The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is 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 show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS. We show levels of R. gnavus, tryptamine, and phenethylamine are positively associated with insulin resistance in T2D patients and IBS patients. Monoassociation of R. gnavus impairs insulin sensitivity and glucose control in germ-free mice. Mechanistically, treatment of R. gnavus-derived metabolites tryptamine and phenethylamine directly impair insulin signaling in major metabolic tissues of healthy mice and monkeys and this effect is mediated by the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. 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.

肠易激综合征（IBS）患者代谢综合征的发生率明显较高，但其机制仍不清楚。肠道菌群与代谢功能障碍和胃肠道疾病的发生密切相关，因此IBS中的肠道菌群失调可能会导致代谢综合征的发生。在这里，我们表明，人类肠道细菌齿胃球菌衍生的色胺和苯乙胺在肠道菌群失调诱导的 2 型糖尿病 (T2D) 和 IBS 的胰岛素抵抗中发挥致病作用。我们发现，R. gnavus、色胺和苯乙胺的水平与 T2D 患者和 IBS 患者的胰岛素抵抗呈正相关。R. gnavus的单一结合会损害无菌小鼠的胰岛素敏感性和葡萄糖控制。从机制上讲，R. gnavus衍生代谢物色胺和苯乙胺的治疗会直接损害健康小鼠和猴子主要代谢组织中的胰岛素信号传导，并且这种作用是由痕量胺相关受体 1 (TAAR1) - 细胞外信号调节激酶 (ERK) 介导的) 信号轴。我们的研究结果表明色胺/苯乙胺产生者在胰岛素抵抗的发展中具有因果作用，提供了 IBS 中代谢综合征患病率增加的分子机制，并强调 TAAR1 信号轴作为管理由胰岛素抵抗引起的代谢综合征的潜在治疗靶点。由肠道菌群失调引起。