Urinary metabolic modulation in human participants residing in Siachen: a 1H NMR metabolomics approach

Abstract

The main physiological challenge in high altitude environment is hypoxia which affects the aerobic metabolism reducing the energy supply. These changes may further progress toward extreme environment-related diseases. These are further reflected in changes in small molecular weight metabolites and metabolic pathways. In the present study, metabolic changes due to chronic environmental hypoxia were assessed using 1H NMR metabolomics by analysing the urinary metabolic profile of 70 people at sea level and 40 people at Siachen camp (3700 m) for 1 year. Multivariate statistical analysis was carried out, and PLSDA detected 15 metabolites based on VIP score > 1. ROC analysis detected cis-aconitate, Nicotinamide Mononucleotide, Tyrosine, Choline and Creatinine metabolites with a high range of sensitivity and specificity. Pathway analysis revealed 16 pathways impact > 0.05, and phenylalanine tyrosine and tryptophan biosynthesis was the most prominent altered pathway indicating metabolic remodelling to meet the energy requirements. TCA cycle, Glycine serine and Threonine metabolism, Glutathione metabolism and Cysteine alterations were other metabolic pathways affected during long-term high-altitude hypoxia exposure. Present findings will help unlock a new dimension for the potential application of NMR metabolomics to address extreme environment-related health problems, early detection and developing strategies to combat high altitude hypoxia.

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“…2 D and Table S4 ). The abundance of tyrosine increased, which might be associated with regulating oxidative stress and inflammation to protect against damage [ 30 , 31 ]. l -phenylalanine is the precursor for tyrosine, which was increased as it needed to be converted to tyrosine [ 30 ].…”

“…The abundance of tyrosine increased, which might be associated with regulating oxidative stress and inflammation to protect against damage [ 30 , 31 ]. l -phenylalanine is the precursor for tyrosine, which was increased as it needed to be converted to tyrosine [ 30 ]. Furthermore, isoleucine and l -valine, two branched-chain amino acids, increased after hypoxic treatment with FCs of 1.447 and 1.380 ( Fig.…”

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“…The model is validated by calculating the "out-of-bag" error ( prediction error). In this work, each forest contained 5000 trees, [41][42][43][44] 45 Important features (m/z) selected by random forest were putatively annotated (in accordance with the Metabolomics Standards Initiative) 46 by combining the high mass accuracy m/z values and isotopic distribution (for chlorinated compounds) with the Human Metabolome Database -HMDB (https://hmdb.ca/) along with scientific literature reports. The statistical differences of each feature in patient samples (up-or down-regulation) were assessed by a t-test with FDR-adjusted p-value < 0.05.…”

“…The model is validated by calculating the “out-of-bag” error (prediction error). In this work, each forest contained 5000 trees, 41–44 and the most important m / z values for classification were ranked by mean decrease accuracy. The performance of the classification model was evaluated by the parameters of accuracy (overall probability of a patient sample being correctly classified based on ACR values), sensitivity (probability of the test correctly classifying diseased samples based on ACR values), and specificity (probability of the test correctly classifying healthy samples based on ACR values).…”

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“…Amino acids can regulate neuronal activity through a variety of mechanisms, ranging from the synthesis of neurotransmitters (such as precursor amino acids phenylalanine, tyrosine and tryptophan) to direct neurotransmission and neuromodulation (such as the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter glycine) (48,49). Phenylalanine, tyrosine and tryptophan biosynthesis signaling pathways are related to oxidative stress, immune response and inflammation regulation, and can also be used as energy compensation in extreme environments such as hypoxia (50). Phenylalanine can be converted into tyrosine, and tyrosine can further produce dopamine, norepinephrine and epinephrine.…”