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, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 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.

中文翻译：

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微生物群依赖性色氨酸代谢物通过肝 AhR/TSC2/mTORC1 轴减轻高脂饮食诱导的胰岛素抵抗


2 型糖尿病 (T2D) 可能与色氨酸代谢紊乱有关，色氨酸代谢紊乱归因于饮食、肠道微生物群和宿主生理学之间复杂的相互作用。然而，根本机制尚不清楚。比较正常饮食 (ND) 和高脂饮食 (HFD) 小鼠的肠道微生物组和代谢组差异，我们发现肠道微生物组依赖的色氨酸代谢物 5-羟基吲哚-3-乙酸 (5-HIAA) 存在与没有胰岛素抵抗的小鼠相比，其浓度较低。我们进一步证明色氨酸向 5-HIAA 的微生物转化是由伯克霍尔德杆菌介导的。此外，我们还发现，给予 5-HIAA 可以改善 HFD 喂养小鼠的葡萄糖耐受不良和肥胖，同时保持肝脏胰岛素敏感性。从机制上讲，5-HIAA 通过直接激活 AhR 来促进肝脏胰岛素信号传导，AhR 刺激 TSC2 转录，从而抑制 mTORC1 信号传导。此外，T2D 患者粪便中 5-HIAA 水平降低。我们的研究结果确定了微生物从色氨酸产生 5-HIAA 的非典型途径，并表明 5-HIAA 可能减轻 T2D 的发病机制。