Objective: We aim to investigate the microbiome composition and functional profiles in Parkinson’s disease (PD) patients with and without premotor rapid eye movement sleep behavior disorder (RBD) with focus on the alpha-synuclein aggregation.

Background: Alpha-synuclein accumulation in the enteric nerves can link PD with gut microbiome imbalances. Previous studies suggested that the gut microbiome could promote alpha-synuclein aggregation. Particularly, patients with premotor RBD might be more affected by alpha-synuclein-related gut microbiome changes, warranting an investigation into the distinct microbiome functions and dynamics of this group.

Method: We investigated patients with PD and their spouses as healthy controls (HC). Patients with PD were categorized as PD-RBD(+) and PD-RBD(-) based on RBD presence before the PD diagnosis. We evaluated the microbiome differences between these groups according to the disease progression stage, with taxonomic and functional differential abundance analyses, and carbohydrate-active enzyme (CAZyme) profiles based on metagenome-assembled genomes.

Results: We investigated 80 patients with PD and 84 HC, with 55 patients (68.75%) categorized as PD-RBD(+) and 25 patients (31.25%) as PD-RBD(-) based on RBD presence before the PD diagnosis. The PD-RBD(+) gut microbiome showed a distinct microbiome composition regardless of disease stage compared to that in the HC, whereas the microbiome in PD-RBD(-) was initially similar to HC but diverged toward PD-RBD(+) with disease progression. In early-stage PD-RBD(+), Escherichia and Akkermansia were enriched, which were associated with higher pathogenic biofilm formation and host mucin degradation in the functional analysis. We found that genes of the UDP-GlcNAc synthesis/recycling pathway were negatively correlated with biofilm formation and this finding was also validated in another cohort. Further, fiber intake-associated taxa were decreased in early-stage PD-RBD(+), supported by the and biased mucin-degrading capacity of CAZyme compared to fiber degradation.

Conclusion: We identified that the gut microbiome dynamics of PD depends on the presence of premotor RBD. Early-stage PD-RBD(+) showed distinct gut microbial characteristics, potentially impacting alpha-synuclein aggregation, which may contribute to the new therapeutic development targeting the gut microbiome in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/distinct-gut-microbiome-in-parkinsons-disease-based-on-the-presence-of-premotor-rapid-eye-movement-sleep-behavior-disorders-exploring-the-alpha-synuclein/