Enteric Neuronal Regulation of Intestinal Inflammation

Abstract

Recent research has highlighted the importance of the two-way interaction between the nervous and immune systems. This interaction is particularly important in the bowel because of the unique properties of this organ. The lumen of the gut is lined by a very large but remarkably thin surface that separates the body from the enteric microbiome. Immune defenses against microbial invasion are thus well developed and neuroimmune interactions are important in regulating and integrating these defenses. Important concepts in the phylogeny of neuroimmunity, enteric neuronal and glial regulation of immunity, changes that occur in the enteric nervous system during inflammation, the fundamental role of serotonin (5-HT) in enteric neuroimmune mechanisms, and future perspectives are reviewed.

Keywords: 5-HT; enteric glia; enteric nervous system; inflammatory bowel disease; microbiome; neuroimmunity; serotonin.

Figure 1. Interactions That Modulate Intestinal Inflammation

5-HT is stored in enterochromaffin (EC; yellow) cells of the gastrointestinal mucosa. The secretion of 5-HT from EC cells is proinflammatory. 5-HT has been postulated to stimulate 5-HT₇ receptors, which dendritic cells (red) express and, in turn, drive immunity and inflammation. Contrary evidence, however, suggests that the 5-HT₇ mediated effect on dendritic cells is inhibitory. Enteric neurons located in ganglia (green) of the myenteric plexus, between the circular and longitudinal layers of smooth muscle, also produce 5-HT. Terminals of these neurons project to the submucosal plexus (green). The neuronal pool of 5-HT is anti-inflammatory and, through 5-HT4 receptor stimulation, exerts neuroprotective effects and promotes neurogenesis to help enable the enteric nervous system to survive the detrimental effects of inflammation.