The potential role and research progress of the gut microbiota–NGF axis in postmenopausal bone homeostasis imbalance

Postmenopausal osteoporosis(PMOP)is a common metabolic bone disease characterized by an imbalance in bone remodeling due to estrogen deficiency. Increasing evidence suggests that alterations in gut microbiota, intestinal barrier, immune response, microbial metabolites, and autonomic nervous activity are involved in postmenopausal bone loss. Nerve growth factor (NGF) and its receptors tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75 NTR) are implicated in sensory nerve innervation, inflammation regulation, bone adaptation, bone repair, and pain sensitization, thus potentially serving as a molecular interface linking microbiota, nerves, immunity, and skeletal processes. This review evaluates the proposed gut microbiota–NGF–bone relationship by distinguishing between mechanisms supported by experimental evidence, indirect evidence, and speculative hypotheses. Existing studies support the regulation of NGF by gut microbiota under specific neuroimmune contexts, the gut microbiota–immune–bone interactions in estrogen deficiency models, and the roles of NGF and its receptors in neurobiology and skeletal biology. However, these findings originate from independent experimental systems. Currently, no studies have simultaneously demonstrated that gut microbiota-induced changes in NGF signaling are a necessary or sufficient condition for the abnormal bone remodeling associated with PMOP. Therefore, the gut microbiota–NGF–bone axis should be viewed as a conceptual framework connecting the microbiome, immunity, neuroendocrine factors, and bone metabolism, rather than as an established causal pathway. This framework aids in integrating existing evidence, clarifying mechanistic gaps, and proposing testable scientific questions. Future research should combine the manipulation of gut microbiota with tissue or cell-specific regulation of NGF, TrkA, or p75 NTR, while also conducting rescue experiments, longitudinal multi-omics analyses, and systematic skeletal phenotype evaluations. Direct causal validation must be obtained before applying gut microbiota or NGF-targeting strategies for the precise prevention and treatment of PMOP.