Hypoxia-Induced Gut-Brain Axis Remodeling and Insomnia: Mechanisms and Microbiota Adaptive Regulation from a Translational Perspective
Abstract
High-altitude hypoxia frequently disrupts sleep-wake cycles, causing insomnia that impairs acclimatization, performance, and health. Emerging evidence implicates the gut-brain axis (GBA) in this disorder. Prolonged or severe hypoxia can disturb intestinal epithelial homeostasis through oxidative, inflammatory, and metabolic changes, increasing barrier permeability and facilitating the translocation of lipopolysaccharide (LPS) and other bacterial products into the circulation. Concurrent gut microbial dysbiosis reduces the production of short-chain fatty acids (SCFAs) and redirects tryptophan metabolism toward the kynurenine pathway, thereby promoting systemic and neuroinflammation. Peripheral inflammatory signals communicate with the central nervous system (CNS) through a compromised blood-brain barrier (BBB), circumventricular organs (CVOs), and vagal afferents, while neuroendocrine stress responses involving the hypothalamic-pituitary-adrenal (HPA) axis and cortisol may further link hypoxia and inflammation to sleep disruption. Together, these pathways activate arousal circuits while inhibiting sleep-promoting gamma-aminobutyric acid (GABA)-ergic neurons, contributing to the characteristic electroencephalographic features of high-altitude insomnia. High-altitude-specific evidence for conventional sleep therapies remains limited, underscoring the need for biologically grounded strategies tailored to hypoxic environments. Preliminary probiotic evidence suggests potential…
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