摘要：SummaryRecent studies emphasize the role of microbial metabolites in regulating gastrointestinal (GI) physiology through activation of host receptors, highlighting the potential for inter-kingdom signaling in treating GI disorders. In this study, we show that tryptamine, a tryptophan-derived bacterial metabolite, stimulates mucus release from goblet cells via activation of G-protein-coupled receptor (GPCR) 5-HT4R. Germ-free mice colonized with engineeredBacteroides thetaiotaomicronoptimized to produce tryptamine (Trp D+) exhibit decreased weight loss and increased mucus release following dextran sodium sulfate treatment when compared with mice colonized with controlB. thetaiotaomicron(Trp D-). Additional beneficial effects in preventing barrier disruption and lower disease activity index were seen only in female mice, highlighting sex-specific effects of the bacterial metabolite. This study demonstrates potential for the precise modulation of mucus release by microbially produced 5-HT4 GPCR agonist as a therapeutic strategy to treat inflammatory conditions of the GI tract.Graphical AbstractDisplay OmittedHighlights•Tryptamine increases serotonin-receptor4-dependent colonic mucus release•Bacterially derived tryptamine attenuates weight loss in DSS colitis mouse model•Protective effect of tryptamine in DSS colitis is more pronounced in female mice•Tryptamine reduces colitis severity and barrier disruption specifically in female miceRodent Gastroenterology; Microbiology
