Parkinson's disease and the gut microbiota connection: unveiling dysbiosis and exploring therapeutic horizons

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss, α-synuclein aggregation, and sustained neuroinflammation. Emerging evidence supports the gut-brain-microbiota axis as a pivotal player in the disease's pathogenesis. Dysbiosis, disruptions in the gut microbial composition, has been consistently observed in individuals with PD, with notable reductions in beneficial, short-chain fatty acid-producing bacteria and elevations in pro-inflammatory microbial species. These alterations contribute to increased intestinal permeability, systemic inflammation, and heightened neuroinflammatory responses that may drive α-synuclein misfolding and dopaminergic degeneration. In addition, microbial metabolites, including lipopolysaccharides and amyloid proteins such as curli, may promote neurodegeneration via immune and molecular mimicry pathways. Recent advances highlight the bidirectional influence of the microbiota-gut-brain axis on PD symptoms, ranging from motor deficits to non-motor features like constipation, depression, and cognitive decline. Several microbiota-modulating interventions, including probiotics, prebiotics, dietary strategies, antibiotics, and fecal microbiota transplantation, have demonstrated neuroprotective potential in both preclinical and clinical contexts. However, inter-individual variability, methodological heterogeneity, and the absence of longitudinal, multi-omics-integrated studies limit current understanding. The gut microbiome also holds promise as a non-invasive biomarker for early PD detection and prognosis, though standardization remains a challenge. Future research must clarify causal mechanisms, optimize therapeutic delivery, and integrate genetic, metabolic, and environmental data to advance precision medicine approaches. This review consolidates current knowledge on gut microbiota's role in PD pathophysiology and therapeutic innovation, providing a roadmap for future research directions.

Keywords: Dysbiosis; Gut microbiota; Microbiota-targeted therapies; Neuroinflammation; Parkinson’s disease; α-Synuclein aggregation.