The TAAR1 antagonist EPPTB ameliorates colitis via serotonin inhibition

Inflammatory bowel disease (IBD) is characterized by gut dysbiosis and impaired microbial metabolite signaling. Emerging evidence suggests that gut microbial metabolites, such as trace amines (tryptamine, phenethylamine, and tyramine), function as endogenous TAAR1 agonists and may contribute to IBD pathogenesis. Our study identified elevated fecal trace amine levels in ulcerative colitis (UC) patients and DSS-induced colitis mice. In vitro, exposure to these trace amines enhanced 5-HT secretion in QGP-1 cells and ex vivo mouse colonic tissues, and this effect could be blocked by the TAAR1 antagonist EPPTB. In vivo, EPPTB treatment significantly mitigated DSS-induced colitis, as demonstrated by reduced weight loss, improved disease activity index (DAI), preserved colon length, and attenuated histopathological damage. Moreover, TAAR1 blockade reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and increased IκB-α expression, restored intestinal barrier integrity (upregulating occludin and ZO-1, while downregulating cclaudin-2), and lowered colonic 5-HT levels by suppressing TPH1 expression. These findings suggest that TAAR1 inhibition alleviates colitis by modulating 5-HT signaling, positioning it as a promising therapeutic target for IBD. • TAAR1 antagonism suppresses trace amine-stimulated 5-HT secretion in QGP-1 cells and ex vivo mouse colonic tissues. • TAAR1 inhibition alleviates colitis severity, intestinal inflammation, and barrier dysfunction. • TAAR1 antagonism reduces colonic 5-HT content through transcriptional downregulation of TPH1. • Targeting TAAR1 presents a promising new therapeutic paradigm for IBD management.