Serum metabolite changes are implicated in high-altitude acclimatization and de-acclimatization

Abstract For individuals from lowland areas traveling to high-altitude regions, acclimatization and de-acclimatization (ADA) to high altitudes is an inevitable physiological process, accompanied by complex metabolic adjustments. In this study, we investigated 18 subjects (nine males and nine females) who traveled to and remained at an altitude of 4200 m for 3 months. We used untargeted metabolomics to analyze serum metabolomic changes after this period and then at specific time points after their return to the plains. We observed considerable differential serum metabolite expression at T1 (after the 3 month-high-altitude stay), T2 (day 2 after returning to the plains), and T3 (day 30 after returning to the plains). Gender differences and initial high-altitude response levels also affected metabolite changes. Metabolite-related signaling pathway analyses showed that the most significant differential metabolic pathways at T1 and T2 were pentose phosphate pathway (PPP), butanoate metabolism, arginine biosynthesis, and glucagon signaling pathways. The most significant differential metabolic pathways at T1 and T3 were galactose metabolism, arginine biosynthesis, sphingolipid signaling pathway, ATP-binding cassette (ABC) transporter, and biosynthesis of unsaturated fatty acid (FA) pathways. The most significant differential metabolic pathways between males and females at T1 were ABC transporter, purine metabolism (PM), central carbon metabolism in cancer (CCMiC), ascorbate and aldarate metabolism (AAM), and valine, leucine, and isoleucine biosynthesis pathways. Thus, during ADA to high altitudes, ABC transporter, PP, pentose and glucuronate interconversion (PGI), and PM signaling pathways had important roles. Our data provide new insights into the metabolic changes during ADA to high altitudes.