Gut Microbiota Regulates Brain–Bone Axis to Influence Osteoporosis Pathogenesis and Treatment

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Abstract
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, impaired microarchitecture, and increased fracture risk, primarily resulting from dysregulated bone remodeling. Increasing evidence highlights a close interaction between bone metabolism and the gut microbiota. Alterations in bone mineral density can influence gut microbial composition. Conversely, microbial dysbiosis disrupts bone homeostasis through multiple pathways, including microbial metabolites, immune regulation, and neuroendocrine signaling. Short-chain fatty acids suppress osteoclast differentiation and enhance intestinal calcium absorption, while gut dysbiosis promotes bone loss by impairing intestinal barrier integrity and increasing proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The gut–brain–bone axis represents an important regulatory network linking the central nervous system, gut-derived signals, and skeletal remodeling. Chronic stress and neurodegenerative conditions activate the hypothalamic–pituitary–adrenal axis and bone-derived extracellular vesicle signaling, thereby favoring bone resorption. Estrogen deficiency further disrupts the receptor activator of nuclear factor κΒ ligand/osteoprotegerin signaling pathway and alters gut microbial composition, contributing to postmenopausal bone loss. Therapeutic strategies targeting this axis, including probiotics, prebiotics, fecal microbiota transplantation, dietary fiber supplementation, and pharmacological or natural compounds, show potential in restoring microbial balance and improving bone metabolism. Future studies integrating multiomics approaches and well-designed clinical trials are needed to clarify microbiome–bone interactions and support the development of targeted interventions for osteoporosis.
Funding Information
  • National Natural Science Foundation of China (82101956)
  • Science and Technology Development Fund, Macau SAR (file No.0114/2022/A 0018/2024/RIA1)
  • High Level Key Discipline Construction Project of the State Administration of Traditional Chinese Medicine (zyyzdxk-2023123)
  • Integration Development Strategy Project of Jinan City and College (JNSX2024046)
  • clinical-basic joint innovation team project of Shandong First Medical University (CX202408)
  • Natural Science Foundation of Shandong Province (ZR2024MH189)
  • University Youth Innovation Team of Shandong Province (2023KJ176)
  • Young Talent of Lifting engineering for Science and Technology in Shandong (SDAST2024QTA044)
  • Shandong Province Traditional Chinese Medicine Science and Technology Project (M-2023106, M-2022253)
  • Medicine and Health Science and Technology Project of Shandong Province (202404070291)
  • Qingchuang Talents Induction Program of Shandong Higher Education Institution (2024Y08)
  • Cultivating Plan Program for the Leader in Science and Technology of Yunnan Province (25110100011)

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