The gut microbiota mediates memory impairment under high-altitude hypoxia via the gut-brain axis in mice.

Hypoxia is a predominant risk factor at high altitudes, and evidence suggests that high-altitude hypoxia alters the gut microbiota, which plays an essential regulatory role in memory function. However, the causal relationship between the gut microbiota and memory impairment under hypoxic conditions remains unclear. In this study, we employed a high-altitude hypoxia model combined with fecal microbiota transplantation (FMT) approach in mice to explore the effects of the gut microbiota on memory impairment in a hypoxic environment. We observed that high-altitude hypoxia exposure reduced short- and long-term memory and hippocampus-dependent fear memory abilities, along with decreased relative abundance of Ligilactobacillus and Muribaculum. Moreover, hypoxic conditions increased intestinal and blood-brain barrier permeability. FMT from hypoxia-exposed mice into naïve antibiotic-treated mice resulted in similar memory impairments, Ligilactobacillus and Muribaculum abundance changes, and increased intestinal/blood-brain barrier permeability. Correlation analysis showed a robust positive association between Ligilactobacillus and Muribaculum with hippocampus-dependent contextual fear memory. Likewise, Ligilactobacillus was positively correlated with short-term memory. Therefore, Ligilactobacillus and Muribaculum may be key microbes in reducing memory ability in hypoxia, with the intestinal and blood-brain barriers as primary pathways. Our findings provide further evidence for the potential regulatory mechanism by which gut microbiota dysbiosis may contribute to memory impairment in a high-altitude environment.