Deciphering the heterogeneity of prodromal α-synucleinopathy: linking brain biotyping and gut dysbiosis in isolated REM sleep behaviour disorder

BACKGROUND: Isolated/idiopathic REM sleep behaviour disorder (iRBD) is a specific prodrome of α-synucleinopathies. We previously identified two distinct clinical-neuroimaging biotypes in iRBD: Biotype 1, marked by widespread cortical-subcortical-cerebellar atrophy with motor and cognitive deficits, and Biotype 2, with preserved brain structure and neurocognition. Converging evidence implicates the gut-brain axis in early α-synucleinopathy, yet its role in these divergent iRBD phenotypes remains unexplored. METHODS: We analysed faecal microbiota using shotgun metagenomic sequencing and structural neuroimaging data from 167 participants (42 Biotype 1, 50 Biotype 2, 75 controls). Microbial features and brain structure were compared across groups. Gut-brain associations were assessed using sparse partial least squares regression to link microbiome features with neuroanatomical patterns. FINDINGS: Overall microbial composition did not significantly differ between Biotype 1 and Biotype 2, and both biotypes showed depletion of short-chain fatty acid-producing bacteria. Relative to the shared dysbiotic background, Biotype 1 displayed more pronounced taxon- and pathway-level alterations, including enrichment of Collinsella aerofaciens, Cloacibacillus evryensis, and Mogibacterium sp. BX12, which were associated with Biotype 1-specific brain atrophy. Biotype 2 showed milder dysbiosis with fewer differentially abundant species. These patterns were consistent in sensitivity analyses and fully adjusted models. INTERPRETATION: Beyond a shared depletion of short-chain fatty acid-producing bacteria, iRBD biotypes exhibit differences in taxonomic and functional profiles, with these differences being more pronounced in Biotype 1. These findings support a role for the gut-brain axis in early α-synucleinopathy and its phenotypic heterogeneity. FUNDING: This study was funded by the Health and Medical Research Fund of the Food and Health Bureau (Ref No.: 05162876 and 10210686) and Research Grants Council (RGC-CRF Ref No.: C4044-21G) of Hong Kong.