Gut microbiota in high-altitude acclimatization and adaptation: microbiota homeostasis, double-edged roles, and gut-X axis-specific microbiota reconstruction

The extreme environment in high-altitude regions presents significant physiological challenges to human survival. With more than 80 million individuals residing above 2,500 m, elucidating the biological mechanisms underlying adaptation and acclimatization is a critical area of research in human health. Emerging evidence implicates the gut microbiota in multi-organ dysfunction during high-altitude acclimatization and adaptation, although its precise role remains under-characterized. The Qinghai-Xizang Plateau, also known as the "Third Pole", offers a distinctive natural environment for investigating these mechanisms. This review summarizes the microbial signatures of indigenous populations and the dynamic remodeling in migrants, highlighting static adaptive baselines and temporal shifts in acclimatization. We integrate clinical and basic research to delineate the double-edged role of the microbiota via complex gut-X axes, elucidate the link between dysbiosis and high-altitude pathology, as well as the protective mechanisms of microbial modulation. Finally, we propose therapeutic strategies focused on restoring individualized, axis-specific gut microbial homeostasis to support high-altitude acclimatization and adaptation.