Effects of α-synuclein on the taxonomic composition and functional potential in adult rats. Injection of α-synuclein into the gut alters faecal microbiome composition

Toxic misfolded forms of α-synuclein, is the major pathogenic protein associated with Parkinson’s disease (PD). Neither the native functions of α-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 α-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 α-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.