Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes

Abstract Objective Multiple studies have shown that gut microbes contribute to atherosclerosis, and there is mounting evidence that microbial metabolism of dietary nutrients influences pathophysiology. We hypothesized that indole- and phenyl-derived metabolites that originate solely or in part from bacterial sources would differ between patients with advanced atherosclerosis and age- and sex-matched controls without clinically apparent atherosclerosis. Methods Plasma from the advanced atherosclerosis cohort (n = 100) was from patients who underwent carotid endarterectomy, open infrainguinal leg revascularization, or major leg amputation for critical limb ischemia. The controls (n = 22) were age- and sex-matched participants who had no peripheral arterial disease or history of stroke or myocardial infarction. Patients with chronic kidney disease were excluded. Metabolites and internal standards were measured using high-performance liquid chromatography and tandem mass spectrometry. Results Plasma metabolite concentrations differed significantly between the advanced atherosclerosis and control cohorts. After adjustment for traditional atherosclerosis risk factors, indole (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.75-0.95; P  = .004), tryptophan (OR,  P P  = .02), and indole-3-aldehyde (OR, 0.12; 95% CI, 0.014-0.92; P  = .04) concentrations negatively associated with advanced atherosclerosis, whereas the kynurenine/tryptophan ratio (OR, 61.7; 95% CI, 1.9->999; P  = .02) was positively associated. Furthermore, tryptophan and indole-3-propionic acid concentrations (Spearman coefficients of 0.63 and 0.56, respectively; P P  = .001) and hippuric acid ( P  = .03). In a multivariate analysis, only the kynurenine/tryptophan ratio remained significantly associated with a postoperative cardiac complication (OR, 44.1; 95% CI, 3.3-587.1; P  = .004). Twenty patients in the advanced atherosclerosis cohort experienced a major adverse cardiac event during the follow-up period, which was associated with hippuric acid ( P  = .002) and the kynurenine/tryptophan ratio ( P Conclusions Specific microbe-derived metabolite signatures associate with advanced human atherosclerosis and postoperative cardiac complications. We suggest that these metabolites are potential novel biomarkers for atherosclerotic disease burden and that further investigation into mechanistic links between defined microbial metabolic pathways and cardiovascular disease is warranted.