Research progress on the role of gut microbiota in skeletal muscle atrophy

Skeletal muscle is a fundamental tissue within the locomotor system, indispensable not only for movement and structural support but also as a critical regulator of systemic metabolism. Skeletal muscle atrophy, a debilitating condition characterized by a progressive decline in muscle mass, strength, and function, arises from a multitude of etiological factors including specific diseases, aging, nerve injuries, disuse, and cancer cachexia. This deterioration significantly compromises patients' physical autonomy, metabolic health, and overall quality of life, making it a paramount concern in medical research. Concurrently, the gut microbiota, a complex and dynamic ecosystem of microorganisms residing in the gastrointestinal tract, is increasingly recognized as a central modulator of host physiology, influencing processes from nutrient metabolism to immune and inflammatory responses. The emergent concept of a "gut-muscle axis" posits a bidirectional communication network between the gut microbiota and skeletal muscle homeostasis. This article reviews the research progress of gut microbiota in skeletal muscle atrophy, mainly including the interaction mechanism between gut microbiota and skeletal muscle, the role of gut microbiota in different types of skeletal muscle atrophy, and the strategies for intervening gut microbiota to treat skeletal muscle atrophy, aiming to provide new ideas and strategies for the research and treatment of diseases related to skeletal muscle atrophy. The core of this article provides a detailed elaboration of the primary mechanisms through which the gut microbiota influences skeletal muscle physiology and pathology. These mechanisms are multifaceted: Firstly, microbial metabolites play a pivotal role. Short-chain fatty acids like butyrate, propionate, and acetate, produced by bacterial fermentation of dietary fiber, are crucial mediators. They influence muscle energy metabolism, and help maintain systemic inflammatory homeostasis by preserving intestinal barrier integrity. Other metabolites, including secondary bile acids and metabolites of dietary tryptophan, also significantly impact muscle protein synthesis, mitochondrial function, and inflammatory status. Secondly, immunoregulation is a major pathway. The gut microbiota is essential for the proper development and function of the host immune system. Dysbiosis can disrupt intestinal barrier function, leading to systemic inflammation characterized by elevated pro-inflammatory cytokines, which are potent drivers of muscle catabolism. Furthermore, the microbiota shapes the differentiation and balance of T-cell subsets, which can subsequently influence the inflammatory milieu within the muscle microenvironment, either exacerbating or ameliorating atrophy. The review further analyzes the specific alterations and roles of the gut microbiota in distinct types of skeletal muscle atrophy, highlighting the interplay between specific pathological contexts and microbial ecology. In Duchenne muscular dystrophy, dysbiosis is characterized by an increase in LPS-producing Gram-negative bacteria, leading to impaired gut barrier, systemic inflammation, and disrupted SCFA metabolism. Interventions like sodium butyrate supplementation have shown promise in improving muscle function in models. In myotonic dystrophy type 1, patients exhibit an altered Firmicutes/Bacteroidetes ratio and a reduction in beneficial Lactobacillus, suggesting a link between gastrointestinal symptoms and muscle pathology. In age-related sarcopenia, decreased microbial diversity and reduced SCFA production are associated with chronic inflammation and anabolic resistance. In neurogenic atrophy, distinct microbial shifts are observed, which may contribute to disease progression through heightened neuroinflammation and disrupted energy metabolism. Lastly, in cancer cachexia, microbial dysbiosis is implicated in driving the severe inflammatory response and metabolic wasting. The article also evaluates strategies for intervening in the gut microbiota to prevent or treat skeletal muscle atrophy. These include probiotics, prebiotics to stimulate the growth of beneficial bacteria, and fecal microbiota transplantation to reconstitute a healthy microbial community. Clinical evidence, particularly from studies on elderly sarcopenia, shows that multi-strain probiotic interventions can lead to measurable improvements in muscle strength and reductions in inflammatory markers. The potential of targeted delivery systems, such as engineered probiotics encapsulated in nanomaterials to precisely modulate the gut environment, is also discussed as an emerging frontier. In conclusion, the evidence compellingly supports the gut microbiota as a critical modifier of skeletal muscle health and a key player in the pathophysiology of various muscle atrophies. Targeting the gut-muscle axis presents a novel and promising therapeutic paradigm. Future research should focus on validating these findings in large-scale human trials, elucidating the precise molecular signals involved, and developing personalized microbiota-based interventions to combat muscle wasting and improve patient outcomes.