Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome

Abstract The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota has been causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we showed that human gut bacterium Ruminococcus gnavus play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. Monoassociation of R. gnavus impaired insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impaired insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect was mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Moreover, we showed levels of R. gnavus, tryptamine and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Our findings suggest a causal role for tryptamine/phenethylamine-producers in the development of insulin resistance, provide molecular mechanisms for the increased prevalence of metabolic syndrome in IBS, and highlight the TAAR1 signaling axis as a potential therapeutic target for the management of metabolic syndrome induced by gut dysbiosis.