A Metabolome-Wide Association Study of fruit and vegetable consumption and associations with cardiovascular risk factors: the INTERMAP study.

Background: Epidemiological evidence linking blood pressure (BP) and body weight-lowering effects with fruit and vegetable consumption mostly relies on self-reported dietary assessment prone to misreport and under- or overestimation of relationships. We characterized objective 24-hr urinary metabolites and a derived metabolite score associated with fruit and vegetable intake and assessed their associations with BP and body mass index (BMI), with validation across cohorts.

Methods: We used untargeted proton nuclear magnetic resonance spectroscopy (¹H NMR) of two timed repeated 24-hr urine collections from free-living participants from the US (n=2,032) and the UK (n=449) of the cross-sectional International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). We evaluated correlations between fruit and vegetable intake assessed by 24-hr dietary recalls with 7,100 ¹H NMR features, adjusted for confounders and multiple testing. We related identified metabolites and a metabolite score with BP and BMI using extensively adjusted multiple linear regression models.

Results: We characterized eleven ¹H NMR-derived 24-hr urinary metabolites related to fruit and vegetable intake, reproducible across multiple 24-hr urine collections of both cohorts. Proline betaine, citrate, N-methylproline, scyllo-inositol, 2-hydroxy-2-(4-methyl cyclohex-3-en-1-yl) propoxyglucuronide, and proline were associated with fruit intake, specifically with Rutaceae intake, while S-methyl-L-cysteine sulfoxide and S-methyl-L-cysteine sulfoxide metabolite were associated with Brassicacea intake. The metabolite score, explaining 39.8% of fruit and vegetable intake, was inversely associated with systolic BP (-1.65 mmHg; 95% confidence interval (CI): -2.68,-0.62, P<0.002) and BMI (-1.21 kg/m²; 95% CI: -1.62,-0.78, P<0.0001). These associations were to a large extent explained by urinary citrate excretion.

Conclusion: We identified ¹H NMR-derived urinary metabolites associated with fruit and vegetable consumption, consistent and reproducible between urine collections and across populations. A higher fruit and vegetable-related metabolite score showed associations with lower systolic BP and BMI, mainly mediated by citrate, but would need confirmation in further studies.

Study registration: This study was registered at the clinicaltrials.gov registration (https://clinicaltrials.gov/study/NCT00005271?term=NCT00005271&rank=1) as NCT00005271.