The gut, its microbiome, and the brain: connections and communications
Michael D. Gershon, Kara Gross Margolis
Michael D. Gershon, Kara Gross Margolis
Published September 15, 2021
Citation Information: J Clin Invest. 2021;131(18):e143768. https://doi.org/10.1172/JCI143768.
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Review Series

The gut, its microbiome, and the brain: connections and communications

Abstract

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.

Authors

Michael D. Gershon, Kara Gross Margolis

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Figure 2

Paracrine transmitters, such as 5-HT, are enablers of microbiota-gut-brain “connectome” signaling.

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Paracrine transmitters, such as 5-HT, are enablers of microbiota-gut-bra...
Microbiota within the lumen of the bowel produce metabolites, which include short-chain fatty acids (SCFAs) and other neuroactive molecules that can lead to the stimulation of IPANs and ExPANs. This stimulation can be direct, following the absorption of the microbial metabolites, or it can be indirect, involving stimulation of receptors on mucosal epithelial cells. Epithelial cells also have receptors for MAMPs that allow them to react to contact with the microbial surface. Activation of EC cells, the most common of the enteroendocrine (EE) cells of the gut, causes these cells to secrete 5-HT into the underlying lamina propria. EC cells, which express Piezo2, are mechanosensitive and can also be stimulated to secrete by increases in intraluminal pressure or sympathetic nerve stimulation. Terminals of IPANs and ExPANs both express 5-HT3 and 5-HT4 receptors, allowing 5-HT from EC cells to stimulate IPANs and ExPANs. The activated IPANs thus result in the manifestation of peristaltic and secretory reflexes, while activated vagal ExPANs transmit sensations of nausea or satiety and spinal ExPANs transmit the sensation of pain or discomfort to the CNS. Interneurons are present in both submucosal and myenteric plexuses and presumably are critical for the ability of the ENS to manifest integrated neuronal activity and reflexes in the absence of CNS input.