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Microbiota-mediated mechanisms of mucosal immunity across the lifespan

Nature Immunology volume 26, pages 1645–1659 (2025)Cite this article

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Abstract

The microbiota has a fundamental role in regulating homeostasis and inflammation across the barrier surfaces of the body. The gut is a unique bioreactor where the high concentration of microorganisms, microbial and dietary metabolites, microbial-derived molecular structures, immune cells, stroma and neurons form a complex, highly interactive and precisely regulated system. The mucosal immune system in the gut has profound local and systemic effects, influencing both health and disease. A critical period of immune imprinting occurs early in life, shaped by the neonatal microbiota and nutrition, to influence immune development and long-term disease susceptibility. Microbiota-derived metabolites have crucial roles in immune modulation, influencing epithelial integrity, oral tolerance and inflammatory responses. This Review explores the interactions between the microbiota and the mucosal immune system from infancy to adulthood, highlighting the impact on health and disease. We also discuss therapeutic interventions, including microbiota-derived molecules, dietary metabolites and emerging microbiome-based co-therapies.

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Fig. 1: Regulation of mucosal immunity circuits by gut microbiota and dietary components.
Fig. 2: Mechanisms of cell death.
Fig. 3: The intestinal microbiota is a critical regulator of inflammation and antitumor immunity.

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Acknowledgements

We thank the following funding agencies for their support: US National Institutes of Health (NIH; R01DK113136, R01DK121977, R01AI178683, R01CA286920, R01AI163007, R01DK135816, AI172027, DK132244, AT013241, R01HD110118, R01HL169989, R01AI143842, R01AI123368, R01AI145989, U01AI095608, R01AI162936, R01CA274534, R37AI174468, R01DK126871, R01AI151599, R01AI095466, R01AR070116, R01AI182043, R00CA252443, R21AI178327, R01AI170832, R01AI170897), the Cancer Research Institute, the Sanders Family Foundation, the Rosanne H. Silbermann Foundation, Linda and Glenn Greenberg, the Allen Discovery Center Program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation, the Hartwell Foundation and Starr Cancer Consortium, the Leona M. and Harry B. Helmsley Charitable Trust, the Burroughs Wellcome Fund: Pathogenesis of Infectious Disease (PATH), Crohn’s and Colitis Foundation, Kenneth Rainin Foundation and the Canadian Institute for Advanced Research (CIFAR) Fungal Kingdom: Threats and Opportunities research program.

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Authors and Affiliations

  1. Joan and Sanford I. Weill Department of Medicine, Gastroenterology and Hepatology Division, Weill Cornell Medicine, New York, NY, USA

    Iliyan D. Iliev, J. Magarian Blander, Nicholas Collins, Chun-Jun Guo, Randy S. Longman, Gregory F. Sonnenberg & David Artis

  2. The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA

    Iliyan D. Iliev, J. Magarian Blander, Chun-Jun Guo, Randy S. Longman, Gregory F. Sonnenberg & David Artis

  3. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA

    Iliyan D. Iliev, J. Magarian Blander, Nicholas Collins, Chun-Jun Guo, Randy S. Longman, Gregory F. Sonnenberg & David Artis

  4. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Iliyan D. Iliev, J. Magarian Blander, Nicholas Collins, Chun-Jun Guo, Randy S. Longman, Gregory F. Sonnenberg, Melody Y. Zeng & David Artis

  5. Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Nicholas Collins & David Artis

  6. Gale and Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, New York, NY, USA

    Melody Y. Zeng

  7. Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA

    Melody Y. Zeng

  8. Allen Discovery Center for Neuroimmune Interactions, New York, NY, USA

    David Artis

Authors
  1. Iliyan D. Iliev
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  2. J. Magarian Blander
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  3. Nicholas Collins
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  4. Chun-Jun Guo
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  5. Randy S. Longman
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  6. Gregory F. Sonnenberg
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  7. Melody Y. Zeng
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  8. David Artis
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Corresponding author

Correspondence to Iliyan D. Iliev.

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Nature Immunology thanks Andreas Diefenbach and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

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Iliev, I.D., Blander, J.M., Collins, N. et al. Microbiota-mediated mechanisms of mucosal immunity across the lifespan. Nat Immunol 26, 1645–1659 (2025). https://doi.org/10.1038/s41590-025-02281-w

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