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

The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. This study shows 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. Levels of *R. gnavus*, tryptamine, and phenethylamine are positively associated with insulin resistance. Monoassociation of *R. gnavus* impairs insulin sensitivity in germ-free mice. Mechanistically, tryptamine and phenethylamine impair insulin signaling via the TAAR1-ERK signaling axis. These findings suggest a causal role for tryptamine/phenethylamine-producers in insulin resistance and highlight the TAAR1 signaling axis as a potential therapeutic target.

Lixiang Zhai, Haitao Xiao, Chengyuan Lin, Hoi Leong Xavier Wong, Yan Y. Lam, Mengxue Gong, Guojun Wu, Ziwan Ning, Chunhua Huang, Yijing Zhang, Chao Yang, Jingyuan Luo, Lu Zhang, Ling Zhao, Chenhong Zhang, Johnson Yiu-Nam Lau, Aiping Lu, Lok-Ting Lau, Wei Jia, Liping Zhao, Zhao-Xiang Bian