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 3

Interactions between macrophages, enteric neurons, and parasympathetic and sympathetic nerves contribute to the maintenance of intestinal homeostasis in inflammation and bacterial infection.

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Interactions between macrophages, enteric neurons, and parasympathetic a...
(i) Muscularis macrophages (MMs) secrete BMP2, which activates BMP receptors on enteric neurons and thus affects intestinal motility. Enteric neurons reciprocally secrete CSF1, a growth factor required for macrophage development. Enteric microbiota stimulate secretion, of both BMP2 and CSF1, and thus enhance the crosstalk between enteric neurons and MMs. (ii) Provocation of intestinal inflammation, for example by postoperative ileus, signals to the NTS in the brain via vagal afferent nerves. This leads to activation of vagal efferent nerves, originating in the dorsal motor nucleus (DMX), which stimulate cholinergic enteric neurons to secrete acetylcholine (ACh). This ACh activates α7 nicotinic receptors on MMs to downregulate their inflammatory effects. (iii) Infection of the bowel with bacteria, including pathogens such as species of Salmonella or Toxoplasma, can cause NLRP6 inflammasome– and caspase-11–mediated cell death of enteric neurons. Stress activation of sympathetic nerves leads to the release of norepinephrine (NE) from sympathetic nerve terminals in the gut. NE stimulates β2-adrenoceptors on MMs, which in turn activates the arginase-1/polyamine axis, leading to the release of polyamines, such as spermine, which are neuroprotective. Macrophages can thus protect enteric neurons from infection-induced cell death.