Microbiome- metabolome signatures and Behavioral alterations in a progressive MPTP-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, motor deficits, and systemic metabolic dysfunction. Using a chronic MPTP-induced C57BL/6 mouse model, we integrated behavioral, transcriptional, metabolomic, and microbiome analyses to investigate gut-metabolite-brain interactions in PD. MPTP-treated mice exhibited significant motor and non-motor impairments alongside increased α-synuclein and inflammatory markers in the midbrain. Untargeted LC-MS metabolomics revealed differential enrichment of host- and microbiome-derived metabolites, including altered arginine/proline, sphingolipid, tryptophan, and riboflavin metabolism. 16S rRNA sequencing demonstrated decreased Firmicutes/Bacteroidetes ratio and enrichment of lipopolysaccharide-producing taxa, functionally linked to amino-acid metabolism via correlation network analysis. These data define a coordinated gut-metabolite-brain axis underpinning PD pathology, highlighting microbiome-derived circulating metabolites as potential early biomarkers and therapeutic targets. While these findings are derived from a toxin-based, male-only PD model, they delineate robust gut-metabolite-brain signatures that provide a strong framework for future validation in α-synucleinopathy models and mixed-sex cohorts.