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Review
. 2018 Apr 12;6(2):133-148.
doi: 10.1016/j.jcmgh.2018.04.003. eCollection 2018.

The Brain-Gut-Microbiome Axis

Clair R Martin  1 , Vadim Osadchiy  1 , Amir Kalani  1 , Emeran A Mayer  1
Affiliations
Review

The Brain-Gut-Microbiome Axis

Clair R Martin et al. Cell Mol Gastroenterol Hepatol. .

Abstract

Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases.

Keywords: 2BA, secondary bile acid; 5-HT, serotonin; ANS, autonomic nervous system; ASD, autism spectrum disorder; BBB, blood-brain barrier; BGM, brain-gut-microbiome; CNS, central nervous system; ECC, enterochromaffin cell; EEC, enteroendocrine cell; FFAR, free fatty acid receptor; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GF, germ-free; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GPR, G-protein–coupled receptor; IBS, irritable bowel syndrome; Intestinal Permeability; Irritable Bowel Syndrome; LPS, lipopolysaccharide; SCFA, short-chain fatty acid; SPF, specific-pathogen-free; Serotonin; Stress; TGR5, G protein-coupled bile acid receptor; Trp, tryptophan.

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Figures

Figure 1
Figure 1
Bidirectional brain-gut-microbiome interactions related to serotonin signaling. Enterochromaffin cells (shown in green) contain more than 90% of the body’s serotonin (5-HT). 5-HT synthesis in ECCs is modulated by SCFAs and 2BAs produced by spore-forming Clostridiales, which increase their stimulatory actions on ECCs with increased dietary tryptophan availability. ECCs communicate with afferent nerve fibers through synapse-like connections between neuropod-like extensions and afferent nerve terminals. The autonomic nervous system can activate ECCs to release 5-HT into the gut lumen, where it can interact with gut microbes. TPH1, tryptophan hydroxylase type 1.
Figure 2
Figure 2
Systems biological model of brain-gut-microbiome interactions. The gut microbiota communicate with the gut connectome, the network of interacting cell types in the gut that include neuronal, glial, endocrine, and immune cells, via microbial metabolites, while changes in gut function can modulate gut microbial behavior. The brain connectome, the multiple interconnected structural networks of the central nervous system, generates and regulates autonomic nervous system influences that alter gut microbial composition and function indirectly by modulating the microbial environment in the gut. The gut microbiota can communicate to the brain indirectly via gut-derived molecules acting on afferent vagal and/or spinal nerve endings, or directly via microbe-generated signals. Alterations in the gain of these bidirectional interactions in response to perturbations such as psychosocial or gut-directed (eg, diet, medication, infection) stress can alter the stability and behavior of this system, manifesting as brain-gut disorders. Modified from Fung et al.
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