The microbiota- dependent tryptophan metabolite alleviates high- fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis

• 成果类型: Article
• 署名作者: Du, Wei; Jiang, Shanshan; Yin, Shengxiang; Wang, Rongjiang; Zhang, Chunling; Yin, Bin - Cheng; Li, Jialin; Li, Li; Qi, Nan; Zhou, Ying; Ye, Bang-Ce
• 署名单位: East China University of Science & Technology; Zhejiang University of Technology; Ningbo University; Guangzhou Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13439
• DOI: 10.1073/pnas.2400385121
• 发表日期: 2024-08-27
• 关键词: aryl-hydrocarbon receptor; gut microbiota; activation; serotonin; PATHWAY; acids; tsc2

摘要

Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high- fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5- hydroxyindole- 3- acetic acid (5- HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5- HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5- HIAA improves glucose intolerance and obesity in HFD- fed mice, 5- HIAA. Our findings identify a noncanonical pathway of microbially producing 5- HIAA from tryptophan and indicate that 5- HIAA might alleviate the pathogenesis of T2D.