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

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Targeting gut dysbiosis against inflammation and impaired autophagy in Duchenne muscular dystrophy

Today’s pick is by Kalkan et al published in EMBO Molecular Medicine on the dysbiosis of the gut in the mdx Duchenne mouse model. DOI: 10.15252/emmm.202216225

Duchenne is caused by lack of dystrophin, which causes chronic inflammation of the skeletal muscle, impaired regeneration and inevitably replacement of muscle with fat and fibrotic tissue. Corticosteroid treatment (prednisone or deflazacort) slows down disease progression. The authors here focus on the gut: we have billions of bacteria living in our gut (microbiota). In fact we have more bacteria in our gut than cells in our body! The microbiota produce metabolites, e.g. small fatty acids, that will go into the blood and can act on the body.

This interaction is especially potent for the skeletal muscle and acts via the endocannabinoid system. Here authors studied the gut microbiota of wild type and mdx (mice without dystrophin). First they analyzed which bacteria were present in the poo of both. This revealed a difference in bacteria types between mdx and wild type mice. Interestingly, treatment with deflazacort normalized the types of bacteria present in the mdx gut. The misregulation of gut bacteria types is called dysbiosis.

This dysbiosis resulted in differences in serum levels of metabolites, e.g. a reduction in metabolites to produce butyrate. As this metabolite influences inflammation and autophagy (which are too high and too low in mdx mice), authors proceeded with treating mice with butyrate.

This treatment resulted in longer running times on the rotarod and increased strength (though the strength test is strange and involves holding different weights for different mice, so it is not clear whether the wild type mice held higher weights than mdx…)

Authors also tested an inhibitor of cannabinoid signaling which improved autophagy in mdx mice. To study pathways in more detail, authors moved to cell models (C2C12 mainly) showing butyrate reduced inflammation after stimulation with LPS (very potent inflammatory inducer).

Butyrate also promoted autophagy. Authors further show that micro-RNAs play a role and are influenced by the butyrate and cannabinoid signaling inhibitors to then influence inflammation and autophagy.

Authors conclude there is a dysbiosis for mdx mice, which has an impact on muscle function & metabolism. They anticipate there is also dysbiosis in Duchenne patients. It is interesting that deflazacort improves dysbiosis – may outline an additional way steroids work for Duchenne.

Authors also conclude that this means that treating the microbiota of Duchenne patients might have therapeutic effects. Before doing this, of course more research is needed. e.g. Mdx mice live in the lab in very clean and controlled conditions (standardized chow).

Also, the authors do not mention the sex of the mice. Ideally they used only males, as most Duchenne patients are men and the sex will influence the microbiota as well. While authors did study some aspects in human cell cultures, additional studies in patient feces are needed.

Likely there will be much more variability between patients and between unaffected controls in microbiota, due to different living environments and diets. Having said that, the constant de- and regeneration of muscle in Duchenne patients, likely will influence microbiota.

This is another difference between mice and men though: mdx have very efficient muscle regeneration, while Duchenne patients have worse regeneration and lose muscle mass. So it is possible the effect on microbiota is different and that therefore different intervention is needed.

This is all speculation for now. Bottom line is that the paper is interesting and confirms a role between gut and muscle, a dysbiosis in Duchenne mice, which means this is a topic that requires further study in patients.