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The gut microbiota–brain axis in behaviour and brain disorders

Abstract

In a striking display of trans-kingdom symbiosis, gut bacteria cooperate with their animal hosts to regulate the development and function of the immune, metabolic and nervous systems through dynamic bidirectional communication along the ‘gut–brain axis’. These processes may affect human health, as certain animal behaviours appear to correlate with the composition of gut bacteria, and disruptions in microbial communities have been implicated in several neurological disorders. Most insights about host–microbiota interactions come from animal models, which represent crucial tools for studying the various pathways linking the gut and the brain. However, there are complexities and manifest limitations inherent in translating complex human disease to reductionist animal models. In this Review, we discuss emerging and exciting evidence of intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to neurological disorders. Continued advances from this frontier of biomedicine may lead to tangible impacts on human health.

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Fig. 1: The gut microbiota–brain axis.
Fig. 2: Microbiota and microbial-derived molecules modulate host behaviour and nervous system function.

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Acknowledgements

S.K.M. is the Luis & Nelly Soux Professor of Microbiology at the California Institute of Technology (Caltech). His laboratory explores biological mechanisms by which the gut microbiota impacts immunological and neurological diseases, including research into mouse models of inflammatory bowel disease, autism spectrum disorder and Parkinson disease. The laboratory is supported by funding from the National Institutes of Health, the Department of Defense, the Heritage Medical Research Institute, the Michael J. Fox Foundation, Autism Speaks, Aligning Science Across Parkinson’s and other charitable organizations and individuals. L.H.M. is a postdoctoral scholar at Caltech and recipient of am American Parkinson’s Disease Association postdoctoral fellowship. H.L.S.IV is a postdoctoral scholar at Caltech and recipient of a Della Martin fellowship. The authors thank R. Abdel-Haq, J. Ousey and G. Sharon for constructive comments and N.J. Cruz and G. Tofani for assistance with the figures.

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L.H.M. wrote the initial draft of the manuscript with editorial input from H.L.S.IV and S.K.M. All authors contributed substantially to all aspects of the article and revised versions.

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Correspondence to Livia H. Morais or Sarkis K. Mazmanian.

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S.K.M. has financial interests in Axial Biotherapeutics, although not directly related to the contents of this article. All other authors declare no competing interests.

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Nature Reviews Microbiology thanks M. Costa-Mattioli, J. Raes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Microglia

The primary resident immune cells in the central nervous system, responsible for pathogen surveillance, immune protection and synaptic pruning. Microglia have been implicated in psychiatric and neurodegenerative disorders, largely in animal models.

Astrocytes

A subtype of glial cells in the central nervous system that play an essential role in blood–brain barrier formation and function, among other activates such as interfacing with microglia and neurons.

Oligodendrocytes

Brain cells that regulate development of neurons and insulate neuronal axons through the formation of the protective myelin sheath.

Homeostasis

The process of maintaining physiological functions necessary for survival of an organism.

Neuroplasticity

The ability of the nervous system to change activity by reorganizing its structure and function.

Epigenetic

DNA modifications that do not alter the sequence but can impact gene expression and biological outcomes.

Brain-derived neurotrophic factor

(BDNF). A protein that has an important role in neuronal survival, growth and synaptic plasticity. Alterations in expression are associated with mood disorders.

γ-Aminobutyric acid

(GABA). The main inhibitory neurotransmitter in the adult brain; crucial for synaptic plasticity and learning.

Serotonin

(5-Hydroxytryptamine (5-HT)). A neurotransmitter involved in controlling mood, social behaviour, gut motility and the sleep cycle.

Blood–brain barrier

(BBB). A physical gatekeeper to separate the brain microenvironment from the rest of the body, formed by mural and microvascular endothelial cells connected by tight-junction proteins.

Internal validity

A measure of the reliability of cause-and-effect relationships determined in a research setting. Internal validity can be improved with an experimental design including blind testing, unbiased analysis and appropriate statistical power.

External validity

A measure of how translatable findings from one experimental setting can be to other experimental settings and to the rest of the world. External validity fails when confounding factors are not considered or controlled in research.

Stress

A physiological and neurological response to demands for change in response to real or perceived threats.

Developmental windows

Crucial periods (for example, prenatal, early life and adolescence) in which dynamic changes in development and maturation of multiple physiological systems are susceptible to environmental factors, such as those of the microbiota.

Synapses

Highly specialized contacts between nerve cells that are the connections underlying dynamic and complex neuronal systems networks.

Oxytocin system

A key neuropeptide system that modulates social behaviour, bonding, mating and stress in animals. Known to be associated with symptoms of autism spectrum disorder.

Face and construct validity

Face validity is achieved when a wide range of features present in human disorders, such as behaviour and circuit abnormalities, are reproduced in an animal model. Construct validity refers to mimicking a disease aetiology in animals, such as environmental or genetic risks for human disease.

Vagotomy

A surgical procedure that severs the vagus nerve in one of several locations, disrupting signalling from various peripheral organs to the brain.

Allostasis

The active process of the body to maintain homeostasis in the face of stress.

Anhedonia

A reduced capacity to experience pleasure.

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Morais, L.H., Schreiber, H.L. & Mazmanian, S.K. The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol 19, 241–255 (2021). https://doi.org/10.1038/s41579-020-00460-0

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