Insight into the Role of Gut Microbiota in Duchenne Muscular Dystrophy: An Age-Related Study in Mdx Mice

Abstract

Dystrophindeficiency alters the sarcolemma structure, leading to muscle dystrophy, muscle disuse, and ultimately death. Beyond limb muscle deficits, patients with Duchenne muscular dystrophy have numerous transit disorders. Many studies have highlighted the strong relationship between gut microbiota and skeletal muscle. The aims of this study were: i) to characterize the gut microbiota composition over time up to 1 year in dystrophin-deficientmdxmice, and ii) to analyze the intestine structure and function and expression of genes linked to bacterial-derived metabolites in ileum, blood, and skeletal muscles to study interorgan interactions.Mdxmice displayed a significant reduction in the overall number of different operational taxonomic units and their abundance (α-diversity).Mdxgenotype predicted 20% ofβ-diversity divergence, with a large taxonomic modification of Actinobacteria, Proteobacteria, Tenericutes, and Deferribacteres phyla and the included genera. Interestingly, mdx intestinal motility and gene expressions of tight junction andFfar2receptor were down-regulated in the ileum. Concomitantly, circulating inflammatory markers relatedto gut microbiota (tumor necrosis factor, IL-6, monocyte chemoattractant protein-1) and muscle inflammationTlr4/Myd88pathway (Toll-like receptor 4, which recognizes pathogen-associated molecular patterns) were up-regulated. Finally, inmdxmice, adiponectin was reduced in blood and its receptor modulated in muscles. This study highlights a specific gut microbiota composition and highlights interorgan interactions inmdxphysiopathology with gut microbiota as the potential central metabolic organ.