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

Mar 9, 2026Journal of hypertension

Cold and low oxygen together may increase high blood pressure through the gut-brain connection

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Abstract

Short-term exposure to cold (4°C) and hypoxia (61 kPa) is associated with elevated blood pressure.

Cold and hypoxia exposure led to gut microbiota dysbiosis and intestinal inflammation.
Impaired intestinal barrier function was observed alongside increased levels of circulating lipopolysaccharide (LPS) and pro-inflammatory cytokines.
Vascular inflammation, oxidative stress, and endothelial dysfunction occurred in response to the environmental stressors.
The blood-brain barrier showed impairment with increased accumulation of LPS and cytokines in specific brain regions, indicating neuroinflammation.
Activation of the LPS-TLR4/MyD88/NF-κB signaling pathway was indicated in both the gut and brain.
GABA supplementation resulted in lowered blood pressure and restoration of the microbiota-gut-brain axis.

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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.