From Gut Dysbiosis to Nigrostriatal Degeneration: Mechanistic Pathways and Therapeutic Opportunities in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder character-ized by α-synuclein aggregation and degeneration of nigrostriatal dopaminergic neu-rons. Increasing evidence implicates gut microbiota (GM) dysbiosis as a potential con-tributor to PD pathophysiology through bidirectional gut–brain interactions. This narrative review integrates recent taxonomic, functional, metabolomic, im-munological, and interventional evidence linking GM alterations to basal ganglia dys-function. Across multiple cohorts, PD is consistently associated with reduced abun-dance of short-chain fatty acid (SCFA)-producing taxa (e.g., Faecalibacterium, Roseburia) and enrichment of mucin-degrading and pro-inflammatory organisms (e.g., Akkermansia). Shotgun metagenomic studies further reveal alterations in vitamin biosynthesis pathways, carbohydrate metabolism, and microbial network architecture. Metabolomic and Mendelian randomization analyses implicate SCFAs, branched-chain amino acids, bile acids, and GABA metabolism in modulating intestinal permeability, immune activation, and dopaminergic vulnerability. Experimental mi-crobiota transplantation models support mechanistic links involving intestinal barrier disruption, Toll-like receptor signaling, microglial priming, and potential vagal prop-agation of α-syn pathology. Emerging microbiome-targeted strategies—including dietary modulation, probi-otics, prebiotics, fecal microbiota transplantation, and interventions targeting bacterial levodopa metabolism—demonstrate early translational promise. However, inter-cohort heterogeneity and limited longitudinal data highlight the need for precision microbi-ome stratification and prodromal studies. Overall, current multi-level evidence supports gut dysbiosis as a biologically plausible contributor to PD pathogenesis and a promising target for adjunctive nutri-tional and pharmacomicrobiomic interventions.