Body-first and Brain-first Parkinson's Disease Subtypes Exhibit Distinctive Gut Microbial Dysbiotic Patterns

Abstract

Abstract Parkinson's disease, a complex neurodegenerative disorder characterized by the degeneration of dopamine-producing neurons and the presence of alpha-synuclein aggregates in Lewy bodies, exhibits clinical diversity prompting a proposed classification into two subtypes: body-first, originating in the peripheral nervous system, and brain-first, initiating in the central nervous system. Recent evidence links gut microbiome dysbiosis to alpha-synuclein aggregation in the gut, prompting a comprehensive study utilizing shotgun metagenomics to explore the roles of the gut microbiome in these subtypes. Categorizing patients based on premotor rapid eye movement (REM) sleep behavior disorder (RBD) and cardiac meta-iodobenzylguanidine (MIBG) uptake revealed significant beta diversity differences between body-first and brain-first subtypes. The body-first subtype exhibited more pronounced dysbiosis, characterized by increased Escherichia, Enterobacter, and Akkermansia, and decreased Roseburia, Agathobacter, and Faecalibacterium. Functionally, these changes were associated with alpha-synuclein aggregation pathways and decreased neuroprotective putrescine/spermidine biosynthesis. Premotor RBD and heart MIBG were considered as subtype indicators based on microbiome profiles, with the latter showing higher sensitivity and the former demonstrating better specificity. Random forest analysis confirmed their combination as optimal indicators for gut microbiome-based classification, shedding light on Parkinson's disease heterogeneity and emphasizing the gut microbiome's substantial impact on both subtypes. The study underscores the potential for innovative therapeutic interventions targeting the gut microbiome in Parkinson's disease, marking a significant step toward personalized approaches for diagnosis, treatment, and management based on subtype-specific characteristics and microbial signatures.