Gut microbiome composition in Huntington's disease: Stage-dependent differences between premanifest and manifest patients.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder with substantial clinical heterogeneity. The gut microbiome has been proposed as a potential modulator of neurodegeneration, but its role in HD and across disease stages remains unclear. METHODS: This cross-sectional case-control study included 50 individuals with HD (35 manifest, 15 pre-manifest) and 36 age- and sex-matched cohabiting controls. Stool samples were analysed using 16S rRNA sequencing. Clinical, lifestyle, and dietary variables were recorded. Microbial diversity and differential taxonomic abundance were assessed, accounting for relevant covariates. RESULTS: No significant differences in global microbial diversity were observed between HD and controls. Age was the main factor associated with both alpha and beta diversity. However, HD was associated with discrete taxonomic differences. More pronounced alterations were identified between manifest and pre-manifest stages, with exploratory genus-level compositional differences identified between disease stages. Antibiotic exposure significantly reduced microbial richness and influenced community structure. CONCLUSIONS: Gut microbiome alterations in HD may differ across clinical stages rather than reflecting global dysbiosis. These exploratory findings suggest that microbiome composition may contribute to disease heterogeneity, although confirmation in larger longitudinal and independent cohorts is required before considering its potential as a biomarker or therapeutic target.