Ultra-processed foods (UPFs) intake may increase cardiovascular disease (CVD) risk, but the mechanisms remain unclear and evidence on UPF biomarkers is limited. Leveraging untargeted blood metabolomics in three prospective cohorts, we identified and validated circulating metabolites associated with UPF intake and CVD risk and mortality. Discovery was conducted in the Southern Community Cohort Study (N=1,688), with validation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=2,315) and the Atherosclerosis Risk in Communities Study (N=3,682). We identified (n=142) and validated (n=43) metabolites associated with UPF intake, with several of these metabolites further linked to incident coronary heart disease (n=5), CVD mortality (n=2), and total mortality (n=20). Importantly, we developed a metabolite signature for UPF intake, which demonstrated strong associations with outcomes (OR/HR=1.25–1.46 per 1-SD increase) and explained 59–77% of the UPF-disease associations. These findings may enhance the assessment and mechanistic understanding of how UPFs impact human health.

The authors have declared no competing interest.

This analysis is supported by R01HL149779 from the National Heart, Lung, and Blood Institute. The Southern Community Cohort Study is funded by U01CA202979 from the National Cancer Institute. Data collection for the Southern Community Cohort Study was performed by the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485). The Atherosclerosis Risk in Communities Study is funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). Metabolomic measurements were funded by the National Human Genome Research Institute (3U01HG004402-02S1). DKG receives research support from the National Heart, Lung, and Blood Institute (R01HL148661). CMR receives research support from the National Heart, Lung, and Blood Institute (R01HL153178). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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