Targeting gut dysbiosis against inflammation and impaired autophagy in Duchenne muscular dystrophy

Abstract

Nothing is known about the potential implication of gut microbiota in skeletal muscle disorders. Here, we provide evidence that fecal microbiota composition along with circulating levels of shortchain fatty acids (SCFAs) and related metabolites are altered in the mdx mouse model of Duchenne muscular dystrophy (DMD) compared with healthy controls. Supplementation with sodium butyrate (NaB) in mdx mice 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 LPSstimulated C2C12 myoblasts, NaB reduces inflammation, promotes autophagy, and prevents dysregulation of microRNAs targeting the endocannabinoid CB1 receptor gene, in a manner depending on the activation of GPR109A and PPARc receptors. In sum, we propose a novel disease-modifying approach in DMD that may have benefits also in other muscular dystrophies.

When dysbiosis meets dystrophy: an unwanted gut‐muscle connection

“…Interestingly, among the microbial metabolites that differed between wildtype and mdx groups, SCFA and key precursors in the biosynthesis pathway of SCFA were found to be significantly reduced in the plasma. Notably, in addition to reversing deficits in locomotor activity, SCFA levels, muscle autophagy, and inflammation, Kalkan et al show that DFZ treatment induced a remarkable increase in the concentration of SCFA, butyrate, known to have beneficial roles including anti‐inflammatory and immunomodulatory properties (Fernandes et al , 2020; Kalkan et al , 2023).…”

“…Given that gastrointestinal and metabolic issues are common in patients with DMD, these two studies unfold the possibility of using gut microbiota metabolite intervention strategies for managing or reversing DMD symptoms (Farini et al , 2022; Kalkan et al , 2023). If the use of SCFA or molecules stimulating the production of SCFA can be shown to have beneficial effects in patients with DMD, they may increase the arsenal of therapies that may slow down the progression of DMD and complement steroid treatment.…”

“…In the last 10 years, several publications have firmly established that when an organ pathologically declines in the host, longlasting alterations of gut microbiota composition occur, often resulting in dysbiosis, worsening in turn the disease symptoms (DeJong et al, 2020). Along these lines, two recent studies (Farini et al, 2022;Kalkan et al, 2023) report on the role of gut dysbiosis in a DMD mouse model, the mdx dystrophic murine model (Fig 1).…”

The Gut Microbiome–Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior

“…In particular, Proteobacteria bloomed and Bacteroidetes declined in the presence of NAEs. Kalkan et al 8 recently showed that in mdx mice, a model of Duchenne’s Muscular Dystrophy (DMD), the disease is associated with a significant alteration in gut microbiota composition, which results in the reduction of the plasma levels of SCFAs. Administration of one such molecule, sodium butyrate (NaB), rescued impaired muscle strength and autophagy, and prevented inflammation, all of which were due to excessive eCB signaling at CB1 receptors.…”

“…NaB simultaneously reduced anandamide and CB1 receptor expression levels in mdx mouse skeletal muscle, and, in both murine and DMD human myoblasts, it exerted anti-inflammatory effects, promoted autophagy, and prevented excessive CB1 signaling by restoring normal levels of microRNAs that suppress CB1 expression. 8 …”