Abstract
BACKGROUND: Parkinson’s disease (PD) is a prevalent neurodegenerative disease and its pathogenesis is still unclear. Emerging evidence supports the gut-origin hypothesis, highlighting gut microbiota dysbiosis as a contributing factor in PD pathogenesis. Our previous clinical study showed that Bacteroides coprocola (B. coprocola), a gut bacterium producing short-chain fatty acids (SCFAs), was significantly reduced in PD patients. This study was aimed to investigate the potential of B. coprocola in ameliorating PD pathology and explore the underlying mechanisms in a rotenone-induced PD mouse model. METHODS: The rotenone-induced PD mouse model was treated by orally administering B. coprocola for three weeks. Immunofluorescence, Western blotting, flow cytometry, 16S rRNA sequencing, and metabolomics were performed to assess midbrain and intestinal changes, NLRP3 inflammasome activation, macrophage polarization, gut microbiota, and SCFA levels. In vitro, LPS-stimulated bone marrow-derived macrophages were used to validate the role of NLRP3 signaling in macrophage polarization following sodium acetate and sodium butyrate treatment via siRNA and molecular assays. RESULTS: B. coprocola treatment alleviated PD-related motor deficits, neuroinflammation, gut microbiota dysbiosis, and intestinal barrier permeability in the rotenone-induced PD mouse model. Mechanistically, B. coprocola reshaped the gut microbiota composition and modulated macrophage polarization, which were associated with the inhibition of the NLRP3 inflammasome signaling pathway. Furthermore, in vitro experiments confirmed that the acetate and butyrate-key metabolites of B. coprocola-attenuated the inflammatory responses and promoted M2-like macrophage polarization via free fatty acid receptor (FFAR) 2/3 receptors, thereby suppressing NLRP3 activation. CONCLUSIONS: In conclusion, B. coprocola treatment can improve motor deficits, neuroinflammation, and intestinal function in the rotenone-induced PD mouse model. The effects are associated with microbiota remodeling, regulation of macrophage polarization, and inhibition of the NLRP3 inflammasome pathway. Acetate and butyrate, key metabolites of B. coprocola, might play an important role in promoting M2 macrophage polarization through FFAR2/3 receptors.