Hydrogen intervention attenuates chronic hypoxia-induced bone degeneration and multi-organ damage via modulation of the gut microbiota.

High-altitude hypoxia disrupts bone metabolic homeostasis and accelerates bone loss. However, effective strategies for preventing and treating hypoxia-induced osteoporosis remain limited. This study aimed to evaluate the protective effects of hydrogen-rich water (HRW) and coral calcium hydride (CCH) against bone degeneration and multi-organ injury in a mouse model of chronic hypoxic exposure. Mice exposed to a hypoxic environment simulating 5500 m altitude for 4 months showed progressive bone deterioration from prolonged hypoxic exposure, which was significantly ameliorated by HRW intervention. Hydrogen intervention also markedly attenuated hypoxia-induced inflammation and damage in multiple organs such as the liver, lungs, kidneys, and colon. Hypoxia exposure led to changes in the diversity of gut microbiota, along with a decrease in the abundance of aerobic bacteria and beneficial bacteria (e.g., Lactobacillus), while hydrogen intervention could partially reverse this dysbiosis. At the molecular level, hypoxia significantly up-regulated the expression of HIF-1α, RANKL, and TRAP in bone tissue, and suppressed Nrf2 protein levels. However, hydrogen intervention did not directly alter the expression of these molecules. Hydrogen intervention may exert a bone-protective effect through the "gut-bone axis" by regulating the homeostasis of gut microbiota and alleviating systemic inflammation and oxidative stress, rather than directly acting on the classical hypoxia signaling pathway. Therefore, hydrogen intervention is a potential strategy to alleviate chronic hypoxia-induced bone loss and multi-organ damage by regulating gut microbiota homeostasis, which provides new insights and directions for the prevention and treatment of high-altitude bone-related diseases.