Combined exposure of cold and hypoxia: a driver for hypertension and the underlying role of the microbiota-gut-brain axis.

Abstract

BACKGROUND: Cold and hypoxic conditions often coexist in high-altitude environments and are associated with alterations in blood pressure during short-term exposure. Increasing evidence suggests that the microbiota-gut-brain axis may be involved in blood pressure regulation under environmental stress. However, evidence remains scarce, especially the related mechanisms. AIMS: This study aimed to investigate whether short-term combined exposure to cold and hypoxia is associated with blood pressure elevation and to explore the potential involvement of the microbiota-gut-brain axis in this process. METHODS: A rat model was established using combined exposure to cold (4°C) and hypoxia (61 kPa). Blood pressure, gut microbiota composition, intestinal and blood-brain barrier integrity, inflammatory responses, endothelial function, neuroinflammation, and sympathetic activity were assessed. The role of microbiota-gut-brain axis was also examined by γ-aminobutyric acid (GABA) supplementation. RESULTS: Short-term cold and hypoxia exposure was associated with elevated blood pressure, accompanied by gut microbiota dysbiosis, intestinal inflammation, and impaired intestinal barrier function. These changes coincided with increased circulating lipopolysaccharide (LPS) and pro-inflammatory cytokines, which were associated with vascular inflammation, oxidative stress, and endothelial dysfunction. Concurrently, impairment of the blood-brain barrier was detected, accompanied by increased accumulation of LPS and cytokines in the paraventricular nucleus, neuroinflammation, activation of microglia, and heightened sympathetic activity. Mechanistic analyses indicated the activation of the LPS-TLR4/MyD88/NF-κB signaling pathway in both the gut and brain. GABA supplementation lowered the blood pressure, restored the microbiota-gut-brain axis, and suppressed the LPS-TLR4/MyD88/NF-κB signaling pathway. CONCLUSION: Short-term cold-hypoxia exposure may contribute to hypertension through disruption of the microbiota-gut-brain axis, suggesting it may act as a potential therapeutic target for hypertension prevention during short-term cold-hypoxia conditions.