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Gut microbial molecules in behavioural and neurodegenerative conditions

Abstract

Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut–brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.

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Fig. 1: Neurological disorders and models associated with shifts in gut microbiota.
Fig. 2: Gut bacterial metabolites.
Fig. 3: Mechanistic examples of the routes of gut–brain communication.
Fig. 4: Brain cell-specific effects of microbial metabolites.

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S.K.M. and B.D.N. researched data for the article and made substantial contributions to the discussion of content, writing, reviewing and editing of the manuscript before submission. R.K.-D. contributed to the review and editing of the manuscript before submission.

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Correspondence to Brittany D. Needham or Sarkis K. Mazmanian.

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S.K.M. has financial interest in Axial Biotherapeutics. B.D.N. and R.K.-D. declare no competing interests.

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Nature Reviews Neuroscience thanks Peter Holzer, who co-reviewed with Aitak Farzi; John Cryan; and Mauro Costa-Mattioli for their contribution to the peer review of this work.

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Glossary

Bile acids

Complex lipid products of host cholesterol metabolism that play a major role in fat digestion and signalling in energy metabolism. Host bile acids (primary bile acids) are commonly modified by bacteria into secondary bile acids.

Enterochromaffin cells

Neuroendocrine cells in the gut lining that aid in gastrointestinal motility and produce 90% of the body’s serotonin in response to persistent intestinal signals.

Germ-free mice

Mice reared in conditions completely absent of microbial exposure.

Gut microbiota

An intestinal community comprising bacteria and other microorganisms including viruses, fungi, protists and archaea that permanently or transiently inhabit the lower gastrointestinal tract, especially the small intestine and colon.

Microorganism-associated molecular patterns

(MAMPs). Well-conserved components of microbial cells that are acutely detected by the innate immune system of the host throughout the body, including the brain.

Polyphenols

A vast class of thousands of plant-derived molecules containing at least one phenol group that are generally poorly absorbed by the host until being transformed by the gut microbiota into bioavailable and bioactive metabolites.

Short-chain fatty acids

(SCFAs). Fatty acids with chains of fewer than six carbons that are the end product of bacterial fermentation of complex polysaccharides and serve as energy source and signalling molecule in the host.

Specific pathogen-free mice

Mice conventionally colonized with a complete gut microbiota.

Steroid hormones

Circulating signalling molecules derived from cholesterol with an organic chemical structure consisting of four carbon rings and various regulatory roles in the host.

Vagus nerve

A principle neuronal connection between the gut and brain, comprising a bundle of neurons that sends and receives signals directly between gut tissue (and other organs) and the brainstem. These signals can then be further transmitted throughout the brain.

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Needham, B.D., Kaddurah-Daouk, R. & Mazmanian, S.K. Gut microbial molecules in behavioural and neurodegenerative conditions. Nat Rev Neurosci 21, 717–731 (2020). https://doi.org/10.1038/s41583-020-00381-0

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