THE GUT-MUSCULOSKELETAL AXIS AS A PHARMACOLOGICAL TARGET: MICROBIOME-BASED THERAPEUTICS FOR OSTEOPOROSIS, OSTEOARTHRITIS, SARCOPENIA, AND PAIN MANAGEMENT

Abstract

The gut-muscular system axis has become a key paradigm to explain the systemic interactions between gut microbial communities and the skeletal muscle, pain regulation and bone and joint diseases. This narrative review will discuss the potential role of gut dysbiosis in osteoporosis, osteoarthritis, sarcopenia and chronic musculoskeletal pain via disruption of the intestinal barrier, microbial translocation, immune activation, nutrient handling modification, endocrine disturbance and changes in microbial metabolites. The role of short-chain fatty acids, bile acids, indole derivatives, lipopolysaccharides as mediators of bone remodelling, cartilage degeneration, muscle protein metabolism, mitochondrial function, insulin sensitivity, and nociceptive signalling is highlighted. Experimental studies support gut–bone, gut–joint, gut–muscle and gut–brain interactions mechanistically, with human evidence further supporting interactions but being heterogeneous. Adjuncts to conventional pharmacological treatment are being explored such as probiotics, prebiotics, synbiotics, postbiotics, dietary interventions, microbial metabolites, faecal microbiota transplantation, bacteriophages and next-generation live biotherapeutics. The clinical application of their use is currently restricted due to interindividual microbiome variability, inconsistent formulations, lack of certainty in dosing, short follow-up, and weak causal evidence. To validate efficacy, safety and treatment durability, standardised methodologies, disease-specific biomarkers, integration of multi-omics and large multicentre trials are needed. While the potential for microbiome-directed strategies to aid in the management of musculoskeletal degeneration and pain in a more precise and integrated manner is possible, the therapies should be considered complementary and not replacements for current therapies.