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

Abstract

Potential health benefits of blueberries may be due to vascular effects of anthocyanins which 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 (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24hambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2fold) 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.

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

“…The most striking finding was a 13-fold increase of miR-181c expression evidenced in PMBC. Specific patterns of 13 metabolites were proven as independent predictors of mRNA expression alteration, and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response and cell differentiation [288]. Anthocyanins are well tolerated and have no side effects, but their bioavailability is rather low, and they are rapidly transformed into phenolic acid derivates [289].…”

“…The effects of anthocyanins and their metabolites on miRNAs expression are still largely unknown, only a few studies having been published. Rodriguez-Mateos et al performed, recently, a nutrigenomic study to explore the mechanism of action of anthocyanins in vivo [288]. They analyzed mRNAs and miRNAs in PBMC isolated from healthy volunteers at the beginning and the end of a 28-day period of anthocyanins-enriched vitamin mix or blueberry consumption.…”

Exploring the Applications of the Photoprotective Properties of Anthocyanins in Biological Systems

“…Anthocyanin’s bioavailability is normally considered rather low; however, today it is widely known that many factors underestimate the real bioavailability of such compounds [ 187 ]. Recent evidence suggests that these compounds can be absorbed at the gastrointestinal level and detected in the systemic circulation [ 120 , 187 , 188 , 189 ]. Together with their metabolites, these compounds can be detected after a few minutes after ingestion.…”

An 8-Week Freeze-Dried Blueberry Supplement Impacts Immune-Related Pathways: A Randomized, Double-Blind Placebo-Controlled Trial

“…Results from studies assessing the impact of highbush blueberries on health have been variable. With a 28-day supplementation of 11 g BBP daily, ow-mediated dilation improved and SBP was signi cantly reduced in men (39).…”