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-HT₃ and 5-HT₄ 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 (ΔI_sc) in GF compared with HM mice. Additionally, 5-HT₃ receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT₃ receptor antagonist, inhibited 5-HT-evoked ΔI_sc in GF mice but not in HM mice. Furthermore, a 5-HT₃ receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher ΔI_sc in GF compared with HM mice. Immunohistochemistry in 5-HT_3A-green fluorescent protein mice localized 5-HT₃ receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked ΔI_sc 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-HT₃ receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT₃ receptor expression via acetate production. Epithelial 5-HT₃ receptor may function as a mediator of gut microbiota-driven change in intestinal secretion.NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT₃ receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT₃ receptor expression in colonoids.View this article's corresponding video summary at https://www.youtube.com/watch?v=aOMYJMuLTcw&feature=youtu.be.

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