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.

BACKGROUND & AIMS:Based largely on results from preclinical studies, the concept of a brain gut microbiome axis has been established, mediating bidirectional communication between the gut, its microbiome, and the nervous system. Limited data obtained in human beings suggest that alterations in these interactions may play a role in several brain gut disorders. METHODS:We reviewed the preclinical and clinical literature related to the topic of brain gut microbiome interactions. RESULTS:Well-characterized bidirectional communication channels, involving neural, endocrine, and inflammatory mechanisms, exist between the gut and the brain. Communication through these channels may be modulated by variations in the permeability of the intestinal wall and the blood-brain barrier. Brain gut microbiome interactions are programmed during the first 3 years of life, including the prenatal period, but can be modulated by diet, medications, and stress throughout life. Based on correlational studies, alterations in these interactions have been implicated in the regulation of food intake, obesity, and in irritable bowel syndrome, even though causality remains to be established. CONCLUSIONS:Targets within the brain gut microbiome axis have the potential to become targets for novel drug development for brain gut disorders.

Preclinical evidence strongly suggests a role for the gut microbiome in modulating the host central nervous system function and behavior. Several communication channels have been identified that enable microbial signals to reach the brain and that enable the brain to influence gut microbial composition and function. In rodent models, endocrine, neural, and inflammatory signals generated by gut microbes can alter brain structure and function, while autonomic nervous system activity can affect the microbiome by modulating the intestinal environment and by directly regulating microbial behavior. The amount of information that reaches the brain is dynamically regulated by the blood-brain barrier and the intestinal barrier. In humans, associations between gut microbial composition and function and several brain disorders have been reported, and fecal microbial transplants from patient populations into gnotobiotic mice have resulted in the reproduction of homologous features in the recipient mice. However, in contrast to preclinical findings, there is little information about a causal role of the gut microbiome in modulating human central nervous system function and behavior. Longitudinal studies in large patient populations with therapeutic interventions are required to demonstrate such causality, which will provide the basis for future clinical trials.

In the last 5 years, interest in the interactions among the gut microbiome, brain, and behavior has exploded. Preclinical evidence supports a role of the gut microbiome in behavioral responses associated with pain, emotion, social interactions, and food intake. Limited, but growing, clinical evidence comes primarily from associations of gut microbial composition and function to behavioral and clinical features and brain structure and function. Converging evidence suggests that the brain and the gut microbiota are in bidirectional communication. Observed dysbiotic states in depression, chronic stress,and autism may reflect altered brain signaling to the gut, while altered gut microbial signaling to the brain may play a role in reinforcing brain alterations. On the other hand, primary dysbiotic states due to Western diets may signal to the brain, altering ingestive behavior. While studies performed in patients with depression and rodent models generated by fecal microbial transfer from such patients suggest causation, evidence for an influence of acute gut microbial alterations on human behavioral and clinical parameters is lacking. Only recently has an open-label microbial transfer therapy in children with autism tentatively validated the gut microbiota as a therapeutic target. The translational potential of preclinical findings remains unclear without further clinical investigation.