Gut-brain axis and Parkinson's disease: navigating the microbial enigma

Parkinson's disease (PD), traditionally seen as a Central Nervous System (CNS) disorder with dopaminergic neuron loss and α-synuclein aggregation, increasingly implicates the gut-brain axis in its pathogenesis. Gut microbiota dysbiosis precedes motor symptoms by years, linking to non-motor issues like constipation and rapid eye movement sleep behavior disorder, with reduced neuroprotective bacteria (e.g., Prevotella), impairing barrier integrity, short-chain fatty acid production, and promoting neuroinflammation. Mechanistically, misfolded α-synuclein may start in the gut, spreading via the vagus nerve, as evidenced by preclinical and human studies; microbial metabolites like lipopolysaccharides worsen aggregation and permeability. Microbial signatures vary due to confounders (geography, diet, and methods), hindering universal biomarkers and requiring standardized longitudinal studies. Therapeutically, probiotics (e.g., Lactobacillus plantarum PS128) restore balance, reduce inflammation, and improve symptoms, while targeted antibiotics (e.g., against Helicobacter pylori) boost levodopa efficacy but risk dysbiosis. Gut modulation shifts PD care toward prodromal prevention, with multi-omics and Artificial Intelligence (AI) aiding future interventions to halt gastrointestinal origin progression.