The link between the gut microbiota and Parkinson's Disease: A systematic mechanism review with focus on α-synuclein transport

Introduction: Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of alpha-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD. Method: A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria. Results: All twenty-two human case-control studies demonstrated an altered gut micmbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, alpha-synuclein pathology and motor deficits. Accumulation of phosphorylated alpha-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of alpha-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain. Conclusion: Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD.