The Gut-Bone Axis and Skeletal Health: Regulatory Mechanisms and Therapeutic Applications of Plant-Derived Bioactive Compounds

The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively retrieve and screen eligible studies from multiple mainstream databases according to standardized inclusion and exclusion criteria, and systematically summarize current research progress on plant-derived bioactive compounds targeting the gut–bone axis for skeletal health regulation. This review systematically explores the underlying mechanisms of the gut–bone axis and critically evaluates the regulatory effects and therapeutic potential of plant-derived bioactive compounds. Particular attention is given to targeted interventions involving prebiotics, probiotics, synbiotics, and plant-rich diets or functional foods. Among these interventions, synbiotics represent the most successful strategy and show the most prominent therapeutic possibilities in bone-related disorders. Different from single prebiotics (only nourish endogenous intestinal microbes), individual probiotics (easy to be degraded in gastrointestinal tract with poor colonization) and ordinary plant-rich diets (unfixed effective dosage and weak targeting property), synbiotics combine prebiotic carriers and viable probiotic strains to produce complementary advantages, which is the core reason for its outstanding therapeutic prospect against bone diseases. Synbiotics exert synergistic effects on gut microecology, mineral absorption, and immune regulation, leading to more robust and consistent improvements in bone health than single prebiotics, probiotics, or general plant-rich diets. They have been verified in preclinical and clinical studies to ameliorate osteoporosis and related skeletal diseases via the gut–bone axis. These strategies offer novel insights into the prevention and treatment of bone metabolic disorders, such as osteoporosis, by targeting the gut–bone axis with phytochemicals. Key outcomes of this review include that synbiotics, soy isoflavones, naringin, curcumin, and resveratrol effectively improve bone mineral density, restore gut microbiota balance, and inhibit pathological bone resorption via the gut–bone axis. Collectively, the above bioactive substances realize bone protection mainly by reshaping gut flora, elevating mineral uptake and suppressing excessive osteoclast activity. Representative cases include soy isoflavones mitigating estrogen-deficient bone loss in OVX models, naringin improving the trabecular microarchitecture, and probiotic BL-11 promoting longitudinal bone growth in children. Future directions will focus on clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to translate plant-derived compounds into clinical therapies.