Comprehensive review synthesizing human and animal evidence that gut microbiota dysbiosis, altered microbial metabolites, and increased intestinal permeability contribute to α-synuclein misfolding and neuroinflammation in Parkinson’s disease, and that microbiome-targeted interventions (diet,…

Identifies actionable, translational targets (microbial metabolites, gut permeability, microbiome modulation) for early biomarkers and interventions in PD while emphasizing the need for standardized, longitudinal, precision studies to validate efficacy and causality.

INTRODUCTION: Parkinson's Disease (PD) is the second most prevalent neurodegenerative disorder, affecting over 8.5 million individuals worldwide, with its incidence expected to rise. It is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and pathological aggregation of α-synuclein into Lewy bodies, leading to motor and non-motor symptoms. Increasing evidence implicates the Gut-Brain Axis (GBA) in PD pathophysiology. METHODS: This review synthesizes findings from human and animal studies investigating the role of gut microbiota, gut permeability, microbial metabolites, and gastrointestinal dysfunction in the development and progression of PD. RESULTS: Gut microbiota dysbiosis is associated with altered production of short-chain fatty acids, tryptophan metabolites, and neurotransmitter precursors, contributing to neuroinflammation, increased intestinal permeability, and α-synuclein misfolding. Gastrointestinal symptoms such as constipation, dysphagia, and gastroparesis often precede motor symptoms by decades, highlighting the gut as a potential origin of pathology. Therapeutic strategies targeting the microbiome, including Mediterranean and ketogenic diets, probiotics, prebiotics, postbiotics, and experimental phage therapy, have demonstrated promising preliminary outcomes. DISCUSSION: Despite encouraging results, inconsistencies in methodology, mechanistic uncertainties, and the lack of longitudinal and individualized studies limit current understanding. Standardization and precision-based approaches are required to clarify causality and therapeutic efficacy. CONCLUSION: Advancing knowledge of the gut-brain axis in PD presents valuable opportunities for early biomarkers and microbiota-targeted interventions, offering novel strategies to delay disease progression and improve patient quality of life.