Comparative impacts of normobaric vs. hypobaric hypoxia on tissue integrity and gut microbiota in acute high-altitude murine models

Normobaric hypoxia (NH) and hypobaric hypoxia (HH) are the two primary approaches currently used to establish high-altitude animal models in lowland laboratories. However, their relative suitability and effectiveness remain debated. This study conducts a comparative assessment of acute high-altitude models generated under NH and HH, specifically comparing their impacts on gut microbiota. Mice from the same batch were exposed to NH or HH conditions equivalent to 5,500 m in a high-altitude simulation chamber. After 72 h of exposure, tissue samples were collected. Histopathological analyses showed that HH caused more severe tissue injury than NH across multiple organs, particularly the lung, liver, hepatic lobule, and prefrontal cortex. Additionally, 16S rRNA sequencing characterized changes in gut microbiota structure, composition, differentially abundant taxa, and predicted functional profiles. These analyses revealed distinct gut microbiota structure between the two hypoxic conditions. The HH group showed a greater increase in Bacillota and a more pronounced decrease in Bacteroidota, along with a higher abundance of <i>Lactobacillus</i>. This comparative evaluation of NH and HH not only provides a critical reference for model selection in high-altitude gut microbiota research but also lays the groundwork for establishing more reliable and optimized experimental modeling strategies for future high-altitude studies.IMPORTANCEThis study demonstrates that hypobaric hypoxia induces more severe tissue injury and more pronounced shifts in gut microbiota composition than normobaric hypoxia at 5,500 m. These results inform experimental design choices and emphasize the need for careful model selection to improve data reliability and strengthen the connection between theoretical research and modeling in high-altitude physiology.