Jena Prasant Kumar, Sheng Lili, Nguyen Michelle, Di Lucente Jacopo, Hu Ying, Li Yongchun, Maezawa Izumi, Jin Lee-Way, Wan Yu-Jui Yvonne
Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA.
Biomark Res. 2020 Nov 6;8(1):59. doi: 10.1186/s40364-020-00239-8.
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.
长期食用高糖高脂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，即饮食诱导的非酒精性脂肪性肝病（NAFLD）的发生和消退对神经可塑性和认知有影响。
自断奶起，将C57BL/6野生型小鼠分别喂食健康对照饮食（CD）或富含果糖、棕榈酸酯和胆固醇（FPC）的饮食。当小鼠3个月大时，将喂食FPC饮食的小鼠随机分为两组，分别继续喂食富含FPC的饮食，其中一组添加6%菊粉，另一组不添加。在8个月大时，对所有三组小鼠实施安乐死，随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产物。
我们的数据显示，摄入FPC饮食会导致肝脏和大脑出现肝脂肪变性和炎症，同时RORγ和IL-17A信号升高。伴随着小胶质细胞激活和海马体长期增强作用减弱，摄入FPC饮食还会降低突触后致密蛋白95和脑源性神经营养因子，而补充菊粉可防止饮食导致的神经可塑性降低和NAFLD的发展。在肠道中，FPC饮食增加了与胆固醇代谢有关的科里杆菌科和丹毒丝菌科以及Allobaculum属，而补充菊粉可使其减少。此外，FPC饮食降低了法尼酯X受体（FXR）和TGR5信号，补充菊粉可逆转这些变化。非靶向盲肠代谢组学分析发现了273种代谢产物，其中104种因摄入FPC饮食或补充菊粉而发生了显著变化。在受影响最大的前10种代谢产物中，喂食FPC的小鼠中胆固醇生物合成代谢产物酵母甾醇显著增加，而具有降低葡萄糖不耐受已知益处的2,8-二羟基喹啉减少；这些变化可通过补充菊粉逆转。此外，Barnesiella、Coprobacter、梭状芽孢杆菌XIVa和丁酸弧菌的丰度与FPC饮食摄入量和盲肠酵母甾醇浓度呈负相关，但与补充菊粉呈正相关，表明它们有益处。
综上所述，现有数据表明饮食会改变肠道微生物群及其代谢产物，包括胆汁酸。这随后会影响IL-17A信号，从而对肝脏代谢和认知功能产生全身性影响。
