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

• DOI: 10.1073/pnas.2400385121
• Publication Date: 2024-08-22T01:31:12Z
• Authors: Wei Du; Shanshan Jiang; Shengxiang Yin; Rongjiang Wang; Chunling Zhang; Bin-Cheng Yin; Jialin Li; Li Li; Nan Qi; Ying Zhou; Bang-Ce Ye
• Keywords: Metabolome

Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing microbiome metabolome differences in mice fed a normal diet (ND) high-fat (HFD), we uncover microbiota–dependent metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) present at lower concentrations with versus without insulin resistance. We further demonstrate microbial transformation of into 5-HIAA mediated by Burkholderia spp. Additionally, show administration improves glucose intolerance obesity HFD-fed mice, while preserving hepatic sensitivity. Mechanistically, promotes signaling directly activating AhR, which stimulates TSC2 transcription thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels 5-HIAA. Our findings identify noncanonical pathway microbially producing from indicate might alleviate pathogenesis T2D.