Mechanistic Analysis of Drug-Induced Gastrointestinal Toxicity Based on Serotonin-Associated Gut Microbiota Dynamics

Abstract

Gastrointestinal (GI) toxicity (e.g., diarrhea) is one of the most serious adverse reactions leading to the discontinuation of oral drug development. However, drug-induced GI toxicity is not easy to assess because its mechanism is complicated by multiple factors. For instance, serotonin (5-HT), a major GI hormone, is associated with gut microbiota, which plays a role in various GI physiology, but its interaction with oral drugs has not been fully clarified yet. In the present study, we examined the hypothesis that changes in GI disposition of 5-HT due to orally administered drugs can influence gut microbiota dynamics, leading to disorders of the GI fluid regulation, using metformin which clinically causes diarrhea as a side effect. Studies using Caco-2 cells and transporter-expressed Xenopus oocytes suggested that metformin inhibits 5-HT uptake mediated by transporters (e.g., SERT). Administration of metformin into the intestinal lumen significantly increased the GI fluid volume and 5-HT levels. A similar tendency was observed after the long-term administration of metformin. Further analysis for fecal microbiota indicated that metformin influences gut microbiota dynamics (mainly Turicibacter) as well as GI 5-HT levels. When transferring the feces of these rats into the intestinal lumen of another untreated rat, the recipient rat showed the same diarrheal symptoms as the donor rat. Our findings indicate that drug-induced GI toxicity is caused by the changes in gut microbiota via an increase of the luminal 5-HT levels by inhibition of transporter-mediated GI 5-HT uptake.