Uncovering the Molecular Footprint of Salt Consumption with UPLC-MS/MS

Novel insights concerning the relationship between sodium intake and cadiometabolic risk have been uncovered through untargeted metabolomic analysis.A recent study examined cross-sectional associations between estimated sodium intake and plasma metabolite profiles in the large Swedish cohort Swedish CardioPulmonary bioImage Study (SCAPIS). Plasma metabolites were measured using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which identified 713 metabolites grouped into eight biochemical classes. A paper based on this research was published in Nutrition & Metabolism (1).

A great deal of previous research has reported that excessive salt consumption is a risk factor for hypertension and cardiovascular disease (2 –7). However, existing studies linking salt intake to the metabolome have been limited by small sample sizes, short-term intervention designs, or targeted analytical platforms (1), resulting in a lack of large-scale, population-based studies using untargeted metabolomics to examine habitual salt intake in free-living humans. This represented to the research team a crucial gap in comprehending the molecular pathways where salt may influence cardiometabolic risk. Previous research by this team resulted in the revelation that increased salt intake is associated with a higher prevalence of manifest sub-clinical coronary and carotid atherosclerosis (8). In the current study, the team leveraged untargeted plasma metabolomics in more than 8000 individuals from SCAPIS for investigating metabolic patterns associated with estimated salt intake in hopes of revealing new insights into mechanistic links between sodium exposure and cardiovascular disease risk (1).

This cross-sectional analysis was conducted in the SCAPIS cohort (mean age 50-64 years, n = 8,957). Sodium intake was estimated using the Kawasaki formula (est24hNa) from urine samples. After the plasma metabolites were measured using UPLC-MS/MS, and the metabolites identified were grouped into the eight classes, principal component analysis (PCA) was conducted for each class with the first principal component (PC1 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 also performed to explore associations (1).

The research revealed that est24hNa was significantly associated with the lipid and energy classes. 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 (1).

This data determined that a lower salt intake was connected to a metabolic profile which indicated increased beta-oxidation, while a higher salt intake was associated with lipid species previously implicated in atherosclerosis. The researchers believe that these findings emphasize potential metabolic pathways through which the intake of salt intake might influence cardiovascular health, and that they deserve additional assessment in longitudinal studies (1).

References

1. Wuopio, J.; Yi-Ting, L.; Dekkers, K. F. et al. The Metabolic Signature of Salt Intake: A Cross-Sectional Analysis from the SCAPIS-Study. Nutr. Metab (Lond). 2025, 22 (1), 104. DOI: 10.1186/s12986-025-00997-y
2. Intersalt Cooperative Research Group. Intersalt. An International Study of Electrolyte Excretion and Blood Pressure. Results for 24 Hour Urinary Sodium and Potassium Excretion. Intersalt Coop Res Group. BMJ 1988, 297 (6644), 319–328.
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4. Graudal, N. A.; Hubeck-Graudal, T.; Jurgens, G. Effects of Low Sodium Diet Versus High Sodium Diet on Blood Pressure, Renin, Aldosterone, Catecholamines, Cholesterol, and Triglyceride. Cochrane Database Syst Rev. 2020, 12 (12), CD004022. DOI: 10.1002/14651858.CD004022.pub5
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6. Wang, Y. J.; Yeh, T. L.; Shih, M. C. et al. Dietary Sodium Intake and Risk of Cardiovascular Disease: A Systematic Review and Dose-Response Meta-Analysis. Nutrients 2020, 12 (10), 2934. DOI: 10.3390/nu12102934
7. Ma, Y.; He, F. J.; Sun Q, et al. 24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk. N. Engl. J. Med. 2022, 386 (3), 252-263. DOI: 10.1056/NEJMoa2109794
8. Wuopio, J.; Ling, Y. T.; Orho-Melander, M. et al. The Association Between Sodium Intake and Coronary and Carotid Atherosclerosis in the General Swedish Population. Eur. Heart J. Open. 2023, 3 (2), oead024. DOI: 10.1093/ehjopen/oead024