Circulating metabolomic signatures of ultra-processed and minimally processed food intake and risk of cardiovascular disease and type 2 diabetes: 20-year follow-up in the Whitehall II cohort
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Published version (article in press)
Author(s)
Type
Journal Article
Abstract
Background
Higher intakes of ultra-processed food (UPF) and minimally processed food (MPF) are linked to increased and decreased cardiometabolic risks, respectively, though mechanisms underlying these associations remain less understood. We aimed to identify metabolomic signatures associated with UPF and MPF intakes, examine their prospective associations with cardiovascular disease (CVD) and type 2 diabetes (T2D), and quantify their mediation of processing-disease associations.
Methods
In the Whitehall II cohort, UPF and MPF intakes in 6010 participants were derived using the Nova classification from 127-item food frequency questionnaires administered at phases 3 and 5 (1991–1994, 1997–1999), averaged across phases. Fasting plasma samples were analysed for 233 metabolites using nuclear magnetic resonance (NMR) spectroscopy. Metabolomic signatures for UPF and MPF intake were derived using elastic net regression. Cox models examined associations between metabolomic signatures and incident CVD and T2D. Mediation analyses quantified the proportion explained by metabolomic signatures.
Results
We identified metabolomic signatures for UPF (34 metabolites) and MPF (50 metabolites). The UPF signature correlated positively with pro-inflammatory and atherogenic metabolites and inversely with omega-3 fatty acids and high-density lipoproteins; the MPF signature showed the opposite pattern. 1094 CVD and 853 T2D events occurred over 20 and 18 years median follow-up, respectively. Comparing the highest to lowest tertile, higher UPF signature scores were associated with greater risk of (hazard ratio [HR] = 1.19; 95% confidence interval [CI] 1.02–1.39) and T2D (HR = 1.20; 95% CI 1.03–1.42), whereas higher MPF signature scores were inversely associated with these outcomes (CVD: HR = 0.81; 95% CI 0.69–0.94; T2D: HR = 0.60; 95% CI 0.48–0.73). Associations between the signatures and outcomes were robust to additional adjustment for UPF or MPF intake. The signatures mediated 42.8–51.1% of processing-disease associations (51.1% for UPF-CVD, 46.6% for MPF-CVD, 42.8% for UPF-T2D, and 47.8% for MPF-T2D; all p < 0.05).
Conclusions
Metabolomic signatures of UPF and MPF intake showed opposing associations with CVD and T2D risk, partially mediating these processing–disease associations. These findings suggest biological pathways linking UPF intake to adverse cardiometabolic outcomes, though the unexplained proportion indicates additional mechanisms may contribute.
Higher intakes of ultra-processed food (UPF) and minimally processed food (MPF) are linked to increased and decreased cardiometabolic risks, respectively, though mechanisms underlying these associations remain less understood. We aimed to identify metabolomic signatures associated with UPF and MPF intakes, examine their prospective associations with cardiovascular disease (CVD) and type 2 diabetes (T2D), and quantify their mediation of processing-disease associations.
Methods
In the Whitehall II cohort, UPF and MPF intakes in 6010 participants were derived using the Nova classification from 127-item food frequency questionnaires administered at phases 3 and 5 (1991–1994, 1997–1999), averaged across phases. Fasting plasma samples were analysed for 233 metabolites using nuclear magnetic resonance (NMR) spectroscopy. Metabolomic signatures for UPF and MPF intake were derived using elastic net regression. Cox models examined associations between metabolomic signatures and incident CVD and T2D. Mediation analyses quantified the proportion explained by metabolomic signatures.
Results
We identified metabolomic signatures for UPF (34 metabolites) and MPF (50 metabolites). The UPF signature correlated positively with pro-inflammatory and atherogenic metabolites and inversely with omega-3 fatty acids and high-density lipoproteins; the MPF signature showed the opposite pattern. 1094 CVD and 853 T2D events occurred over 20 and 18 years median follow-up, respectively. Comparing the highest to lowest tertile, higher UPF signature scores were associated with greater risk of (hazard ratio [HR] = 1.19; 95% confidence interval [CI] 1.02–1.39) and T2D (HR = 1.20; 95% CI 1.03–1.42), whereas higher MPF signature scores were inversely associated with these outcomes (CVD: HR = 0.81; 95% CI 0.69–0.94; T2D: HR = 0.60; 95% CI 0.48–0.73). Associations between the signatures and outcomes were robust to additional adjustment for UPF or MPF intake. The signatures mediated 42.8–51.1% of processing-disease associations (51.1% for UPF-CVD, 46.6% for MPF-CVD, 42.8% for UPF-T2D, and 47.8% for MPF-T2D; all p < 0.05).
Conclusions
Metabolomic signatures of UPF and MPF intake showed opposing associations with CVD and T2D risk, partially mediating these processing–disease associations. These findings suggest biological pathways linking UPF intake to adverse cardiometabolic outcomes, though the unexplained proportion indicates additional mechanisms may contribute.
Date Issued
2026-07-21
Date Acceptance
2026-07-16
Citation
BMC Medicine, 2026
ISSN
1741-7015
Publisher
BMC
Journal / Book Title
BMC Medicine
Copyright Statement
© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42482054
PII: 10.1186/s12916-026-05081-7
Subjects
Cardiovascular disease
Metabolic diseases
Metabolomics
Minimally processed foods
Nutritional epidemiology
Type 2 diabetes
Ultra-processed foods
Publication Status
Published online
Coverage Spatial
England
Date Publish Online
2026-07-21