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

Abstract 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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.