The influence of salt loading and ketone supplementation on the plasma metabolome in apparently healthy adults

Austin Robinson; Soolim Jeong; Braxton Linder; Sofia Sanchez; Kanokwan Bunsawat; Jaapna Dhillon

doi:10.1152/physiol.2026.41.S1.2299315

Abstract only Background: Chronic high salt (sodium chloride) intake is associated with poorer cardiometabolic health. Metabolomics has identified several metabolites influenced by high dietary salt in rodents and in humans. Nutritional ketosis (i.e., increasing beta hydroxybutyrate; β-OHB) counteracts some of the metabolic changes elicited by high salt in rodents, but these findings have not been translated to humans. Therefore, we sought to examine the effects of salt loading and concomitant β-OHB (ketone monoester) supplementation on the plasma metabolome and blood pressure (BP) in apparently healthy adults. Methods: Fifteen participants (11 Males /4 Females; Age: 29.8 ± 10.6 yrs) completed a randomized, crossover study consisting of three 10-day conditions: Low Salt (LS): placebo capsules (dextrose) and placebo drink; High Salt (HS): salt capsules and placebo drink; and High Salt + Ketone (HS+K): salt capsules and ketone monoester drink. Participants received counseling to consume low sodium (~0.8 mg/kcal/day) background diets for all conditions and were supplemented up to ~2 mg/kcal/day of sodium for HS conditions and 36 g β-OHB/day with HS+K condition. Plasma was obtained using vacutainers treated with dipotassium EDTA (i.e., K2-EDTA). Untargeted metabolomics was measured via flow injection analysis with tandem mass spectrometry. Metabolomics data were LOESS-normalized and filtered to retain metabolites present in at least 80% of samples. For each metabolite, a linear mixed-effects model was applied with condition as a fixed effect, adjusting for visit order in the crossover design, and including a random effect for participant. Type III ANOVA tested the fixed effects, and group-level P-values were corrected using the Benjamini–Hochberg FDR procedure. Statistical significance was defined as a group-effect Q < 0.1. For metabolites meeting this threshold, post hoc comparisons were performed using t-tests of model-estimated contrasts, with multivariate t adjustment to control for multiple pairwise comparisons. Results: Resting systolic (P=0.975) and diastolic (P=0.852) BP were not different across conditions (LS: 108.2 ± 10.5/64.8 ± 5.8, HS: 108.3 ± 12.6/64.3 ± 6.9, and HS+K: 107.4 ± 9.1/62.8 ± 5.6 mmHg). Metabolomics analyses detected that 62 out of 743 identified metabolites exhibited significant condition effects. The HS+K vs. HS conditions exhibited the largest number of pairwise differences (P< 0.05), with metabolites related to the TCA cycle; fatty acid and lipid metabolism pathways were elevated in HS+K. Across these pathways, metabolite abundances that were 1.2–2.0-fold higher in HS+K included isocitrate, C16:0, C12:1, C16:2, C16:3, C12:4, C22:5, dodecanoic acid (FA12:0), arachidonic acid, and 3-oxododecanoic acid, with leukotriene A4 exhibiting the greatest separation (~2-fold). Conclusion: Our preliminary data suggest that ketone supplementation may alter metabolic responses to high-salt diets, particularly affecting TCA cycle intermediates and lipid-related metabolites, without influencing resting blood pressure. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

The influence of salt loading and ketone supplementation on the plasma metabolome in apparently healthy adults

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