Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. Our data showed that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signaling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation, suggesting their benefits. Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.

中文翻译：

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胆汁酸受体介导的信号传导失调和 IL-17A 诱导与饮食相关的肝脏健康和认知功能有关


长期食用高糖和高脂肪饮食与肝脏炎症和认知能力下降有关。本文检验了一个假设，即饮食引起的非酒精性脂肪肝 (NAFLD) 的发生和缓解对神经可塑性和认知有影响。自断奶以来，C57BL/6 野生型小鼠采用健康对照饮食 (CD) 或富含果糖、棕榈酸酯和胆固醇 (FPC) 的饮食喂养。当小鼠 3 个月大时，FPC 饮食喂养的小鼠被随机分配接受富含 FPC 的饮食，添加或不添加 6% 菊粉。 8 个月大时，所有三组小鼠均被安乐死，然后分析肝脏和大脑中的炎症信号、肠道微生物群和盲肠代谢物。我们的数据显示，FPC 饮食摄入会诱导肝脏脂肪变性以及肝脏和大脑炎症，同时 RORγ 和 IL-17A 信号传导也会升高。伴随着小胶质细胞的激活和海马长时程增强的减少，FPC 饮食摄入还减少了突触后密度 95 和脑源性神经营养因子，而补充菊粉则可以防止饮食降低的神经可塑性和 NAFLD 的发展。在肠道中，FPC 饮食增加了与胆固醇代谢有关的 Coriobacteriaceae 和 Erysipelotrichaceae 以及 Allobaculum 属，而补充菊粉则减少了它们。此外，FPC 饮食减少了 FXR 和 TGR5 信号传导，而补充菊粉则逆转了这些变化。非靶向盲肠代谢组学分析发现了 273 种代谢物，其中 104 种代谢物由于 FPC 饮食摄入或补充菊粉而发生显着变化。 在受影响最严重的 10 种代谢物中，FPC 喂养的小鼠的酵母甾醇（一种胆固醇生物合成代谢物）显着增加，并且 2,8-二羟基喹啉减少，众所周知，2,8-二羟基喹啉对减少葡萄糖不耐受有好处；这些变化可以通过补充菊粉来逆转。此外，Barnesiella、Coprobacter、Clostridium XIVa 和 Butyrivibrio 的丰度与 FPC 饮食摄入量和盲肠发酵甾醇浓度呈负相关，但与补充菊粉呈正相关，表明它们的益处。综上所述，所提供的数据表明饮食会改变肠道微生物群及其代谢物，包括胆汁酸。这随后将影响 IL-17A 信号传导，从而对肝脏代谢和认知功能产生系统性影响。