Lactobacillus johnsonii HL79 mitigate plateau environment-induced hippocampal dysfunction in mice.

Plateau environment represents a common terrestrial characterized by multistress conditions including hypobaric hypoxia, low temperature, and intense radiation, yet sustain over 100 million permanent or transient inhabitants. While this extreme environment exerts profound impacts on cerebral architecture and gut microbiota homeostasis, precipitating cognitive deficits and microbiome-derived intestinal pathologies, the mechanistic interplay between plateau environment adaptation and microbial dynamics remains contentious. Here, we employ a microbiota-gut-brain axis framework to investigate whether probiotic intervention can ameliorate hippocampal impairments induced by simulated plateau environment exposure (3500-4000 m) in mice. Through simulated plateau environment exposure experiments, we revealed that extreme high-altitude conditions induced hippocampal memory dysfunction in mice, exacerbated oxidative stress damage in hippocampal tissues, and altered synaptic plasticity-related biomarkers including CREB transcription factor, BDNF protein levels, and electrophysiological power spectra. Administration of HL79 alleviated these burdens, including memory dysfunction and tissue damage, though complete reversal was not achieved. Combined hippocampal transcriptomic analyses suggested that HL79's beneficial effects primarily involved modulation of lipid-related gene expression in the hippocampus, consistent with prior reports of plateau environmental impacts on gene expression. Serum metabolomic results further reinforced this inference that differential metabolites regulated by HL79 are mainly enriched in bile secretion, taurine and hypotaurine metabolism, linoleic acid metabolism, and PPAR signaling pathways, though the precise regulatory mechanisms require further elucidation. This research provides a novel microbiota-gut-brain axis-based regulatory strategy for adaptation to extreme plateau environments and offers new evidence for understanding the relationship between gut microbiota and plateau environment adaptation at high elevations.