Urine metabolite profiling in Indian males exposed to high-altitude: a longitudinal pilot study

People who visit high-altitude for research and development work, pilgrimage, recreational purposes and deployments are exposed to different environmental conditions such as low temperature and atmospheric pressure, leading to hypoxia, high radiation, dry air, and non-availability of fresh food and vegetables. These environmental stressors have significant physiological effects on the human body. Among these challenges, hypobaric hypoxia at high-altitude affects aerobic metabolism and thereby reduces the supply of metabolic energy. Metabolic alterations may further lead to extreme environment related maladaptation as evidenced by alterations in the levels of metabolites and metabolic pathways. To investigate the variation in the metabolite profile, urine samples were collected from 16 individuals at baseline (BL, 210 m) and high-altitude (HA, 4200 m). Untargeted urinary metabolic profiling was performed by liquid chromatography-mass spectrometry (LC-MS) in conjunction with statistical analysis. Univariate and multivariate statistical analyses revealed 33 differentially abundant metabolites based on fold change, VIP score and p value. These distinct metabolites were primarily associated with pathways related to phenylalanine, tyrosine and tryptophan biosynthesis; metabolism of phenylalanine, biotin, tyrosine, cysteine and methionine along with alanine, aspartate and glutamate metabolism. Thes pathways are also linked with pentose and glucuronate interconversions, citrate cycle, vitamin B6 and porphyrin metabolism. Furthermore, receiver operating characteristic curve analysis detected five metabolites namely, 2-Tetrahydrothiopheneacetic acid, 1-Benzyl-7,8-dimethoxy-3-phenyl-3H-pyrazolo [3,4-c] isoquinoline, Abietin, 4,4'-Thiobis-2-butanone, and Hydroxyisovaleroyl carnitine with high range of sensitivity and specificity. In summary, this longitudinal study demonstrated novel metabolic variations in humans exposed to high-altitude, utilising the potential of LC-MS based metabolomics. Thus, the present findings shed light on the impact of hypoxic exposure on metabolic adaptation and provide a better understanding about the pathophysiological mechanisms underlying high-altitude illnesses correlated to tissue hypoxia.