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Untargeted metabolomics to explore the interindividual variation in the metabolism of flavan-3-ols after standardized acute intake of cocoa
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International audience. Flavan-3-ols are considered the most important flavonoids in terms of level of intake andcardiometabolic health effects. Their metabolism has been extensively described. However,the exploration of the interindividual variation in their bioavailability has been fairly limited, sincestudies enrolled small numbers of subjects, or did not quantify all relevant metabolites. Ourobjective was to explore the interindividual variation in the metabolism of cocoa flavan-3-olsusing untargeted metabolomics in a large controlled intervention study. We leveraged the COBstudy that enrolled 128 healthy volunteers (half young (18-30y), half older (65-77 y), 50% male,50% female). Volunteers collected urine in different fractions over 48h after consuming incontrolled conditions a polyphenol-rich breakfast composed of cocoa, orange juice, andblackberry and providing 640 mg of flavan-3-ols. Urine samples were analyzed by untargetedmetabolomics (UPLC-QToF-MS, pos&neg). A target-screening approach allowed to identify29 flavan-3-ol specific metabolites, namely epicatechin, phenyl-γ-valerolactones, phenylvalericacids and their methylated, sulfated and glucuronidated derivatives. Thirteen ions highlycorrelated with these flavan-3-ol metabolites were identified as small phenolics or metabolitesof cocoa compounds. Clustering analysis revealed a high interindividual variation in theexcretion of both host and microbial metabolites. Subjects were classified by K-Means in 4metabotypes, which were further characterized by applying V-test on the whole metabolomicprofiles to pinpoint the metabolites that were specifically associated with each metabotypes.Age, gender and BMI did not significantly differ between metabotypes. Analyses are ongoingto identify possible associations with microbiota data (16S) and genotype (SNPs for 112selected genes involved in polyphenol bioavailability) The relevance of the observedmetabotypes regarding the health effects of flavan-3-ols will deserve further investigation.Funding: partly funded by the ANR for the JPI Project FoodPhyt (ANR-19-HDH2-0002-01)
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