Abstract MP23: Circulating Gut Microbiota-Related Metabolites and Risk of Coronary Heart Disease: A Prospective, Multiethnic, Metabolomic Study
Authors: Yang Jae Jeong , Shu Xiao-Ou , Gupta Deepak K , Lipworth Loren , Herrington David M , Yu Bing , Tzoulaki Ioanna , Cai Hui , Saylor Georgia , Yang Yueh Ning , Pinto Rui C , Yu Danxia 
Published: March 2023

Introduction:
Despite the importance of gut microbiota in human cardiometabolic health, the associations between circulating levels of gut microbiota-related metabolites and incident coronary heart disease (CHD) remain largely unexplored.

Hypothesis:
Certain circulating microbial metabolites are associated with incident CHD.

Methods:
This is a multi-stage and multiethnic metabolomics study. We first conducted a global, semi-quantitative assay for discovery among 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively) selected from the Southern Community Cohort Study and Shanghai Men’s and Women’s Health Studies. We focused on 226 metabolites that were potentially related to gut microbiota and applied conditional logistic regression to estimate odds ratios (ORs) of CHD associated with a 1-SD increase of log-transformed metabolites adjusting for traditional CHD risk factors. Then, an in-silico validation was conducted using existing metabolites data of 9,264 participants from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study.

Results:
In the discovery stage, we identified 73 named microbial metabolites related to incident CHD risk with a false discovery rate<0.10 or nominal
p
<0.05 and a large effect size (ORs >1.5 or <0.5). These metabolites were from super pathways of amino acids (n=28), lipids (n=24), nucleotides (n=6), carbohydrates (n=4), energy (n=4), xenobiotics (n=4), and cofactors/vitamins (n=3). Of them, 61 metabolites were available for the in-silico validation, and 30 showed a significant association (
p
<0.05) with the same direction as the discovery results. After further adjustments for established CHD risk factors (e.g., glucose and LDL-cholesterol), 25 metabolites remained significant. A 14%-48% increased risk was observed for N-acetylglutamate (OR=1.48), sphingomyelin (1.42), imidazole propionate (1.37), hypoxanthine (1.29), guaiacol sulfate (1.28), glutamate (1.22), 2-hydroxyphenylacetate (1.20), 3-hydroxybutyrate (1.19), 3-hydroxy-2-ethylpropionate (1.17), 1-methyl-4-imidazoleacetate (1.16), urea (1.16), urate (1.16), 4-hydroxyphenylacetate (1.15), choline (1.15), isoleucine (1.14), and glycerol (1.14). Meanwhile, a significant inverse association was found for taurine (OR=0.64), asparagine (0.75), serotonin (0.78), histidine (0.79), threonine (0.81), glutamine (0.83), glycine (0.84), oxalate (0.85), and N-methylproline (0.89).

Conclusions:
Among ethnically and geographically diverse populations, we identified and validated some circulating gut microbiota-related metabolites as potential novel biomarkers for incident CHD. Targeted quantitative assays to confirm these results are ongoing, which are essential to inform potential clinical utility.