Short-term high-altitude exposure protects working memory by balancing intestinal microbiota

High-altitude environments (> 2500 m) with low oxygen, low pressure, variable climate, large diurnal temperature differences, and high solar and ultraviolet radiation are risky to human health. Mice’s intestinal microbiota changes at high altitude may affect cognition via the gut–brain axis. Short-term high-altitude exposure may have positive effects on organisms. This study explores if short-term high-altitude exposure can protect working memory from restraint stress (RS) and the role of intestinal microbiota in this process. Forty-eight C57BL/6 mice aged eight weeks were divided into four groups: the Control group, RS group (S group), high altitude exposed group (HA group), and high-altitude exposed with RS group (HA-S group). High altitude was simulated via exposure to a low-pressure oxygen chamber at a simulated altitude of 3500–4000 m for 14 days. RS was simulated from days 22–29 and followed by the novel object recognition test to assess working memory. Blood for serum, prefrontal cortex, ileal sections for molecular analysis, and intestinal contents for 16S rRNA sequencing were collected. Compared to control mice that were not exposed to high altitude and did not experience RS, mice that were also exposed to high altitude and experienced restraint stress had significantly greater working memory deficits, whereas mice exposed only to high altitude did not show significant differences in working memory performance. Different gut microbial community structures were observed in these groups, with high altitude-exposed mice exhibiting higher α-diversity. In addition, the difference in β-diversity between restraint stress and high altitude exposed mice was significantly higher, indicating significant differences in microbial community composition. The major bacterial phyla identified were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, with Lactobacillus being more abundant in the restraint stress group, while Bifidobacterium and Muribaculum were relatively more abundant in the high-altitude exposed with restraint stress group, but the relative abundance of Lactobacillus was lower. Short-term high-altitude exposure might possibly protect working memory function by modulating intestinal function through the microbiota–gut–brain axis, with Lactobacillus perhaps contributing to alleviate working memory dysfunction induced by stress. This study may enhance our understanding of the microbiota-gut-brain axis in high-altitude environments and could offer new preventive and therapeutic insights for high-altitude-related health issues, possibly benefiting workers and explorers in such environments.