In this study, we found that in mdx mice, a validated preclinical model of DMD, the disease is associated with a significant alteration in the gut microbiota composition compared with healthy controls. Along with this alteration, the plasma of mdx mice showed a reduction in the levels of gut microbiota‐related metabolites, the short‐chain fatty acids (SCFAs), and an elevation of those of endocannabinoids. Supplementation with the SCFA, sodium butyrate (NaB), rescued muscle strength and autophagy, and prevented inflammation associated with excessive endocannabinoid signaling at CB1 receptors to the same extent as deflazacort (DFZ), the standard palliative care for DMD. In C2C12 myoblasts stimulated with lipopolysaccharide, a pro‐inflammatory molecule derived from a malfunctioning gut microbiota, NaB exerted anti‐inflammatory effects, promoted autophagy, and prevented dysregulation of microRNAs that keep under negative control the CB1 receptor gene and did so in a manner depending on the activation of GPR109A and PPARγ receptors.
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