Effects of a-synuclein on the taxonomic composition and functional potential in adult rats

Toxic misfolded forms of a-synuclein, is the major pathogenic protein associated with Parkinson's disease (PD). Neither the native functions of a-synuclein nor its pathogenic role in PD are fully known. Evidence now implicates a role for the gut in PD pathogenesis, however how the gut is altered in PD is unknown. We hypothesis that a-synuclein in the enteric nervous system (ENS) may interact with and alter gut microbiome composition. This study investigated the temporal profile of faecal microbiota and bile acid composition following injection of ?-synuclein monomer and pre-formed fibrils (PFF) into the rat duodenal wall, in the presence and absence of lipopolysaccharide (LPS) injection. Our results reveal a significant separation of bacterial species between groups at one month, directed by a-synuclein monomer and PFF groups, with no significant differences found at five months and no effect of LPS. This model reveals a significant difference in Lactobacillus Murinus and Akkermansia Muciphila abundance at one month, driven by high abundance in the ?-synuclein monomer and LPS alone groups. Faecal bile acid abundance is altered at five months in LPS, ?-synuclein monomer and monomer + LPS groups compared to baseline levels. Between group analysis at five months shows significant decreases in tauro-conjugated and muricholic biles in LPS, PFF and PFF + LPS groups compared to five month controls. ?-synuclein and LPS alter faecal microbiome composition overtime, however no combination effect is seen. Monomeric ?-synuclein had the most significant impact on the gut microbiome and this study has identified a potential novel role of ?-synuclein in the gut.

α-突触核蛋白（α-synuclein）的毒性错误折叠形式，是与帕金森病（Parkinson's disease, PD）相关的主要致病蛋白。目前人们对α-突触核蛋白的天然生理功能及其在PD发病中的致病作用尚未完全阐明。现有研究提示肠道在PD发病机制中发挥作用，但PD患者肠道的具体改变机制仍不明确。我们提出假说：肠神经系统（enteric nervous system, ENS）中的α-突触核蛋白可能与肠道菌群相互作用，并改变肠道菌群组成。本研究探究了在脂多糖（lipopolysaccharide, LPS）注射存在或缺失的情况下，向大鼠十二指肠壁注射α-突触核蛋白单体及预形成纤维（pre-formed fibrils, PFF）后，粪便菌群与胆汁酸组成的时序变化特征。结果显示，在造模后1个月，各组细菌物种组成出现显著分离，该分离由α-突触核蛋白单体组与PFF组主导；而在造模后5个月，未观察到显著组间差异，且LPS未产生显著影响。本模型发现，造模后1个月时，鼠乳杆菌（Lactobacillus Murinus）与嗜黏蛋白阿克曼氏菌（Akkermansia Muciphila）的丰度存在显著差异，该差异由α-突触核蛋白单体组及单纯LPS注射组的高丰度所驱动。与基线水平相比，LPS组、α-突触核蛋白单体组及单体+LPS组的粪便胆汁酸丰度在造模后5个月出现改变。造模后5个月的组间分析显示，与5个月对照组相比，LPS组、PFF组及PFF+LPS组的牛磺结合胆汁酸与鼠胆酸水平显著降低。α-突触核蛋白与LPS可随时间改变粪便菌群组成，但未观察到二者的联合作用效果。单体α-突触核蛋白对肠道菌群的影响最为显著，本研究揭示了α-突触核蛋白在肠道中潜在的全新功能。