The brain–bone–gut axis: a microbial bridge underlying multisystem comorbidities

Multi-axis interactions among the skeletal system, immune system, and gut microbiota (GM) have become a prominent focus of interdisciplinary research. The brain-bone-gut axis, proposed in recent years, provides an integrative physiological framework describing a bidirectional regulatory network linking the central nervous system, bone metabolism, and the GM via neural, endocrine, and immune pathways, thereby offering a unified perspective on multi-organ comorbidities. This article systematically examines the interconnections and synergistic effects across three core pathways within this framework: the brain-bone axis, the gut-bone axis, and the gut-brain axis. It further emphasizes immune-inflammatory processes as a central hub that connects gut dysbiosis with bone metabolic disturbances and alterations in brain function. On this basis, we propose an integrated approach that combines microecological interventions with nutritional and exercise management to improve gut homeostasis, preserve skeletal health, and support brain function, with the overarching aim of generating coordinated benefits across organ systems.