Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT receptor expression via acetate production.

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT and 5-HT receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ) in GF compared with HM mice. Additionally, 5-HT receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT receptor antagonist, inhibited 5-HT-evoked Δ in GF mice but not in HM mice. Furthermore, a 5-HT receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ in GF compared with HM mice. Immunohistochemistry in 5-HT-green fluorescent protein mice localized 5-HT receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ between GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT receptor expression via acetate production. Epithelial 5-HT receptor may function as a mediator of gut microbiota-driven change in intestinal secretion. We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT receptor expression in colonoids.View this article's corresponding video summary at https://www.youtube.com/watch?v=aOMYJMuLTcw&feature=youtu.be.