Change in Metabolomic Profile Associated with an Average Increase in Plain Water Intake of >+1 L/day, Sustained over 4 Weeks, in Healthy Young Men with Initial Total Water Intake below 2 L/day

Abstract

Cells adapt to chronic extracellular hypotonicity by altering metabolism, such that cell‐level chronic disease risk factors are reduced. Corresponding effects of sustained whole‐body hydration are hypothesized but remain to be confirmed and translated into population‐level chronic disease prevention.This analysis aimed to 1) describe change in urine and serum metabolomic profiles associated with change in hydration, induced by four weeks of sustained higher intake of drinking water, 2) check if features recognized as key osmolytes in specific tissues changed in urine and/or serum, and 3) identify which metabolic pathways might potentially be impacted by sustained hypotonic hydration.Adapt Study [Stookey JD et al., Physiol Rep 2013;1(5)] data from for 4 healthy, normal weight men (20‐25 years) who transitioned from not meeting to meeting 3 osmolality criteria (urine:<800mmol/kg, serum:<295mmol/kg and saliva:<100mmol/kg) over 4 weeks of >+1L/d intake of drinking water were used for this analysis. Untargeted metabolomic assays were performed by the UC Davis West Coast Metabolomic Center on first‐morning urine collected after overnight food and water restriction and urine (t+60min) and serum (t+90min) collected after a 750 ml bolus of drinking water. Metaboanalyst 5.0 was used to compare Week 1 vs Week 6 metabolomic profiles, using heatmap, OPLS‐DA, fold‐change, and pathway analyses.In heatmap and OPLS‐DA plots, metabolomic profiles appeared more similar in Week 6.Over 350 metabolic features decreased by 2‐fold or more relative to creatinine for at least 3 out of 4 participants in first‐morning and post‐bolus urine. Over 200 features increased by 2‐fold or more relative to creatinine in serum. A wide variety of known compounds changed by 2‐fold or more in at least one specimen type, including alcohols, monosaccharides, disaccharides, sugar acids, polyols, azoline, lactone, nucleosides, phenols, purines, pyridines, pyrimidines, fatty acids, cholesterol, glycerolipids, amino acids, carboxylic acids, phosphate, and urea. Based on hypergeometric test p‐value <0.05 or pathway impact factor >0.2, sustained +1L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a ‘reverse’ Warburg‐like pattern favoring carbohydrate oxidation via the TCA cycle in Week 6.The results warrant further work to leverage cell hydration effects for chronic disease prevention.