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,¹⁹² 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,¹⁹³ 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.⁹⁹