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Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota–gut–brain axis

Nature Reviews Gastroenterology & Hepatology volume 21, pages 222–247 (2024)Cite this article

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A Publisher Correction to this article was published on 04 April 2024

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Abstract

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut–brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood–brain barrier and the blood–cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut–microbiota–brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut–brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as ‘leaky gut’. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders.

Key points

  • Barriers across the microbiota–gut–brain axis are key elements in the communication across this axis.

  • By enabling a physical segregation between the host and microbiome, barriers have played key parts in the evolution of the holobiont.

  • Gut and brain barriers are epithelial or endothelial in nature and they have different levels of permissiveness under physiological conditions, which is important for their function.

  • Barriers are dynamic in nature and their function varies across the lifespan.

  • Preclinical studies provide direct evidence of microbial metabolites influencing barrier functioning, linking gut microbial alterations to barrier dysfunction and the subsequent abnormal passage of substances (microbial and non-microbial) along the gut–brain axis.

  • Barrier dysregulation has been shown to be a hallmark in disorders of the gut and of the brain, and could underlie some of their comorbidities.

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Fig. 1: Schematic cross section of gastrointestinal and brain barriers in vertebrates.
Fig. 2: Cross-species comparison of gastrointestinal and brain barriers.
Fig. 3: Mechanistic overview of microbial modulation of barriers across the microbiota–gut–brain axis.
Fig. 4: The interaction between barriers and the gut microbiota in microbiota–gut–brain axis communication.

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Acknowledgements

M.R.A. gratefully acknowledges the support of the ERC-StG (RADIOGUT, project 101040951) and SFI-IRC Pathway Programme (SFI21/PATH-S/9424). J.F.C. gratefully acknowledges the support of the Science Foundation Ireland (SFI/12/RC/2273_P2). The authors thank J. Nagpal and K. O’Riordan (APC Microbiome Ireland, University College Cork) for critical and constructive reading of the manuscript. The authors thank the reviewers for their time and their valuable comments that helped to improve the quality of the manuscript.

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  1. APC Microbiome Ireland, University College Cork, Cork, Ireland

    María R. Aburto & John F. Cryan

  2. Department of Anatomy and Neuroscience, School of Medicine, University College Cork, Cork, Ireland

    María R. Aburto & John F. Cryan

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Both authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. M.R.A. wrote the article.

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J.F.C. has been an invited speaker at conferences organized by Mead Johnson, Ordesa, and Yakult, and has received research funding from Reckitt, Nutricia, Dupont/IFF and Nestlé. M.R.A. has no competing interests.

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Aburto, M.R., Cryan, J.F. Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota–gut–brain axis. Nat Rev Gastroenterol Hepatol 21, 222–247 (2024). https://doi.org/10.1038/s41575-023-00890-0

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