driven oncogenesis: The role of metabolites in tumorigenesis. Iscience, 28(12).
50.Wan, T., Wang, Y., He, K., & Zhu, S. (2023). Microbial sensing in the intestine. Protein & Cell, 14(11), 824-860.
51.Wang, J., Zhao, Q., Zhang, S., Liu, J., Fan, X., Han, B., ... & Ai, X. (2025). Microbial short chain fatty acids: Effective histone deacetylase inhibitors in immune regulation. International Journal of Molecular Medicine, 57(1), 16.
52.Wang, L., Zhu, L., & Qin, S. (2019). Gut microbiota modulation on intestinal mucosal adaptive immunity. Journal of immunology research, 2019(1), 4735040.
53.Wang, Y., Liu, H., & Zhao, J. (2020). Macrophage polarization induced by probiotic bacteria: a concise review. Probiotics and antimicrobial proteins, 12(3), 798-808.
54.Willmann, K., & Moita, L. F. (2024). Physiologic disruption and metabolic reprogramming in infection and sepsis. Cell metabolism, 36(5), 927-946.
55.Woelfel, S., Silva, M. S., & Stecher, B. (2024). Intestinal colonization resistance in the context of environmental, host, and microbial determinants. Cell host & microbe, 32(6), 820-836.
56.Xu, Y., Wang, J., Yuan, R., Qin, Z., Long, K., & Gao, P. (2025). Targeting the immuno-inflammatory-microbial network: a key strategy for sepsis treatment. Frontiers in Immunology, 16, 1575516.
57.Yamada, T., & Palm, N. W. (2025). A host-centric view of the microbiota metabolome. Immunity, 58(12), 2940-2956.
58.Yan, W., Zhang, K., Guo, J., & Xu, L. (2025). Bile acid-mediated gut-liver axis crosstalk: the role of nuclear receptor signaling in dynamic regulation of inflammatory networks. Frontiers in immunology, 16, 1595486.
59.Yang, W., Wu, H., Li, X., Wan, Z., Kong, W., & Huang, C. (2025). Gut–lung axis in allergic rhinitis: microbial dysbiosis and therapeutic strategies. Frontiers in Microbiology, 16, 1654997.
60.Yoshii, K., Hosomi, K., Sawane, K., & Kunisawa, J. (2019). Metabolism of dietary and microbial vitamin B family in the regulation of host immunity. Frontiers in nutrition, 6, 434971.
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Published
2026-10-08
How to Cite
Anna M. Müller. (2026). MICROBIAL METABOLITES AS REGULATORS OF HOST IMMUNITY: MOLECULAR PATHWAYS, IMMUNE HOMEOSTASIS, AND DISEASE PROGRESSION. IJRDO - JOURNAL OF BIOLOGICAL SCIENCE, 12(1), 123-141. https://doi.org/10.69980/bs.v12i1.6801
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Articles
Copyright (c) 2026 IJRDO - JOURNAL OF BIOLOGICAL SCIENCE
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