Gut-brain axis and environmental factors in Parkinson's disease: bidirectional link between disease onset and progression

Parkinson's disease has long been considered a disorder that primarily affects the brain, as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies containing alpha-synuclein protein. In recent decades, however, accumulating research has revealed that Parkinson's disease also involves the gut and uncovered an intimate and important bidirectional link between the brain and the gut, called the "gut-brain axis." Numerous clinical studies demonstrate that gut dysfunction frequently precedes motor symptoms in Parkinson's disease patients, with findings including impaired intestinal permeability, heightened inflammation, and distinct gut microbiome profiles and metabolites. Furthermore, alpha-synuclein deposition has been consistently observed in the gut of Parkinson's disease patients, suggesting a potential role in disease initiation. Importantly, individuals with vagotomy have a reduced Parkinson's disease risk. From these observations, researchers have hypothesized that alpha-synuclein accumulation may initiate in the gut and subsequently propagate to the central dopaminergic neurons through the gut-brain axis, leading to Parkinson's disease. This review comprehensively examines the gut's involvement in Parkinson's disease, focusing on the concept of a gut-origin for the disease. We also examine the interplay between altered gut-related factors and the accumulation of pathological alpha-synuclein in the gut of Parkinson's disease patients. Given the accessibility of the gut to both dietary and pharmacological interventions, targeting gut-localized alpha-synuclein represents a promising avenue for developing effective Parkinson's disease therapies.