Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
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DOI：
10.1016/j.cell.2018.09.055
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发表时间：
2018-11-01
期刊：
影响因子：
64.5
通讯作者：
Backhed, Fredrik
中科院分区：
文献类型：
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作者：
Koh, Ara;Molinaro, Antonio;Backhed, Fredrik
肠道菌群、饮食和宿主之间的相互作用可能导致代谢性疾病的发生。在这里，我们确定咪唑丙酸是一种微生物产生的组氨酸衍生代谢物，在2型糖尿病患者中浓度高于非2型糖尿病患者。我们表明，当使用来自2型糖尿病受试者与非2型糖尿病受试者的粪便微生物群时，在肠道模拟器中以较高浓度由组氨酸产生丙酸咪唑，并且当给药给小鼠时，它会损害葡萄糖耐量。我们进一步表明，丙酸咪唑通过激活p38 γ MAPK，在胰岛素受体底物水平上损害胰岛素信号传导，从而促进p62磷酸化，随后激活雷帕霉素复合物1 （mTORC1）的机制靶点。我们还证实了2型糖尿病患者肝脏中p62和mTORC1的活化增加。我们的研究结果表明，微生物代谢物咪唑丙酸可能与2型糖尿病的发病机制有关。
Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38 gamma MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes.