Inhibition of peripheral serotonin synthesis by a gut microbe-derived TPH1 inhibitor, hyodeoxycholic acid, alleviates irritable bowel syndrome

Gut dysbiosis significantly contributes to the pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D) by enhancing serotonin (5-HT) biosynthesis, which exacerbates diarrhea symptoms. Current treatments aimed at peripheral 5-HT signaling in IBS-D are often limited by efficacy and side effects. This study presents hyodeoxycholic acid (HDCA), a gut-microbial metabolite, as a novel therapeutic strategy that directly inhibits peripheral 5-HT synthesis via tryptophan hydroxylase 1 (TPH1). Our research indicates that HDCA levels are notably reduced in IBS-D patients and show a negative correlation with both diarrhea severity and peripheral 5-HT levels. Furthermore, we demonstrate that HDCA and PULVIS FELLIS SUIS, a traditional Chinese medicine abundant in HDCA, effectively alleviate diarrhea symptoms and inhibit peripheral 5-HT production without impacting central 5-HT levels or mood behaviors in mouse models of IBS. Mechanistically, HDCA directly binds to and inhibits TPH1, thereby suppressing peripheral 5-HT biosynthesis, a critical pathological factor in IBS-D. These findings suggest that HDCA is a promising candidate for microbiota-driven therapeutic interventions and gut-brain axis regulation. This study demonstrates the use of a microbiota-derived metabolite and traditional medicine specifically targeting peripheral 5-HT biosynthesis for treating gastrointestinal disorders. Our results pave the way for new IBS treatment strategies and other conditions requiring TPH1 inhibition, offering novel insights and potential clinical applications. ClinicalTrials.gov no: NCT02822677 and NCT03457324