Gut microbiota's role in high-altitude cognitive impairment: the therapeutic potential of Clostridium sp. supplementation.

Prolonged exposure to high-altitude environments may increase the risk of cognitive decline in young migrants. Recent studies suggest that hypobaric hypoxia-induced alterations in gut microbial composition could partly contribute to this risk. However, the absence of direct evidence from cohort studies and an unclear mechanism hinder intervention development based on this hypothesis. This study recruited 109 young male migrants living in Xizang to investigate the microbial mechanisms underlying cognitive impairment associated with high-altitude migration. Multi-omic analysis revealed distinct microbiome and metabolome features in migrants with cognitive decline, notably a reduced abundance of Clostridium species and disrupted fecal absorption of L-valine. Mechanistic studies showed that hypobaric hypoxia significantly damaged the intestinal barrier, leading to lipopolysaccharide (LPS) leakage and an influx of inflammatory factors into the peripheral blood, which activated microglia and caused neuronal injury in the hippocampus of mice. Additionally, compromised L-valine absorption due to intestinal barrier damage correlated with lower hippocampal glutamate levels and neurotrophic factors. Intervention with Clostridium sp. effectively restored the intestinal barrier and enhanced L-valine absorption, which mitigated hypobaric hypoxia-induced inflammation and hippocampal neural damage in mice. In conclusion, cognitive impairment among young migrants at high altitude may be attributed to hypobaric hypoxia-induced gut microbiota disruption and subsequent intestinal barrier dysfunction. This study may provide a promising approach for preventing and treating high-altitude-associated cognitive impairment.