Butyrate acts as a positive allosteric modulator of serotonin transporter to decrease ileal serotonin availability

Abstract

Background and PurposeRadiation therapy‐induced gastrointestinal distress is partly associated with the elimination of gut microbiota. The effectiveness of serotonin receptor blocker to treat radiation therapy‐induced emesis suggests the pathophysiological role of serotonin. Peripheral serotonin is derived from intestinal epithelium. We aim to investigate the role of gut microbiota in regulating intestinal serotonin availability.Experimental ApproachA radiation therapy murine model accompanied by faecal microbiota transplantation (FMT) from donors fed different diets was investigated, and mouse ileal organoid was employed for mechanistic study. The clinical relevance was validated by a small‐scale human study.Key ResultsShort‐term high‐fat diet (HFD) induced gut bacteria to produce butyrate, and the irradiated mice receiving HFD‐induced microbiome had the lowest ileal serotonin level compared with other recipients. The treatment with butyrate increased the serotonin uptake in mouse ileal organoids, such process was visualized by the real‐time tracking of a fluorescent substrate for monoamine transporters. Silencing serotonin transporter (SERT) in the organoids abolished the butyrate‐stimulated serotonin uptake. The competitive tests using different types of selective serotonin 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 serotonin, but only butyrate was positively correlated with BMI in human.Conclusion and ImplicationsShort‐term HFD may be beneficial for alleviating gastrointestinal reactions by increasing butyrate to suppress local serotonin level and providing energy to cancer patients undergoing radiation.