Chondroitin sulfate restores muscle mass via gut–muscle axis remodeling through sugar–bile acid metabolism reprogramming

Abstract Glucocorticoid‐induced myopathy is characterized by progressive muscle atrophy and impaired regeneration, yet effective microbiota‐oriented interventions for preserving muscle homeostasis remain largely unexplored. Here, we demonstrate that dietary chondroitin sulfate (DCS) restores muscle mass and function through a microbiota‐dependent gut–muscle metabolic axis. DCS failed to confer protection in germ‐free or antibiotic‐treated mice, establishing gut microbiota as a prerequisite for its efficacy. Microbiota transplantation and mono‐colonization experiments identified Lactobacillus johnsonii Z‐RW as a functionally relevant mediator capable of recapitulating muscle protection under controlled microbial conditions. Integrated metagenomic, metabolomic, and proteomic analyses revealed coordinated reprogramming of intestinal sugar utilization and bile acid metabolism following DCS administration. Notably, DCS promoted bile acid deconjugation and enrichment of secondary bile acids, coinciding with restoration of muscle regenerative and energetic programs, including upregulation of NMRK2, PAX7, and SIRT1. Metabolite supplementation further implicated bile acids as candidate mediators linking microbial metabolism to muscle phenotypes. To quantitatively integrate these shifts, we introduce the sugar‐bile acid ratio as a systems‐level descriptor of microbiota‐driven metabolic remodeling. Our findings delineate a microbiota‐dependent metabolic framework through which a functional polysaccharide reshapes intestinal biochemistry to influence distal muscle physiology. This work highlights bile acid‐associated signaling as a central relay within the gut‐muscle axis and provides a conceptual foundation for microbiota‐targeted strategies to mitigate muscle wasting.