The gut-kidney axis in high-altitude hypoxia: pathophysiological mechanisms and the central role of hypoxia inducible factor.

The high-altitude plateau environment, defined by hypobaric hypoxia, poses considerable health risks to human populations. Due to their substantial oxygen requirements, the kidneys are particularly susceptible, as are the intestines, with their intricate microbiota and essential barrier functions. This review examines the pathophysiological consequences of high-altitude hypoxia on renal and intestinal health, specifically highlighting the interorgan communication mediated by the gut-kidney axis. Prolonged hypobaric hypoxia causes notable functional and structural impairment in the kidneys, exacerbating pathologies such as acute kidney injury and chronic kidney disease, and is associated with altitude-induced disorders including polycythemia and hyperuricemia. Simultaneously, the hypoxic milieu disrupts gut microbiota composition, weakens intestinal barrier integrity and alters mucosal immune responses. These intestinal disturbances are increasingly acknowledged as pivotal factors in renal pathophysiology via the gut-kidney axis. Microbial metabolites and compromised barrier function may enter systemic circulation, triggering inflammation and fibrotic processes. The hypoxia-inducible factor pathway emerges as a central molecular mechanism activated in both organs, modulating critical processes such as renal fibrosis and intestinal permeability. Furthermore, dietary habits common among high-altitude populations can influence gut microbiota, introducing additional complexity to this axis and presenting both risks and potential therapeutic opportunities. The gut-kidney axis is critically involved in mediating the adverse health effects of high-altitude hypoxia. A thorough understanding of the HIF pathway, microbial metabolites and barrier dysfunction offers an integrative framework for elucidating the underlying pathogenic mechanisms. Targeting this axis through interventions such as dietary modification and probiotic supplementation represents a promising strategy for preventing and treating high-altitude-related renal and intestinal disorders, thereby improving health outcomes for high-altitude residents.