Habitual Diet, Gut Microbiome Dysbiosis, and α‐Synucleinopathy Conversion in Isolated Rapid Eye Movement ( REM) Sleep Behavior Disorder

BACKGROUND: Accumulating evidence indicates that habitual diet, including plant-based dietary patterns, is associated with neurodegenerative α-synucleinopathy risk. However, the role of diet and its correlation with the gut microbiome in prodromal α-synucleinopathy, specifically among patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), remains unclear. OBJECTIVE: To evaluate dietary patterns, their interplay with gut microbial dysbiosis, and longitudinal effects on neurodegenerative progression in iRBD patients. METHODS: We recruited 287 iRBD patients and 208 age- and sex-matched controls. Plant-based diet indices (PDIs) were derived from food frequency questionnaires. Shotgun metagenomic sequencing was performed in 456 subjects for diet-microbiome analyses. After a median follow-up of 4.2 years, 45 (15.7%) iRBD patients converted to α-synucleinopathies. Cox proportional hazards models assessed the associations between diet and neurodegenerative outcomes. RESULTS: We found that iRBD patients exhibited lower healthful PDIs (adjusted odds ratio [aOR] 95% confidence interval [95% CI]: 0.48 [0.29-0.80], P = 0.005) but higher consumption of unhealthful plant-based foods (refined grains, sweets, and sweeteners). Diet-microbiome interaction analysis identified dietary associations for 84.3% of iRBD-related gut microbes, including co-occurrence between healthful PDI and Clostridium sp. AF20-17LB. Longitudinally, four dietary factors and five iRBD-related microbes were associated with neurodegenerative outcomes; specifically, higher coffee consumption was linked to a lower risk of progression to α-synucleinopathy (aHR [95% CI]: 0.30 [0.11-0.78], P = 0.01). Furthermore, mediation analyses indicated that the iRBD-enriched species Ruthenibacterium lactatiformans mediated the association between unhealthful PDI and dementia-first conversion. CONCLUSIONS: Habitual diet in iRBD is associated with gut microbiome dysbiosis and predicts neurodegenerative progression. These findings highlight diet-microbiome interactions as modifiable targets for intervention in prodromal α-synucleinopathy.