The gut microbiota-derived metabolites regulate bone extracellular matrix homeostasis: Mechanisms and therapeutic implications.

The bone extracellular matrix (ECM) is a dynamic scaffold crucial for skeletal integrity, and its dysregulation underpins pathologies such as achondroplasia (ACH), osteoporosis (OP), and osteoarthritis (OA). Emerging evidence reveals that the gut microbiota acts as a critical regulator of bone homeostasis via its metabolites. The key metabolites, including short-chain fatty acids (SCFAs), tryptophan derivatives (indole metabolites), bile acids (BAs), and bacterial extracellular vesicles (BEVs), modulate bone ECM homeostasis through multiple pathways, such as enhancing mineral absorption, regulating immune and endocrine signaling (e.g., GH/IGF-1, AhR/PXR, and FXR/TGR5), and influencing the differentiation and activity of bone cells. They also promote metabolite host interactions to impact critical ECM components, including collagen mineralization and non-collagenous protein expression. Although preclinical studies demonstrate the therapeutic potential of microbiota derived metabolites for skeletal disorders, significant challenges remain in elucidating precise molecular mechanisms and translating these findings into clinical applications. This review summarizes recent advances in understanding how gut microbiota derived metabolites regulate bone ECM biosynthesis and remodeling. We emphasize that targeting these metabolites presents a promising strategy for promoting bone health by orchestrating ECM homeostasis. Understanding this interaction provides a novel insight for developing innovative strategies to improve skeletal health.