Butyrate acts as a positive allosteric modulator of the 5-HT transporter to decrease availability of 5-HT in the ileum.

Abstract

Radiation therapy-induced gastrointestinal distress is partly associated with the elimination of gut microbiota. The effectiveness of 5-HT receptor antagonists to treat radiation therapy-induced emesis implies a pathophysiological role of 5-HT. Peripheral 5-HT is derived from intestinal epithelium. We have investigated the role of gut microbiota in regulating intestinal 5-HT availability. A radiation therapy murine model accompanied by faecal microbiota transplantation from donors fed different diets was investigated, and mouse ileal organoids were used for mechanistic studies. The clinical relevance was validated by a small-scale human study. Short-term high-fat diet (HFD) induced gut bacteria to produce butyrate. Irradiated mice receiving HFD-induced microbiome had the lowest ileal levels of 5-HT, compared with other recipients. Treatment with butyrate increased 5-HT uptake in mouse ileal organoids, assayed by the real-time tracking of a fluorescent substrate for monoamine transporters. Silencing the 5-HT transporter (SERT) in the organoids abolished butyrate-stimulated 5-HT uptake. The competitive tests using different types of selective 5-HT reuptake inhibitors suggested that butyrate acted as a positive allosteric modulator of SERT. In human gut microbiota, butyrate production was associated with the interconversion between acetate and butyrate. Faecal contents of both acetate and butyrate were negatively associated with serum 5-HT, but only butyrate was positively correlated with body mass index in humans. Short-term HFD may be beneficial for alleviating gastrointestinal reactions by increasing butyrate to suppress local 5-HT levels and providing energy to cancer patients given radiation therapy.