University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 1-29-2016 Significance of Polyphenol Metabolism in Explaining the Bioactivity of Polyphenol-rich Foods Liyang Xie [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Xie, Liyang, "Significance of Polyphenol Metabolism in Explaining the Bioactivity of Polyphenol-rich Foods" (2016). Doctoral Dissertations. 1131. https://opencommons.uconn.edu/dissertations/1131 Significance of Polyphenol Metabolism in Explaining the Bioactivity of Polyphenol-rich Foods Liyang Xie, Ph.D. University of Connecticut, 2016 ABSTRACT Dietary polyphenols are non-essential phytonutrients that are extensively metabolized upon consumption. Based on our previous studies, we hypothesized that the bioavailability of polyphenol metabolites is more important than unmetabolized polyphenols for the health- promoting effects of polyphenol-rich foods. We tested this hypothesis with three objectives. First we developed a more complete polyphenol profile for almond, by characterizing its tannins and stilbenes. Tannins and stilbenes are extensively metabolized prior to or upon absorption. In almond, hydrolysable tannin content was 54.7 ± 2.3 mg ellagic acid and 27.4 ± 7.3 mg gallic acid per 100 g almond among varieties. The stilbene resveratrol-3-O-glucoside was identified in almond extracts, with 7.19–8.52 µg/100 g almond. These results suggested that almonds have a large pool of polyphenols that would be extensively metabolized in the colon prior to absorption. Second, we determined the efficiency by which aronia berry polyphenols are metabolized in an acute pharmacokinetic study in humans. In this experiment, polyphenol metabolites constituted at least 99% of the total polyphenol pool measured in plasma and urine. Third, we determined the association between aronia polyphenol metabolites and changes in key biomarkers of CVD risk in an intervention study. Former smokers, which were at greater risk for CVD, consumed aronia berry extract for 12 wk. Aronia consumption reduced fasting plasma total cholesterol (TC) level by 8% during the 12-week treatment compared with placebo group, and reduced plasma LDL-C level by 7% and 11% at both 6 wks and 12 wks compared with placebo group. In addition, participants in the aronia group who showed the largest decreases in TC had stronger correlations of urinary peonidin-3-O-galactoside and cyanidin-3-O-galactoside than those who did not respond to the intervention. These results suggested that increases in polyphenol metabolites were more highly correlated with reduced biomarkers of chronic disease than parent polyphenols. Thus, this study demonstrated that the cholesterol-lowering activity of polyphenol- rich foods is associated in-part with its tissue metabolites. Significance of Polyphenol Metabolism in Explaining the Bioactivity of Polyphenol-rich Foods Liyang Xie, Ph.D. B.E., China Agricultural University, 2008 M.S., China Agricultural University, 2011 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2016 Copyright by Liyang Xie 2016 ii APPROVAL PAGE Doctor of Philosophy Dissertation Significance of Polyphenol Metabolism in Explaining the Bioactivity of Polyphenol-rich Foods Presented by Liyang Xie, B.E., M.S. Major Advisor _________________________________________________________________________ Bradley Bolling, Ph.D. Associate Advisor ___________________________________________________________________ Ji-Young Lee, Ph.D. Associate Advisor ___________________________________________________________________ Ock Chun, Ph.D. Associate Advisor ___________________________________________________________________ Marcy Balunas, Ph.D. Associate Advisor ___________________________________________________________________ William Baker, Jr., Pharm D. University of Connecticut 2016 iii ACKNOWLEDGEMENTS This dissertation is the collaborative work of many people to whom I would like to express my sincerest gratitude. First, I would like to thank my major advisor Dr. Bradley Bolling, for giving me to opportunity to work with you and to learn from you, for providing me with all the support, resources and techniques that are necessary to complete this dissertation. I would like to thank Dr. Lee, Dr. Chun, Dr. Balunas, and Pharm D. Baker, thank you for serving on my doctoral committee, for giving me instructions and advice on my experiment and dissertation writing, for asking me hard questions to make me an active thinker and a better scientist. It has been a great honor working with every one of you. To professors at NUSC, Dr. Koo, Dr. Fernandez, Dr. Freake, Dr. Park, Dr. Rodriguez, and Dr. Mobley, thank you for your great lecture and your support to my study. I would like to thank my lab mates, Diana, Derek, Rod, Ruisong, Anna, for all your help in my life. Thank you, Sanggil, Xi, Terry, Bohkyung, Christian, Ying, Patrice, and Katherine, for helping me with collecting the data for this dissertation. I also would like to thank Xiaoyu, Lai, Jianping, Chai Siah, Yue, Tho, Jeff, and Mo, for your friendship and help. Thank all the study participants for their time and support that made this study possible, and thank the funding agency California almond board and Connecticut department of public health for the financial support. Most importantly, I would like to thank my parents, Yurong and Yin. Mom and Dad, thank you for supporting me every decision over the years. iv Table of Content APPROVAL PAGE ....................................................................................................................... iii ACKNOWLEDGEMENTS ........................................................................................................... iv List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................. x List of Abbreviations .................................................................................................................... xii Chapter 1: Introduction ................................................................................................................... 1 1.1 Overview ............................................................................................................................... 2 1.2 Central Hypothesis and Specific Aims ................................................................................. 2 1.2.1 Objective 1: Characterize the tannin and stilbene composition of almonds. ................. 3 1.2.2 Objective 2: Determine the pharmacokinetics of aronia berry polyphenols and its metabolites. ............................................................................................................................. 5 1.2.3 Objective 3: Determine the extent to which polyphenol metabolites are associated with changes in plasma cholesterol in former smokers after 12 wk of chronic consumption of aronia berry extract. ................................................................................................................ 6 1.3 References ............................................................................................................................. 8 Chapter 2: Literature Review ........................................................................................................ 11 2.1 Introduction ......................................................................................................................... 12 2.2 Polyphenol variety and consumption .................................................................................. 12 2.3 Polyphenol absorption ........................................................................................................ 16 2.4 Polyphenol distribution ....................................................................................................... 20 2.5 Polyphenol metabolism ....................................................................................................... 21 2.6 Polyphenol excretion .......................................................................................................... 23 2.7 Polyphenols and CVD Risk ................................................................................................ 24 2.7.1 Anthocyanins ............................................................................................................... 27 2.7.2 Proanthocyanidins ........................................................................................................ 31 2.8 Conclusion .......................................................................................................................... 34 2.9 References ........................................................................................................................... 35 Chapter 3: Characterize the tannin and stilbene composition of almonds .................................... 47 3.1 Abstract ............................................................................................................................... 49 3.2 Introduction ......................................................................................................................... 50 3.3 Materials and Methods .......................................................................................................