The Mediterranean diet, plasma metabolome, and cardiovascular disease risk

Abstract

Aims To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. Methods and results Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses’ Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28–0.37 between the signature and MEDAS; P = 3 × 10−35 to 4 × 10−118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). Conclusions We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

The Effects of a Mediterranean Diet Intervention on Targeted Plasma Metabolic Biomarkers among US Firefighters: A Pilot Cluster-Randomized Trial

“…Our results highlighting the changes in plasma metabolites related to lipid metabolism are in line with other studies [20,26]. A recent investigation that identified a metabolic signature of adherence to the MedDiet showed that out of 67 metabolites, 45 were lipids followed by 19 amino acids, 2 vitamins and 1 xenobiotic [26]. Although we used a different methodology and a different set of biomarkers, and thus we could not replicate this metabolic signature, our results support that the MedDiet may induce changes in relevant lipid species and subclasses related to atherogenic risk.…”

“…Our results highlighting the changes in plasma metabolites related to lipid metabolism are in line with other studies [20,26]. A recent investigation that identified a metabolic signature of adherence to the MedDiet showed that out of 67 metabolites, 45 were lipids followed by 19 amino acids, 2 vitamins and 1 xenobiotic [26].…”

“…There is observational epidemiological evidence that acylcarnitines, Trimethylamine N-oxide (TMAO), some amino acids such as phenylalanine, glutamate as well as several lipid classes are associated with CVD risk [14]. While the effects of individual dietary ingredients on metabolome have been reported [15][16][17][18][19][20], only a few studies have focused on overall dietary patterns [21][22][23][24][25][26]. Some cross-sectional studies such as the Whitehall II study showed that a healthy diet was associated with specific fatty acids that reduced the risk of CVD [27].…”

“…In the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study, some metabolites were also cross-sectionally associated with dietary recommendations [28]. More recently, a metabolic signature of the Mediterranean Diet has been consistently identified in two large cohorts [26].…”

Recent Trends in Dietary Habits of the Italian Population: Potential Impact on Health and the Environment

“…Data on the relationships between NCDs and dairy foods and eggs are less consistent but overall indicate possible harm at very high intakes [ 28 , 30 ]. Moreover, the PREDIMED (Primary Prevention of Cardiovascular Disease with Mediterranean Diet) trial has shown that the implementation of a diet resembling the traditional Mediterranean diet, in many ways similar to the dietary pattern proposed by the Eat–Lancet Commission, substantially reduces the incidence of cardiovascular diseases and diabetes [ 31 , 32 ].…”