Metagenomic Analysis Reveals Large-Scale Disruptions of the Gut Microbiome in Parkinson's Disease

Background: Parkinson's disease (PD) has been consistently linked to alterations within the gut microbiome. Objective: Our goal was to identify microbial features associated with PD incidence and progression. Methods: Metagenomic sequencing was used to characterize taxonomic and functional changes to the PD microbiome and to explore their relation to bacterial metabolites and disease progression. Motor and non-motor symptoms were tracked using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and levodopa equivalent dose across <= 5 yearly study visits. Stool samples were collected at baseline for metagenomic sequencing (176 PD, 100 controls). Results: PD-derived stool samples had reduced intermicrobial connectivity and seven differentially abundant species compared to controls. A suite of bacterial functions differed between PD and controls, including depletion of carbohydrate degradation pathways and enrichment of ribosomal genes. Faecalibacterium prausnitzii-specific reads contributed significantly to more than half of all differentially abundant functional terms. A subset of disease-associated functional terms correlated with faster progression of MDS-UPDRS part IV and separated those with slow and fast progression with moderate accuracy within a random forest model (area under curve = 0.70). Most PD-associated microbial trends were stronger in those with symmetric motor symptoms. Conclusion: We provide further evidence that the PD microbiome is characterized by reduced intermicrobial communication and a shift to proteolytic metabolism in lieu of short-chain fatty acid production, and suggest that these microbial alterations may be relevant to disease progression. We also describe how our results support the existence of gut-first versus brain-first PD subtypes. (c) 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.