Urinary Metabolites as Predictors of Acute Mountain Sickness Severity.

Isaie Sibomana,Michael L Raymer,J Philip Karl,Stefan M Pasiakos,Andrew J Young,Claire E Berryman,Nicholas V Reo,Daniel P Foose,Camilla A Mauzy

doi:10.3389/fphys.2021.709804

Abstract

Individuals sojourning at high altitude (≥2,500m) often develop acute mountain sickness (AMS). However, substantial unexplained inter-individual variability in AMS severity exists. Untargeted metabolomics assays are increasingly used to identify novel biomarkers of susceptibility to illness, and to elucidate biological pathways linking environmental exposures to health outcomes. This study used untargeted nuclear magnetic resonance (NMR)-based metabolomics to identify urine metabolites associated with AMS severity during high altitude sojourn. Following a 21-day stay at sea level (SL; 55m), 17 healthy males were transported to high altitude (HA; 4,300m) for a 22-day sojourn. AMS symptoms measured twice daily during the first 5days at HA were used to dichotomize participants according to AMS severity: moderate/severe AMS (AMS; n=11) or no/mild AMS (NoAMS; n=6). Urine samples collected on SL day 12 and HA days 1 and 18 were analyzed using proton NMR tools and the data were subjected to multivariate analyses. The SL urinary metabolite profiles were significantly different (p≤0.05) between AMS vs. NoAMS individuals prior to high altitude exposure. Differentially expressed metabolites included elevated levels of creatine and acetylcarnitine, and decreased levels of hypoxanthine and taurine in the AMS vs. NoAMS group. In addition, the levels of two amino acid derivatives (4-hydroxyphenylpyruvate and N-methylhistidine) and two unidentified metabolites (doublet peaks at 3.33ppm and a singlet at 8.20ppm) were significantly different between groups at SL. By HA day 18, the differences in urinary metabolites between AMS and NoAMS participants had largely resolved. Pathway analysis of these differentially expressed metabolites indicated that they directly or indirectly play a role in energy metabolism. These observations suggest that alterations in energy metabolism before high altitude exposure may contribute to AMS susceptibility at altitude. If validated in larger cohorts, these markers could inform development of a non-invasive assay to screen individuals for AMS susceptibility prior to high altitude sojourn.

Highlights

At high altitude, hypobaric hypoxia elicits a series of physiological responses that are highly variable in humans
Principal Component Analysis (PCA) analysis indicated that the urinary metabolite profiles for both groups changed over the time course of the study with the acute mountain sickness (AMS) group displaying greater variation in data at high altitude on days 1 (HA1) compared to no/mild AMS (NoAMS) (Figure 1)
This study identified a set of eight urinary metabolites using nuclear magnetic resonance (NMR)-based metabolomics that, at sea level prior to altitude exposures, discriminated individuals who later experienced more severe acute mountain sickness upon ascent to high altitude

Summary

Introduction

Hypobaric hypoxia elicits a series of physiological responses that are highly variable in humans. These responses assist in adapting to high altitude (HA; ≥2,500 m) conditions, but can lead to development of acute mountain sickness (AMS) or life-threatening forms of altitude-induced illness such as high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE; Luks et al, 2017). Non-pharmaceutical approaches include pre-acclimatization by intermittent exposure to normobaric hypoxia (Treml et al, 2020) or spending time at moderate altitude before ascending to higher elevations (Luks et al, 2017). Identifying individuals at highest risk of severe AMS before ascent would be a useful decision aid for medical preparation and planning prior to high altitude sojourn

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Discussion

Conclusion