Microbial dysbiosis exacerbates exercise fatigue in mice under hypobaric hypoxia

Aims To determine whether hypobaric hypoxia-induced alterations of the intestinal microbiota contribute to impaired exercise performance and intestinal dysfunction under simulated high-altitude conditions. Methods and Results A mouse model of exhaustive exercise under simulated 4 500 m hypobaric hypoxia was used to assess exercise performance, oxidative stress, intestinal barrier integrity, and gut microbial composition. To evaluate the contribution of the intestinal microbiota, fecal microbiota transplantation (FMT) was performed using microbiota from hypoxia-exposed or normoxic donor mice into antibiotic-treated recipients before exhaustive exercise under hypobaric hypoxia. Compared with normoxic controls, hypoxia-exposed mice exhibited reduced endurance, increased oxidative stress, impaired intestinal barrier function, decreased Ruminococcus abundance, and significant alterations in both α- and β-diversity. Recipient mice receiving microbiota from hypoxia-exposed donors developed similar phenotypes, including greater oxidative stress, reduced barrier protein expression, and microbial community profiles resembling those of hypoxic donors. Comparisons with microbiota-depleted controls further indicated that gut microbial alterations contributed to, but were not sufficient alone to cause, impaired exercise performance in the absence of the hypoxic environment. Conclusions Hypobaric hypoxia rapidly remodels the intestinal microbiota, and these microbial alterations contribute to oxidative stress, intestinal barrier dysfunction, and reduced exercise capacity under hypoxic conditions. FMT supports a contributory role of the intestinal microbiota in hypoxia-associated physiological dysfunction while indicating that hypoxic stress remains necessary for the full fatigue phenotype to develop. These findings support further investigation of microbiota-targeted strategies to mitigate exercise impairment during hypobaric hypoxia.