Nickan Research Institute Journal of Parathyroid Disease 2345-6558 13 1 2025 01 01 Brain-gut-bone axis; a review of the association between gut microbiota and osteoporosis e13307 e13307 10.34172/jpd.2025.13307 EN Sina Salem Ahim https://orcid.org/0009-0008-2452-434X Sara Aghaei https://orcid.org/0009-0008-7674-8054 Farzin Banei https://orcid.org/0000-0001-5197-6335 Mohammad Mousavi https://orcid.org/0000-0003-2736-5766 Mohammad Shahsavan https://orcid.org/0000-0003-4402-4103 Kamran Safa https://orcid.org/0000-0002-3630-5418 Amin Norouzbeygi https://orcid.org/0000-0001-9728-5740 Elahe Zaremoghadam https://orcid.org/0000-0002-0550-0122 Faezeh Nesaei https://orcid.org/0009-0004-4495-0398 Journal Article 10.34172/jpd.2025.13307 2025 10 10 2025 11 16 The brain-gut-bone axis plays a crucial and complex role in regulating bone metabolism, particularly in the context of osteoporosis. This multidirectional communication network integrates signals from several physiological systems, including the gut microbiota, immune system, nervous system, and hormonal environment, all of which collectively influence the balance between bone formation by osteoblasts and bone resorption by osteoclasts. The gut microbiota contributes to this axis by producing metabolites such as short-chain fatty acids (SCFAs) and modulating systemic inflammation, which in turn can affect bone cell activity and mineralization processes. The immune system participates through cytokine signaling that either promotes or inhibits bone resorption and formation, linking inflammation to bone health. Meanwhile, the nervous system, via autonomic and sensory pathways, regulates nutrient absorption, bone blood flow, and directly modulates bone cell function through neuropeptides and neurotransmitters. Hormonal factors, including parathyroid hormone, sex steroids, and gut-derived hormones like serotonin, further modulate bone turnover by fine-tuning osteoblast and osteoclast activity. Disruptions in any component of this axis, such as dysbiosis of the gut microbiota, chronic inflammation, neurotransmitter imbalance, or hormonal deficiencies can lead to dysregulated bone remodeling, favoring increased bone resorption, decreased bone formation, and eventually decreased bone density. This manifests clinically as osteoporosis, characterized by fragile bones and elevated fracture risk. Therefore, understanding and targeting the brain-gut-bone axis presents promising therapeutic opportunities. Interventions such as probiotics, anti-inflammatory therapies, neuromodulation, and hormone replacement can potentially restore the balance in this axis, improving bone health and reducing osteoporosis progression. This integrative approach highlights the importance of systemic interactions and opens new avenues for precision medicine in bone metabolic disorders.