Abstract：
Recent insights into Parkinson\'s disease (PD), a progressive neurodegenerative disorder, suggest a significant influence of the gut microbiome on its pathogenesis and progression through the gut-brain axis. This study integrates 16S rRNA sequencing, high-throughput transcriptomic sequencing, and animal model experiments to explore the molecular mechanisms underpinning the role of gut-brain axis in PD, with a focus on short-chain fatty acids (SCFAs) mediated by the SCFA receptors FFAR2 and FFAR3. Our findings highlighted prominent differences in the gut microbiota composition between PD patients and healthy individuals, particularly in taxa such as Escherichia_Shigella and Bacteroidetes, which potentially impact SCFA levels through secondary metabolite biosynthesis. Notably, fecal microbiota transplantation (FMT) from healthy to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models significantly improved motor function, enhanced dopamine and serotonin levels in the striatum, and increased the number of dopaminergic neurons in the substantia nigra while reducing glial cell activation. This therapeutic effect was associated with increased levels of SCFAs such as acetate, propionate, and butyrate in the gut of MPTP-lesioned mice. Moreover, transcriptomic analyses revealed upregulated expression of FFAR2 and FFAR3 in MPTP-lesioned mice, indicating their crucial role in mediating the benefits of FMT on the central nervous system. These results provide compelling evidence that gut microbiota and SCFAs play a critical role in modulating the gut-brain axis, offering new insights into PD\'s etiology and potential targets for therapeutic intervention.
摘要：
最近对帕金森病（PD）的见解，进行性神经退行性疾病，提示肠道微生物组对其发病机理和通过肠-脑轴的进展有重大影响。本研究整合了16SrRNA测序，高通量转录组测序，和动物模型实验，以探索支持肠-脑轴在PD中的作用的分子机制，关注由SCFA受体FFAR2和FFAR3介导的短链脂肪酸（SCFA）。我们的发现强调了PD患者和健康个体之间肠道菌群组成的显著差异，特别是在类群中，如大肠杆菌志贺氏菌和拟杆菌，这可能通过次级代谢产物生物合成影响SCFA水平。值得注意的是,从健康的粪便微生物群移植（FMT）到1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型显着改善运动功能，纹状体中多巴胺和5-羟色胺水平增强，并增加黑质中多巴胺能神经元的数量，同时减少神经胶质细胞的活化。这种治疗效果与SCFA水平的增加有关，如乙酸盐，丙酸盐,MPTP损伤小鼠肠道中的丁酸盐。此外，转录组学分析显示MPTP损伤小鼠中FFAR2和FFAR3的表达上调，表明它们在介导FMT对中枢神经系统的益处中的关键作用。这些结果提供了令人信服的证据，表明肠道微生物群和SCFA在调节肠-脑轴中起着关键作用。为PD的病因和治疗干预的潜在目标提供了新的见解。
