Dystrophic Skeletal Muscle Phenotypes Can Be Horizontally Transferred Via Fecal Microbiome Transplantations

Duchenne Muscular Dystrophy (DMD) is one of the most common and prevalent inherited neuromuscular diseases, accounting for >80% of muscular dystrophy cases around the world. DMD has no cure, and patients experience severe muscle degeneration that continues until death. DMD patients also suffer from gastrointestinal complications, including impaired swallowing, gastro-esophageal reflux and constipation. These features undoubtedly impact DMD patient microbiotas yet, it is unclear whether any differences between healthy and dystrophic microbiotas simply reflect the disease or whether microbes are directly involved in promoting dystrophic muscle phenotypes. Here, we sought to determine a causal role for the microbiota in promoting dystrophic muscle characteristics by performing intra/inter-genotype fecal microbiota transplantations (FMT) between wildtype (C57BL/10) and mdx (C57BL/10ScSn-Dmdmdx/J) mice, and assessed the impact of FMT on muscle phenotypes and microbiota composition over 9 weeks. We found that transplantation of mdx microbiotas into a wildtype mouse induced a mdx-like muscle phenotype while transplantation of wildtype microbiotas into a mdx background improved muscle features. These remarkable switches in muscle phenotypes were accompanied by continuous shifts in microbiota composition over time as the FMT communities adapted to their new hosts. We also identified several taxa that were differentially abundant between wildtype mice receiving either wildtype or mdx FMT, thereby highlighting their potential role in muscle health. Overall, our results indicate that microbes are active participants in impacting muscle health through both beneficial and detrimental mechanisms. Accordingly, microbial factors represent unexploited therapeutic targets for improving overall muscle health outcomes in muscular dystrophies.