Effect of altitudes on serum parameters, metabolome, and gut microbiota in yaks on the Qinghai-Tibet Plateau

Yaks (<i>Bos grunniens</i>), native to the Qinghai-Tibet Plateau, have evolved extraordinary physiological resilience to chronic hypoxia, cold, and nutritional scarcity. However, the integrated metabolic and microbial mechanisms underlying these adaptations remain poorly defined. Here, a comprehensive multi-omics analysis was performed on thirty grazing heifer yaks (2.5 years old) from three altitudes-3,600 m (low altitude [LA]), 4,000 m (middle altitude [MA]), and 4,500 m (high altitude [HA])-to investigate how altitude affects host physiology, metabolism, and gut microbial ecology. Increasing altitude significantly reduced serum total protein, globulin, blood urea nitrogen, and alkaline phosphatase, indicating suppressed anabolic metabolism and nitrogen-sparing strategies. Antioxidant capacity (total superoxide dismutase, total antioxidant capacity) and pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, tumor necrosis factor-α, interferon-γ) increased (<i>P</i> < 0.05), while glutathione peroxidase, IL-4, IL-10, growth hormone, insulin-like growth factor-1, and growth hormone-releasing hormone declined (<i>P</i> < 0.05), reflecting energy reallocation from growth toward antioxidation and immune maintenance under hypoxia. Plasma metabolomics revealed distinct altitude-dependent reprogramming, with enrichment of retinol metabolism at 4,000 m and α-linolenic acid metabolism, tricarboxylic acid (TCA) cycle, and branched-chain amino acid biosynthesis at 4,500 m. These pathways link lipid remodeling, oxidative balance, and oxygen utilization. The gut microbiota displayed altitude-specific shifts, characterized by enrichment of <i>Christensenellaceae_R-7_group</i> and <i>Monoglobus</i> and reduced <i>UCG-005</i> and <i>Rikenellaceae_RC9_gut_group</i>, accompanied by lower fecal volatile fatty acids (<i>P</i> < 0.05). Correlation analyses confirmed tight associations between fermentative taxa and volatile fatty acids production. Collectively, our results establish a serum-metabolome-microbiota axis as a central mechanism supporting yak adaptation to high altitude.IMPORTANCEThis study demonstrates that the gut microbiota plays a crucial role in how yaks adapt to high-altitude hypoxia. Rising altitude not only alters the composition of gut microbes but also shifts their metabolic activity toward improving fermentation efficiency and antioxidant capacity. These microbial changes are closely linked with host metabolism, forming a coordinated serum-metabolome-microbiota network that helps maintain energy balance and immune stability when oxygen is limited. The enrichment of retinol and α-linolenic acid metabolism as altitude-responsive pathways further highlights the metabolic interplay between host and microbes in supporting physiological resilience. Overall, our findings show that microbial flexibility and metabolic cooperation are key factors enabling ruminants to survive in extreme environments, providing a scientific basis for microbiome-informed strategies to enhance yak health and productivity on the Qinghai-Tibet Plateau.