Gut-bone axis crosstalk: Microbiota-driven immune-metabolic-neural networks in bone disorders and precision interventions

The gut microbiota regulates bone metabolism via a complex gut-bone axis involving short-chain fatty acids (SCFAs), immune modulation, and neuroendocrine signals. However, the precise mechanisms remain unclear, and microbiota-targeted interventions (probiotics, prebiotics, fecal microbiota transplantation) are not yet optimized for clinical use. This review systematically synthesizes the immune-metabolic-neural interaction network within the gut-bone axis, highlighting non-linear crosstalk among SCFAs, bile acids, tryptophan derivatives, immune cells (macrophages, Treg/Th17), and vagus nerve signaling. We critically assess translational hurdles, including heterogeneous study designs, confounding factors, and lack of causal evidence. Based on this network perspective, we propose a framework for future research that prioritizes multi-omics approaches, stratified interventions, and rigorous trials. This synthesis advances understanding of how gut dysbiosis drives bone disorders and paves the way for precision skeletal medicine. This review identifies microbial markers for risk stratification of bone metabolic disorders and discusses SCFA-based strategies and fecal microbiota transplantation (FMT) in conditions including osteoporosis, impaired fracture healing, rheumatoid arthritis, and glucocorticoid-associated osteonecrosis. It provides testable hypotheses for large-scale randomized controlled trials (RCTs), directly supporting translation of microbiome research into clinical practice for bone disorders.