Commendamide, a metabolite produced by beneficial gut bacteria that are depleted in people with Duchenne muscular dystrophy (DMD), protects muscle cells from damage by enhancing antioxidant mechanisms, a study found.
“These findings provide new insights into the gut-muscle axis in DMD” and “support further investigation of microbiota-derived metabolites as postbiotic candidates for DMD therapy,” the researchers wrote.
The study, “Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy,” was published in the Journal of Translational Medicine.
DMD is caused by mutations in the gene that encodes dystrophin, a protein that helps maintain the structural integrity of muscle fibers. Without it, muscles progressively break down, leading to muscle weakness and wasting.
Recent research suggests that disruption of the gut microbiome, the community of bacteria and other microbes living in the intestines, may play a role in DMD. Altered gut microbiome composition in a DMD mouse model has been linked to worsened muscle inflammation and degeneration. And restoring the microbiome in these mice improved muscle strength.
Good bacteria
Researchers in Italy explored a connection between the gut microbiome and muscle health in DMD by focusing specifically on the Bacteroides family of gut bacteria.
These microbes, considered good gut bacteria, make up a major portion of the gut microbiome. There, they actively break down complex plant carbohydrates and produce beneficial molecules called short-chain fatty acids (SCFAs), which help regulate metabolism and inflammation.
The researchers began by analyzing stool samples from 11 DMD patients and 12 healthy individuals, as well as from DMD mice and healthy control mice.
Several Bacteroides species were significantly reduced in both patients and mice. Bacteroides vulgatus, a known producer of SCFAs, was particularly low. Levels of commendamide, a fat-like lipid signaling molecule produced by Bacteroides, were also reduced.
The team then confirmed that a specific form of cell death called ferroptosis, driven by iron accumulation, was relevant to DMD. A gene that promotes the production of fats that are prone to ferroptosis was significantly elevated in all muscle types. In contrast, those that protect against ferroptosis were significantly reduced in most muscles tested.
Treating mouse muscle cells and myotubes (which mature into muscle fibers) with commendamide conferred significant protection against induced ferroptosis. Commendamide alone also partly reversed increases in markers of ferroptosis-driven oxidative stress, a response that was more pronounced when combined with SCFAs.
To understand the mechanism underlying commendamide’s protective effects, the researchers investigated a family of receptors called PPARs, which regulate genes involved in metabolism and inflammation. Tests showed that commendamide activated two PPARs: PPAR-alpha and PPAR-gamma, in a concentration-dependent manner.
Computational modeling using molecular docking and molecular dynamics (movement) simulations confirmed that commendamide binds stably to both PPAR-alpha and PPAR-gamma.
Although commendamide activated both PPARs, only PPAR-alpha activation increased the activity of protective antioxidant genes: Gpx4 and Nrf2. When co-treated with GW6471, a compound that selectively blocks PPAR-alpha, the increased activity of Gpx4 was abolished, confirming that the effect depended on PPAR-alpha signaling.
“The identification of a microbiota-derived lipid capable of modulating ferroptosis highlights the potential of targeting gut-derived metabolic signaling as a complementary strategy to dystrophin-focused therapies in DMD,” the researchers concluded. “Rather than replacing current treatments, modulation of the gut-muscle axis may offer a means to attenuate oxidative vulnerability and disease progression.”
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