Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy.
Di Muraglia Noemi, De Vito Martina, Panza Elisabetta, Pagano Ester, Vitale Rosa Maria, Piscitelli Fabiana, Villano Rosaria, Capasso Raffaele, Pota Vincenzo, Pace Caterina, Dongiovanni Salvatore, Di Marzo Vincenzo, Iannotti Fabio Arturo
Abstract
OBJECTIVE: The gut microbiota regulates skeletal muscle physiology, with an increasingly recognised role in Duchenne muscular dystrophy (DMD), the most severe X-linked myopathy. Unlike previous studies, we focussed on the genus Bacteroides and its metabolites, assessing their abundance in DMD mice and patients to clarify their potential contribution to the disease. METHODS: The relative abundance of Bacteroides species was analysed in fecal samples from dystrophic mdx mice and DMD patients, compared with age-matched healthy controls, using PCR-based tecniques. Synthetic and analitical chemistry approaches followed by cell-based assays, in silico and bioinformatic analyses, were employed to identify an unknown mechanism of action of the Bacteroides-derived metabolites. RESULTS: DMD patients and mdx mice exhibited a significant reduction in commensal Bacteroides species, including Bacteroides vulgatus, known producers of SCFAs and commendamide, an endocannabinoid-like molecule with largely uncharacterized biological functions. In skeletal muscles of mdx mice, we observed biochemical features consistent with increased susceptibility to ferroptosis. In murine C2C12 cells and primary human myotubes exposed to the ferroptosis inducer erastin, commendamide conferred significant protective effects, which were further enhanced in the presence of SCFAs. Additionally, we discovered that commendamide acts as an endogenous activator of PPARα and PPARγ, with PPARα preferentially promoting the transcription of the antioxidant genes Gpx4 and Nrf2. CONCLUSION: These findings provide new insights into the gut-muscle axis in DMD, suggesting that the depletion of Bacteroides vulgatus and its metabolites may contribute to skeletal muscle degeneration. In vitro evidence demonstrates that commendamide, through PPARα signaling; and SCFAs, enhances antioxidant mechanisms. Overall, these results support further investigation of microbiota-derived metabolites as postbiotic candidates for DMD therapy.
Key Findings
- DMD patients and mdx mice show a significant reduction in Bacteroides species, including Bacteroides vulgatus, which produce commendamide and SCFAs.
- Skeletal muscles of mdx mice exhibit biochemical features indicating increased susceptibility to ferroptosis.
- Commendamide protects murine C2C12 cells and human myotubes from ferroptosis induced by erastin, an effect enhanced by SCFAs.
- Commendamide acts as an endogenous activator of PPARα and PPARγ, with PPARα promoting transcription of antioxidant genes Gpx4 and Nrf2.
Clinical Significance
These findings suggest that depletion of Bacteroides-derived metabolites contributes to muscle degeneration in DMD and highlight commendamide and SCFAs as potential postbiotic therapies to enhance antioxidant defenses and reduce ferroptosis in skeletal muscle.
Citation
Di Muraglia Noemi, De Vito Martina, Panza Elisabettaet al.. Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy. Journal of translational medicine. 2026-Jun-06.