Role of gut microbiota in the regulation of intestinal serotonin availability

Abstract

Peripheral serotonin mainly produced from enterochromaffin cells plays an essential role in the regulation of gastrointestinal (GI) motility. However, excessive serotonin stimulation initiates different functional GI disorders. The effectiveness of serotonin receptor blockers in the amelioration of radiation therapy-induced emesis suggests the pathophysiological involvement of serotonin. Gut microbiota is closely linked with the health of host via working in partnership with the host digestive system to produce energy and microbial metabolites. Previous studies have demonstrated that radiation therapy-induced GI side effects are in part associated with the alterations of gut microbiota. Relationship between gut microbiota and peripheral serotonin has been proposed, yet the mechanism remains inconclusive. Here, we aim to investigate the role of gut microbiota in the regulation of intestinal serotonin availability. A mouse radiation model followed by fecal microbiota transplantation from donors fed a 3-week grain-based normal chow diet (NCD), synthetic low-fat diet (LFD) or high-fat diet (HFD) was used for in vivo investigation. As a result, the suppression of intestinal serotonin level by HFD-induced microbiome (HFM) was found to be attributed to an increase in butyrate production at ileum level in irradiated recipient mice. Treatment with butyrate in irradiated mouse ileal organoids increased the uptake of extracellular serotonin, and the process was visualized by real-time tracking of a fluorescent substrate for monoamine transporters. Silencing serotonin transporter (SERT) in the organoids abolished the effect of butyrate on serotonin uptake. However, in both in vivo and in vitro studies, there was no significant change in either mRNA abundance or protein expression of SERT in response to butyrate. Combined treatment with selective serotonin reuptake inhibitors and butyrate suggested butyrate acted as a positive allosteric modulator of SERT. The analysis of human gut microbiome revealed that butyrate production was associated with the interconversion between acetate and butyrate, and fecal contents of both acetate and butyrate which were strongly correlated were negatively associated with serum serotonin level. However, only fecal butyrate level was positively correlated with body mass index (BMI) in human. Our findings reveal that short-term HFD-associated gut microbiota decreased the serotonin level in the ileum through stimulating the production of butyrate. Furthermore, short-term HFD may be beneficial for alleviating GI symptoms by increasing butyrate to suppress local serotonin level and providing extra energy to cancer patients undergoing radiation.