Metabolomic signature of ultra-processed foods and cardiovascular morbidity and mortality.

BACKGROUND & AIMS: High intake of ultra-processed foods (UPFs) increases cardiovascular disease (CVD) risk, but the underlying mechanisms are unclear. Leveraging untargeted blood metabolomics in three prospective cohorts, we aimed to identify and validate circulating metabolites associated with UPF intake and CVD risk and mortality.

METHODS

This two-stage metabolomics study involved a discovery stage conducted in the Southern Community Cohort Study (SCCS; N = 1688) and a validation stage performed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; N = 2315) and the Atherosclerosis Risk in Communities Study (ARIC; N = 3682). UPF intake (classified by Nova) was quantified as weight percentage or servings per day based on food frequency questionnaires administered at cohort baseline. Untargeted profiling of baseline blood metabolites was performed in selected participants without cancer or CVD. For discovery, linear regression was used to evaluate UPF intake in association with 1100 metabolites, and conditional logistic and Cox regression models were used to further examine the associations of UPF-related metabolites and metabolite signature (MetSig) with incident coronary heart disease (CHD), CVD mortality, and total mortality. Significant findings (FDR<0.1) were proceeded for validation using similar methods.

RESULTS

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; e.g., N2,N2-dimethylguanosine and mannitol/sorbitol), CVD mortality (n = 2; e.g., N-acetylglucosamine/N-acetylgalactosamine), and total mortality (n = 20; e.g., purine/pyrimidine metabolism-related nucleosides). Importantly, we developed a MetSig for UPF intake, which demonstrated stronger associations with these outcomes compared with UPF intake (CHD incidence: OR = 1.46 vs 1.10; CVD mortality: HR = 1.27 vs 1.16; total mortality: HR = 1.25 vs 1.12 per 1-standard deviation increase). Additionally, this MetSig explained 59-77% of the UPF-disease associations and showed consistent adverse associations across subpopulations.

CONCLUSIONS

We identified and validated circulating metabolites associated with UPF intake and CVD risk and mortality in three prospective cohorts. These findings may enhance the assessment and mechanistic understanding of how UPFs impact human health.