Abstract

<b>Background:</b> High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies.<b>Objective:</b> We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure.<b>Design:</b> The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions (<i>N</i> = 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting <i>P</i> values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups.<b>Results:</b> Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, γ-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate ≤0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold (<i>P</i> &lt; 10^-5). Adjustment for coinciding change in blood pressure did not substantively alter the association for the top-ranked metabolites.<b>Conclusion:</b> Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and γ-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608.