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The role of gut microbial metabolites in the T cell lifecycle

Nature Immunology volume 26, pages 1246–1257 (2025)Cite this article

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Abstract

T cells, a cornerstone of the adaptive immune system, have pivotal roles at the host–microorganism interface. The gut microbiome profoundly influences T cell biology by producing a diverse repertoire of small molecules that are sensed by host cells. These microbial metabolites regulate all aspects of the T cell lifecycle, from cell development to differentiation and activation to exhaustion. Recent studies have uncovered microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, as potent regulators of T cell function. However, the full scope of microbial metabolite–T cell interactions remains largely unexplored. This Review presents a mechanistic framework linking gut microbial metabolites to discrete stages of T cell fate and function. Expanding our understanding of these intricate host–microbiome interactions will reveal new aspects of immune regulation and inspire microbiome-guided therapeutic strategies for infections, autoimmune diseases and cancer immunotherapy.

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Fig. 1: The presence of a microbiome has broad effects on thymic function.
Fig. 2: Microbial metabolites influence T cell differentiation and function through indirect mechanisms involving surrounding cells.
Fig. 3: Microbial metabolites regulate T cell function directly through T cell-intrinsic mechanisms.

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Acknowledgements

This work was supported by National Institutes of Health grants R01 DK110559 (J.R.H. and A.S.D.), R35 GM128618 (A.S.D.) and a Harvard Medical School Van Maanen Fellowship (M.T.).

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  1. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Melissa Tran & Jun R. Huh

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Melissa Tran & A. Sloan Devlin

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M.T., J.R.H. and A.S.D. conceptualized the Review and wrote the manuscript.

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Correspondence to Jun R. Huh or A. Sloan Devlin.

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Competing interests

A.S.D. is a consultant for Axial Therapeutics. J.R.H. is a consultant for CJ CheilJedang, hy and Interon Laboratories and an advisor on the Samsung Bio Advisory Board. M.T. declares no competing interests.

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Nature Immunology thanks Jochen Mattner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Laurie A. Dempsey, in collaboration with the Nature Immunology team.

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Tran, M., Huh, J.R. & Devlin, A.S. The role of gut microbial metabolites in the T cell lifecycle. Nat Immunol 26, 1246–1257 (2025). https://doi.org/10.1038/s41590-025-02227-2

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