Temporal changes in circulating metabolites after metabolic and bariatric surgery and risk of incident coronary heart disease: evidence from prospective cohort and nested case–control studies

Background: Metabolic and bariatric surgery (MBS) has notable cardiovascular benefits beyond weight loss. Methods: The Gut Microbiome in Metabolic Surgery Study (GUMMY) enrolled patients who underwent first-time Roux-en-Y gastric bypass or sleeve gastrectomy, with blood samples collected at pre- and 3- and 12-month post-surgery. Significant metabolite changes were identified using paired Wilcoxon signed-rank tests with a false discovery rate (FDR) < 0.05 and |log 2 fold change| > log 2 1.5, comparing 3-month post- vs. pre-surgery (early phase) and 12- vs. 3-month post-surgery (late phase). Significantly changed metabolites were classified into three patterns: early changed, late sustained; early changed, late reversed; and early unchanged, late changed. Subsequently, a nested case–control study within the Southern Community Cohort Study (SCCS) assessed the associations between surgery-altered metabolites and incident coronary heart disease (CHD) risk using conditional logistic regression. The same untargeted metabolomic assay was conducted in GUMMY and SCCS plasma samples. Results: Among 115 surgical patients, the mean (SD) age was 44.9 (9.5) years, and 90 (78%) were women. Significant changes were observed in 224 metabolites, mainly encompassing sustained increases in bile acids and decreases in branched-chain amino acids, lactoyl, and lysine amino acids; reversed changes in some ketone bodies, phospholipids, lysophospholipids, and glycogen metabolites; late increases in taurine, caffeine, benzoate, and some tryptophan metabolites; and late decreases in ceramide metabolites and certain fatty acids. In the SCCS ( n = 1194; 597 case–control pairs), 37 surgery-altered metabolites were significantly associated with incident CHD (FDR < 0.1), 28 with concordant effects, i.e., post-surgical increases were associated with reduced CHD risk and vice versa. Conclusions: MBS elicits substantial metabolomic alterations, with many altered metabolites associated with incident CHD. These findings provide mechanistic insights into the cardiovascular benefits of MBS and suggest potential therapeutic targets for CHD prevention.