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Circulating anthocyanin metabolites mediate vascular benefits of blueberries:

insights from randomized controlled trials, metabolomics, and nutrigenomics.

J Gerontol A Biol Sci Med Sci. 2019 Feb 16. pii: glz047. doi: 10.1093/gerona/glz047. [Epub ahead of print] Circulating anthocyanin metabolites mediate vascular benefits of blueberries: insights from randomized controlled trials, metabolomics, and nutrigenomics. Rodriguez-Mateos A1,2, Istas G1,2, Boschek L2, Feliciano RP2, Mills CE1,3, Boby C4, Gomez-Alonso S5, Milenkovic D4,6, Heiss C2,7,8. Author information 1Department of Nutritional Sciences, School of Life Course Sciences, King’s College London, UK.2Division of Cardiology, Pulmonology, and Vascular Medicine, University Duesseldorf, Germany.3Department of Food and Nutritional Sciences, University of Reading, UK.4INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, Clermont Université, Université d’Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France.5Instituto Regional de Investigación Científica Aplicada, Universidad de Castilla-La Mancha, Spain.6Department of Internal Medicine, Division of Cardiovascular Medicine, University of California Davis, Davis, California, USA.7University of Surrey, Faculty of Health and Medical Sciences, Guildfort, UK.8Surrey and Sussex Healthcare NHS Trust, Redhill, UK. 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 24h-ambulatory-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 (>1.2-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. © The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: KEYWORDS: blueberries; endothelial function; metabolomics; nutrition; omics; polyphenols

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