Akademik Veri Yönetim Sistemi
Canadian Journal of Neurological Sciences, 2025 (SCI-Expanded)
Background: Gut microbiota affects muscle homeostasis and growing evidence indicates dysbiosis of gut microbiota may be a contributing factor in the pathogenesis of dystrophies. Furthermore, gut microbiota metabolites can interact with DNA methylation. Facioscapulohumeral muscular dystrophy(FSHD) is the second common dystrophy with hypomethylation of DR1 and 5P regions of D4Z4 repeat on 4qter. Objective: Considering alteration of gut microbiota may be contributing factor, we investigated (i)gut microbiota alterations, (ii)the correlation of microbial-derived free-fatty acids(FFAs) with methylation of DR1 and 5P regions in FSHD. Methods: 28 FSHD patients and 28 gender-age-matched controls were included. Gut microbiota characterization was performed through 16S-rRNA sequencing. Methylation levels of DR1 and 5P regions were assessed by bisulfite sequencing. Faecal and circulating FFAs including SCFAs, medium(MCFAs) and long chain fatty acids(LCFAs) were analysed with GC-MS. Results: Altered gut microbiota was observed in patients, along with distinct profiles of faecal and circulating SCFAs, MCFAs, and LCFAs. DR1 and 5P regions exhibited significant hypomethylation in FSHD compared to control. Hypomethylation correlated with faecal and circulating FFAs in patients while no correlation was identified in healthy controls. The severely affected patients exhibited a notable increase in the prevalence of Pasteurellaceae while the FFA profile was similar among mild and severely affected patients. This is the first study revealing that FSHD patients showed compositional and functional gut microbiota dysbiosis. A strong association between proximal D4Z4 hypomethylation with microbial-derived SCFAs was identified. Conclusion: These findings suggest that gut microbiota modulation with its metabolites could be promising strategy for interventions in FSHD management.