Research on the Correlation between Gut Microbiota and Brain Cognitive Function under Chronic Hypoxia at High Altitude

Feng ZengHanxue LiYan MaShuang Ma^*

• Qinghai University, Xining, China

Long-term exposure to high-altitude hypoxia can lead to cognitive impairment, yet the role of the gut microbiota in this process remains unclear. This study investigated the contribution of gut microbiota to cognitive dysfunction induced by chronic hypoxia. C57BL/6J mice were assigned to four groups: control group (NC), control pseudo-germ-free group (CA), hypoxic group (HC), and hypoxic pseudo-germ-free group (HA). HC and HA groups were exposed to a hypobaric oxygen chamber simulating an altitude of 5,000 m (11% O₂) for 28 days. Control mice were housed Xi'ning, 2,200 m altitude (16% O₂). All groups had free access to water; CA and HA groups received oral administration of a four-antibiotic cocktail in drinking water to deplete gut microbiota and establish pseudo-germ-free mouse models. Cognitive function was assessed by the Morris water maze, Expression levels of hippocampal BDNF, SYP, and PSD-95 were determined using Western blotting. H&E staining was used to observe morphological changes in colonic tissues. Gut microbiota composition and metabolic profiles were analyzed through 16S rRNA gene sequencing and metabolomics, respectively, followed by multi-omics correlation analyses. Chronic hypoxia impaired learning and memory in mice, which was further exacerbated by gut microbiota depletion. This was evidenced by prolonged escape latency, and reduced expression of synaptic plasticity-related proteins. Although hypoxia induced colonic injury, pseudo-germ-free status did not aggravate colonic pathology. Hypoxia and microbiota depletion significantly altered gut microbial diversity, with cognitive impairment negatively correlated with Morganella and Klebsiella abundance and positively correlated with Prevotella, Bifidobacterium and Lactobacillus. Additionally, tryptophan metabolism and urea cycle were identified as critical pathways regulating chronic hypobaric hypoxia-induced cognitive dysfunction. S-adenosylhomocysteine and 2-isopropylmalic acid were pinpointed as potential biomarkers for hypoxia-induced cognitive impairment. These findings highlight the regulatory role of the gut microbiota in cognitive dysfunction under chronic hypoxic conditions and suggest potential microbiota-targeted strategies for preventing hypoxia-related brain injury.