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BACKGROUND: Untargeted metabolomic analysis provides novel insights into the relationship between sodium intake and cardiometabolic risk. This study examined cross-sectional associations between estimated sodium intake and plasma metabolite profiles in a large Swedish cohort.

METHODS: This cross-sectional analysis was conducted in the in the SCAPIS cohort (mean age 50-64 years, n = 8,957). Sodium intake was estimated using the Kawasaki formula (est24hNa) from urine samples. Plasma metabolites were measured using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) (Metabolon Inc^®), identifying 713 metabolites grouped into eight biochemical classes (CC). Principal component analysis (PCA) was conducted for each CC, and the first principal component (PC1) was used as the response variable, with est24hNa, age, sex, and cardiovascular risk factors as predictors in restricted cubic spline models. ANOVA and pathway enrichment analyses were performed to explore associations.

RESULTS: Est24hNa was significantly associated with the lipid and energy CC. Lower est24hNa was linked to higher concentrations of free fatty acids and citric acid cycle intermediates, suggesting enhanced beta-oxidation. Bonferroni-adjusted analyses revealed 231 metabolites significantly associated with est24hNa, with 2 S,3R-dihydroxybutyrate (β = -0.13, p = 2.28 × 10^- 37) showing the strongest association. Lipid subgroups including phosphatidylcholines, lysophospholipids, bile acids, and plasmalogens were positively associated with est24hNa. Pathway enrichment suggested links to branched-chain amino acid metabolism and biosynthesis of unsaturated fatty acids.

CONCLUSIONS: Lower salt intake was associated with a metabolic profile indicative of increased beta-oxidation, while higher salt intake was linked to lipid species previously implicated in atherosclerosis. These findings highlight potential metabolic pathways through which salt intake may influence cardiovascular health and merit further evaluation in longitudinal studies.