Zhang Jingting, Chen Keyan, Chen Fu
College of Management, Liaoning Economy Vocational and Technical College, Shenyang, 110122, China.
Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, 110122, China.
J Pharm Anal. 2025 May;15(5):101077. doi: 10.1016/j.jpha.2024.101077. Epub 2024 Aug 19.
This study investigates the molecular complexities of non-alcoholic fatty liver disease (NAFLD)-induced brain dysfunction, with a focus on the liver-intestine-brain axis and potential therapeutic interventions. The main objectives include understanding critical microbiota shifts in NAFLD, exploring altered metabolites, and identifying key regulatory molecules influencing brain function. The methods employed encompassed 16S ribosomal RNA (rRNA) sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals, non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid (DCA) in NAFLD mice, and single-cell RNA sequencing (scRNA-seq) to pinpoint the pivotal gene Hpgd in microglial cells and its downstream Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Behavioral changes and brain function were assessed in NAFLD mice with and without Fecal microbiota transplantation (FMT) treatment, utilizing various assays and analyses. The results revealed significant differences in microbiota composition, with increased levels of in NAFLD patients. Additionally, elevated DCA levels were observed in NAFLD mice, and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction. Hpgd inhibition by DCA activated the JAK2/STAT3 pathway in microglial cells, leading to inflammatory activation, inhibition of mitochondrial autophagy, induction of neuronal apoptosis, and reduction in neuronal action potentials. This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD, and the identification of increased DCA and the impact of JAK2/STAT3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.
本研究调查非酒精性脂肪性肝病（NAFLD）所致脑功能障碍的分子复杂性，重点关注肝-肠-脑轴及潜在治疗干预措施。主要目标包括了解NAFLD中关键微生物群的变化、探索代谢物改变以及识别影响脑功能的关键调节分子。所采用的方法包括16S核糖体RNA（rRNA）测序以检查NAFLD患者和健康个体的粪便微生物群、使用液相色谱-质谱联用的非靶向代谢组学以发现NAFLD小鼠中脱氧胆酸（DCA）水平升高，以及单细胞RNA测序（scRNA-seq）以确定小胶质细胞中的关键基因Hpgd及其下游的Janus激酶2/信号转导子和转录激活子3（JAK2/STAT3）信号通路。利用各种检测和分析方法，对接受和未接受粪便微生物群移植（FMT）治疗的NAFLD小鼠的行为变化和脑功能进行了评估。结果显示微生物群组成存在显著差异，NAFLD患者中[此处原文缺失相关内容]水平升高。此外，在NAFLD小鼠中观察到DCA水平升高，FMT治疗在改善肝功能和脑功能障碍方面显示出疗效。DCA对Hpgd的抑制激活了小胶质细胞中的JAK2/STAT3通路，导致炎症激活、线粒体自噬抑制、神经元凋亡诱导以及神经元动作电位降低。本研究阐明了NAFLD中肝-肠-脑轴潜在的复杂分子机制，DCA升高的鉴定以及JAK2/STAT3信号对小胶质细胞的影响突出了针对NAFLD所致脑功能障碍的潜在治疗靶点。
