Daily consumption of cranberry improves endothelial function in healthy adults: a double blind randomized controlled trial.

Background: Previous studies indicate cardiovascular health benefits of cranberry juice consumption. However, whether daily consumption of whole cranberries will have sustained vascular benefits in healthy individuals is currently unknown. Objective: To investigate the vascular effects of acute and daily consumption of freeze dried whole cranberry in healthy men and how effects relate to circulating cranberry (poly)phenol metabolites. Methods: A double-blind, parallel-group, randomized controlled trial was conducted in 45 healthy male adults randomly allocated to 1 month daily consumption of either cranberry (9 g powder solubilized in water equivalent to 100 g of fresh cranberries, 525 mg total (poly)phenols) or control (9 g powder, no (poly)phenols). Flow-mediated dilation (FMD, primary outcome), pulse wave velocity (PWV), aortic augmentation index (AIx), blood pressure, heart rate, blood lipids, and blood glucose were assessed at baseline and at 2 h on day 1 and after 1 month. Plasma and 24 h-urine were analyzed before and after treatment using targeted quantitative LC-MS methods including 137 (poly)phenol metabolites. Results: Cranberry consumption significantly increased FMD at 2 h and 1-month (1.1% (95% CI: 1.1%, 1.8%); ptreatment ≤ 0.001; ptreatment × time = 0.606) but not PWV, AIx, blood pressure, heart rate, blood lipids, and glucose. Of the 56 and 74 (poly)phenol metabolites quantified in plasma and urine, 13 plasma and 13 urinary metabolites significantly increased 2 h post-consumption and on day 1, respectively, while 4 plasma and 13 urinary metabolites were significantly higher after 1-month of cranberry consumption, in comparison with control. A multi-variable stepwise linear regression analysis showed that plasma cinnamic acid-4'-glucuronide, 4-hydroxybenzoic acid-3-sulfate, 2,5-dihydroxybenzoic acid, 3'-hydroxycinnamic acid, and 5-O-caffeoylquinic acid were significant independent predictors of 2 h FMD effects (R2 = 0.71), while 3'-hydroxycinnamic acid, 4-methoxycinnamic acid-3'-glucuronide, 3-(4'-methoxyphenyl)propanoic acid 3'-sulfate, and 3-(4'-methoxyphenyl)propanoic acid 3'-glucuronide predicted the 1-month FMD effects (R2 = 0.52). Conclusions: Acute and daily consumption of whole cranberry powder for 1 month improves vascular function in healthy men and this is linked with specific metabolite profiles in plasma. The National Institutes of Health (NIH)-randomized trial records held on the NIH ClinicalTrials.gov website (NCT02764749). https://clinicaltrials.gov/ct2/show/NCT02764749.

Circulating Anthocyanin Metabolites Mediate Vascular Benefits of Blueberries: Insights From Randomized Controlled Trials, Metabolomics, and Nutrigenomics.

Potential health benefits of blueberries may be due to vascular effects of anthocyanins that predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation. The effects were similar to those of wild blueberries containing similar amounts of anthocyanins, whereas control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month wild blueberry consumption increased flow-mediated dilation and lowered 24-hour ambulatory systolic blood pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 21 correlated with acute and chronic flow-mediated dilation improvements, respectively. Injection of these metabolites improved flow-mediated dilation in mice. Daily wild blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs. Trial registration: NCT025208.

Breakthroughs in the Health Effects of Plant Food Bioactives: A Perspective on Microbiomics, Nutri(epi)genomics, and Metabolomics.

Plant bioactive compounds consumed as part of our diet are able to influence human health. They include secondary metabolites like (poly)phenols, carotenoids, glucosinolates, alkaloids, and terpenes. Although much knowledge has been gained, there is still need for studies unravelling the effects of plant bioactives on cardiometabolic health at the individual level, using cutting-edge high-resolution and data-rich holistic approaches. The aim of this Perspective is to review the prospects of microbiomics, nutrigenomics and nutriepigenomics, and metabolomics to assess the response to plant bioactive consumption while considering interindividual variability. Insights for future research in the field toward personalized nutrition are discussed.

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses.

Understanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation.