Deficiency of the commensal Bacteroides vulgatus exacerbates skeletal muscle damage in mouse and human models of Duchenne Muscular Dystrophy

Gut microbiota perturbations are increasingly implicated in skeletal muscle disorders. In this study, we analyzed fecal samples from mice and humans with Duchenne muscular dystrophy (DMD), a severe X-linked myopathy, and found significant alterations in the abundance of commensal Bacteroides species compared to healthy control individuals. This prompted us to focus on Bacteroides vulgatus and their metabolites, including short-chain fatty acids (SCFAs, primarily acetate, propionate, and butyrate) and commendamide, a recently identified endocannabinoid-like molecule whose biological properties are poorly known. In dystrophic mouse muscle, we observed activation of ferroptosis, an iron-dependent form of regulated cell death not well studied in DMD. In murine C2C12 and primary human myotubes treated with erastin, a ferroptosis inducer, commendamide restored glutathione homeostasis and prevented the dysregulated expression of ferroptosis-related genes, with effects comparable to and enhanced by SCFAs. Bioinformatic and experimental analyses revealed commendamide as a novel endogenous activator of PPARα and PPARγ. PPARα activation upregulated Gpx4 , a key antioxidant gene, through binding to response sequences in the 5′-untranslated region (5′-UTR). These findings uncover a gut–muscle axis by which microbiota-derived metabolites, particularly commendamide, influence muscle health and highlight their potential as therapeutic agents for DMD and related myopathies.