Gut microbiota orchestrates bone homeostasis: a multi-pathway network from intestine to skeleton

Osteoporosis (OP), a widespread metabolic bone condition characterized by diminished bone mass and compromised microarchitecture, poses a significant global health challenge. The gut microbiota (GM) regulates bone homeostasis through the "gut-bone axis," and this review consolidates its diverse mechanisms. GM-derived metabolites directly/indirectly modulate osteoclast/osteoblast activity. GM also regulates systemic immunity to influence the RANKL/OPG pathway and mediates endocrine signals. Furthermore, it modulates intestinal barrier integrity to facilitate mineral/vitamin absorption and interacts with the nervous system to form the "microbiota-gut-brain-bone" axis. GM imbalance, resulting from factors such as aging, hormonal shifts, or dietary habits, promotes the progression of OP through the perturbation of these networks. This review evaluates the therapeutic potential of GM-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, and underscores the GM as a pivotal therapeutic target, emphasizing that future therapeutic strategies for OP must incorporate the interconnected GM-bone axis for efficacious prevention and treatment.