Host-microbiome multi-omics identifies redox stress and metabolic homeostasis signatures during high-altitude hypoxia and reoxygenation

High-altitude hypoxia and reoxygenation impose systemic challenges that extend beyond isolated organ injury. However, the host-wide physiological responses, redox-linked metabolic alterations, and host-microbiome interactions underlying these processes remain poorly understood, particularly during the reoxygenation phase. Here, we aimed to characterize systemic and organ-level functional changes across hypoxia and reoxygenation, and identify potential microbial biomarkers associated with physiological adaptation. We analyzed 72 hematological markers in 458 participants across multiple stages of hypoxia and reoxygenation. In a subset of 226 individuals, we profiled the gut microbiome, fecal metabolome, and plasma metabolome of high-altitude returnees. Multi-omics factor analysis was then applied to dissect host-microbiome-metabolism interactions related to redox stress and metabolic homeostasis. Physiological adjustments during hypoxia and reoxygenation were prolonged, with markers indicative of myocardial, hepatic, pancreatic, and inflammatory stress persisting for at least one month after descent. High-altitude returnees exhibited reduced microbial diversity, altered community composition, and pronounced metabolic rewiring that closely correlated with systemic and organ-level stress. Multi-omics factor analysis resolved two major biological axes. Within the reoxygenation-associated stress axis, Rhodococcus emerged as a sensitive indicator of oxidative stress-related metabolic disorder that may serve as a biomarker for evaluating post-descent recovery status. The hypoxic adaptation axis centered on Butyrivibrio , which was linked to lipid metabolism and host energy homeostasis. Altitude-related hypoxia and reoxygenation constitute a full-cycle physiological challenge characterized by sustained redox and metabolic stress. Our findings provide a systems-level framework for understanding host-microbiome responses during oxygen fluctuation and identify candidate biomarkers for future monitoring and intervention.