BackgroundThere is a need to understand the underlying biological mechanisms through which ultra-processed foods negatively affect health. Proteomics offers a valuable tool with which to examine different aspects of ultra-processed foods and their impact on health. ObjectiveTo identify protein biomarkers of usual ultra-processed food consumption, and assess their relation to incidence of coronary heart disease, chronic kidney disease, and all-cause mortality risk. MethodsA total of 9,361 participants from the Atherosclerosis Risk in Communities (ARIC) visit 3 (1993-1995) were included. Dietary intake was assessed using a 66-item food frequency questionnaire and the processing levels were categorized based on Nova classification. Plasma proteins were detected using an aptamer-based proteomic assay. We used multivariable linear regressions to examine the association between ultra-processed food and proteins, and Cox proportional hazard models to identify associations between ultra-processed food-related proteins and health outcomes. Models extensively controlled for sociodemographic characteristics, health behaviors, and clinical factors. ResultsIdentified were eight proteins (6 positive, 2 negative) significantly associated with ultra-processed food consumption. Over a median follow-up of 22 years, there were 1,276, 3,084, and 5,127 cases of coronary heart disease, chronic kidney disease, and death, respectively. Three, five, and three ultra-processed food-related proteins were associated with each outcome, respectively. One protein (β-glucuronidase) was significantly associated with higher risk of all three outcomes, and three proteins (receptor-type tyrosine-protein phosphatase U, C-C motif chemokine 25, and twisted gastrulation protein homolog 1) were associated with higher risk of two outcomes. ConclusionsWe identified a panel of protein biomarkers that were significantly associated with ultra-processed food consumption. These proteins may be considered potential biomarkers for ultra-processed food intake and elucidate the biological processes through which ultra-processed foods impact health outcomes.