Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole animal level, treatment of high-fat diet (HFD)-fed C57BL/6J with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of PFKFB3, a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation, and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. CONCLUSIONS: Taken together, our results demonstrate that indole is relevant to human NAFLD, and is capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependnet manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD.

中文翻译：

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吲哚以涉及髓样细胞 PFKFB3 的方式减轻饮食诱导的肝脂肪变性和炎症

吲哚是一种微生物群代谢物，可发挥抗炎反应。然而，吲哚与人类非酒精性脂肪性肝病 (NAFLD) 的相关性尚不清楚。吲哚是否以及如何预防 NAFLD 在很大程度上仍然未知。本研究试图检查人体中吲哚循环水平与肝脏脂肪含量之间的关联，并探索饮食诱导 NAFLD 小鼠中吲哚作用的潜在机制。在 137 名受试者的队列中，吲哚的循环水平与体重指数呈负相关。此外，肥胖受试者的吲哚循环水平显着低于瘦受试者，并伴有肝脏脂肪含量增加。在整个动物层面，用吲哚治疗高脂肪饮食 (HFD) 喂养的 C57BL/6J 导致肝脏脂肪变性和炎症的严重程度显着降低。在培养的细胞中，吲哚处理刺激了糖酵解主调控基因 PFKFB3 的表达，并以 PFKFB3 依赖性方式抑制巨噬细胞促炎激活。此外，骨髓细胞特异性 PFKFB3 的破坏加剧了 HFD 诱导的肝脂肪变性和炎症的严重程度，并减弱了吲哚对缓解饮食诱导的 NAFLD 表型的影响。结论：总的来说，我们的结果表明吲哚与人类 NAFLD 相关，并且能够以骨髓细胞 PFKFB3 依赖性方式减轻小鼠饮食诱导的 NAFLD 表型。所以，