Background-Low birthweight (LBW) has been associated with an increased incidence of adult cardiovascular disease.Endothelial dysfunction and loss of arterial elasticity are early markers of hypertension and atherosclerosis. We studied the prevalence of these markers in 44 healthy, prepubertal (age 9Ϯ1.3 years) children, 22 with LBW for age. Methods and Results-Endothelial function in skin was tested with the local application of acetylcholine (inducing endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation), and local perfusion changes were measured with the laser Doppler method. The elastic properties of the abdominal aorta and common carotid artery were measured with an ultrasonic vessel-wall tracking system. Endothelium-dependent vasodilation was lower in children with LBW (88Ϯ33 perfusion units [PU]) than in normal-birthweight controls (133Ϯ34 PU, PϽ0.001).There was no difference in aortic or carotid elasticity between the 2 groups, but a negative correlation was found between birthweight and stiffness of the carotid artery wall (rϭϪ0.45, PϽ0.01). Endothelium-independent vasodilation and blood pressure were similar in the 2 groups. Conclusions-Schoolchildren with a history of LBW show impaired endothelial function and a trend toward increased carotid stiffness. These findings may be early expressions of vascular compromise, contributing to susceptibility to disease in adult life.

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.

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.