Gut Microbe-Dependent Metabolites as Modulators and Biomarkers of Atherosclerosis

Project: Research project

Project Details

Description

The epidemic of cardiovascular disease, manifesting as myocardial infarction, stroke, and peripheral arterial disease, poses a tremendous global health, economic, and social burden.[1] It is a systemic disease marked by chronic subclinical inflammation and accumulation of cholesterol in the arterial wall. There are accumulating data that the trillions of commensal microbes in the human body ecosystem contribute to cardiovascular risk by influencing the development of diabetes mellitus[4] and obesity,[5] by metabolism of nutrients or production of new metabolites that promote cardiovascular disease,[6] and by direct seeding of atherosclerotic plaques.[7] However, whether altered gut commensal microbes are causal of, or consequential to, atherosclerosis is unknown. Our overall goal is to understand the mechanism(s) by which commensal gut microbes contribute to the severity of atherosclerosis. We theorize that patients with atherosclerosis have altered microbial communities, which translates into differential production of microbial metabolites, which, in turn, has functional consequences. Indeed, a comparison of the gut metagenomes (collective genomes of all gut microbes) of patients with symptomatic carotid stenosis and healthy controls revealed that the relative abundances of microbial strains and the microbial gene product pathways were different between the 2 groups.[8] Furthermore, there is evidence that metabolites that are known to be microbe-dependent are associated with inflammation and cardiovascular disease. For instance, kynurenine, a metabolite of tryptophan, is both a plasma biomarker of inflammation and associated with cardiovascular disease mortality.[3, 9] Interestingly, germ-free mice, which are microbe-deficient and raised in a sterile environment, have decreased plasma kynurenine:tryptophan ratios, which normalize after colonization by gut microbes.[3] As further evidence of the far-reaching impact of gut microbes and their metabolites on the peripheral vasculature, the PI recently demonstrated that rats treated with vancomycin had altered microbial composition and diversity, decreased serum levels of microbe-dependent short chain fatty acids, and exacerbated neointimal hyperplasia development after carotid artery balloon angioplasty.[10] Finally, the PI has performed a targeted metabolomic pilot study and identified that plasma concentrations of 2 microbe-dependent metabolites were significantly different in a cohort of patients with clinically significant peripheral arterial disease (PAD) compared to a cohort of non-PAD controls. Based on these data, our hypothesis is that gut microbial metabolic pathways are differentially regulated in atherosclerosis, rendering the metabolite products to be potential quantitative biomarkers for atherosclerotic disease burden and active modulators of atherogenesis (Figure 1). To test this hypothesis, we propose the following aims (milestones) for this 2-year award:
Milestone 1: To expand our understanding of links between microbe-dependent metabolites and clinically severe atherosclerosis, we will expand the targeted metabolomic pilot study to include 4 related compounds in 2 well–defined cohorts: first, 114 patients undergoing carotid or femoral endarterectomy or major amputation, and second, a control cohort of non-PAD patients.

Milestone 2: To study the impact of microbe-dependent metabolites on systemic and tissue inflammation in patients with severe atherosclerosis, we will link the targeted metabolomics screen from the surgical cohort to plasma inflammatory biomarkers,
StatusFinished
Effective start/end date1/1/17 → 12/31/18

Funding

  • Vascular Cures (CPCR Grant Award 12/26/16)

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