The gut, its microbiome, and the brain: connections and communications Author: Michael D Gershon1, Kara Gross Margolis2 Affiliation: <sup>1</sup> Departments of Pathology and Cell Biology and. <sup>2</sup> Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA. Conference/Journal: J Clin Invest Date published: 2021 Sep 15 Other: Volume ID: 131 , Issue ID: 18 , Pages: 143768 , Special Notes: doi: 10.1172/JCI143768. , Word Count: 185 Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms. PMID: 34523615 DOI: 10.1172/JCI143768