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

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 () and Zhao-Xiang Bian ()
Additional contact information
Lixiang Zhai: Hong Kong Baptist University
Haitao Xiao: Shenzhen University
Chengyuan Lin: Hong Kong Baptist University
Hoi Leong Xavier Wong: Hong Kong Baptist University
Yan Y. Lam: Hong Kong Baptist University
Mengxue Gong: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Guojun Wu: Rutgers University
Ziwan Ning: Hong Kong Baptist University
Chunhua Huang: Hong Kong Baptist University
Yijing Zhang: Hong Kong Baptist University
Chao Yang: Hong Kong Baptist University
Jingyuan Luo: Hong Kong Baptist University
Lu Zhang: Hong Kong Baptist University
Ling Zhao: Shanghai University of Traditional Chinese Medicine
Chenhong Zhang: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Johnson Yiu-Nam Lau: Hong Kong Baptist University
Aiping Lu: Hong Kong Baptist University
Lok-Ting Lau: Hong Kong Baptist University
Wei Jia: Hong Kong Baptist University
Liping Zhao: Rutgers University
Zhao-Xiang Bian: Hong Kong Baptist University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40552-y

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