Human-derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3receptor expression via acetate production
Open accessAbstract
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 3 and 5-HT 4 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 I sc) in GF compared with HM mice. Additionally, 5-HT 3 receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT 3 receptor antagonist, inhibited 5-HT-evoked Δ I sc in GF mice but not in HM mice. Furthermore, a 5-HT 3 receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ I sc in GF compared with HM mice. Immunohistochemistry in 5-HT 3A-green fluorescent protein mice localized 5-HT 3 receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ I 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-HT 3 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 3 receptor expression via acetate production. Epithelial 5-HT 3 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-HT 3 receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT 3 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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SCFAs are important intraluminal determinants of mucus and water secretion through effects on sodium and water influx, duodenal bicarbonate secretion, and colonic epithelial 5-HT3 receptor expression.
“SCFAs, like bile acids, are important intraluminal determinants of mucus and water secretion through effects on sodium and water influx99, duodenal bicarbonate secretion100, and colonic epithelial 5-HT3 receptor expression101.”
From The gut Microbiome in adult and pediatric functional gastrointestinal disorders (2019) · cites this paper as [101]
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- Authors
- Bhattarai, Y., Schmidt, B. A., Linden, D. R., Larson, E. D., Grover, M., Beyder, A., Farrugia, G., & Kashyap, P. C.
- Affiliations
- Mayo Clinic (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Kashyap, Purna C.
- ORCID
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2017-07-01
- Volume
- 313
- Issue
- 1
- Pages
- G80-G87
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- PMC
- PMC5538830
- OpenAlex
- W2607428872
- Cited by
- 102
- References
- 41
- Citations by year
- 2026: 12 · 2025: 6 · 2024: 12 · 2023: 13 · 2022: 11 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 14 · 2017: 3
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK100638, DK103911, DK106456)
- global probiotic council
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- gut microbiota, 5-HT3 receptor, serotonin, intestinal secretion, acetate, colonic mucosa, enterochromaffin cells, ondansetron, short-circuit current, colonic epithelium
- MeSH terms
- Acetates, Animals, Colon, Gene Expression Regulation, Germ-Free Life, Humans, Serotonin, Receptors, Serotonin, 5-HT3, Receptors, Serotonin, 5-HT4, Mice, Microbiota
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