Gut-Brain Axis Dysregulation in Parkinson’s Disease: Mechanisms Linking Microbiota to Neuroinflammation and α-Synuclein Pathology

Parkinson’s disease (PD) is increasingly understood as a multisystem disorder originating not only in the central nervous system (CNS) but also involving the gut-brain axis (GBA). A key driver of PD pathogenesis is gut microbiota dysbiosis, which contributes to disease progression by inducing intestinal inflammation, altered microbial metabolite production, and compromised gut barrier integrity. These alterations can initiate the misfolding and aggregation of α-synuclein in the enteric nervous system (ENS), facilitating its spread to the CNS via vagal pathways. Furthermore, microbiota-derived molecules, including short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS), are implicated in triggering systemic and neuroinflammatory cascades that exacerbate the degeneration of dopaminergic neurons. This review consolidates current evidence on the mechanistic connections between gut microbiota dysregulation, neuroinflammation, and α-synuclein pathology in PD. We also discuss the translational potential of microbiota-focused biomarkers and innovative therapeutic strategies, providing new perspectives for early diagnosis and disease modification. Elucidating the GBA in PD paves the way for personalized medicine and microbiome-targeted therapies.