1932

Abstract

Cardiometabolic disease (CMD) is a leading cause of death worldwide and encompasses the inflammatory metabolic disorders of obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. Flavonoids are polyphenolic plant metabolites that are abundantly present in fruits and vegetables and have biologically relevant protective effects in a number of cardiometabolic disorders. Several epidemiological studies underscored a negative association between dietary flavonoid consumption and the propensity to develop CMD. Recent studies elucidated the contribution of the gut microbiota in metabolizing dietary intake as it relates to CMD. Importantly, the biological efficacy of flavonoids in humans and animal models alike is linked to the gut microbial community. Herein, we discuss the opportunities and challenges of leveraging flavonoid intake as a potential strategy to prevent and treat CMD in a gut microbe–dependent manner, with special emphasis on flavonoid-derived microbial metabolites.

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2021-10-11
2024-06-14
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Literature Cited

  1. 1. 
    Akhlaghi M, Ghobadi S, Mohammad Hosseini M, Gholami Z, Mohammadian F 2018. Flavanols are potential anti-obesity agents, a systematic review and meta-analysis of controlled clinical trials. Nutr. Metab. Cardiovasc. Dis. 28:7675–90
    [Google Scholar]
  2. 2. 
    Amin HP, Czank C, Raheem S, Zhang Q, Botting NP et al. 2015. Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells. Mol. Nutr. Food Res. 59:61095–106
    [Google Scholar]
  3. 3. 
    Arnold SV, Inzucchi SE, Echouffo-Tcheugui JB, Tang F, Lam CSP et al. 2019. Understanding contemporary use of thiazolidinediones. Circ. Heart Failure 12:6e005855
    [Google Scholar]
  4. 4. 
    Aura A-M. 2008. Microbial metabolism of dietary phenolic compounds in the colon. Phytochem. Rev. 7:3407–29
    [Google Scholar]
  5. 5. 
    Aura A-M, Martin-Lopez P, O'Leary KA, Williamson G, Oksman-Caldentey K-M et al. 2005. In vitro metabolism of anthocyanins by human gut microflora. Eur. J. Nutr. 44:3133–42
    [Google Scholar]
  6. 6. 
    Aura A-M, Mattila I, Seppänen-Laakso T, Miettinen J, Oksman-Caldentey K-M, Orešič M. 2008. Microbial metabolism of catechin stereoisomers by human faecal microbiota: comparison of targeted analysis and a non-targeted metabolomics method. Phytochem. Lett. 1:118–22
    [Google Scholar]
  7. 7. 
    Ávila M, Hidalgo M, Sánchez-Moreno C, Pelaez C, Requena T, de Pascual-Teresa S. 2009. Bioconversion of anthocyanin glycosides by Bifidobacteria and Lactobacillus. Food Res. Int. 42:101453–61
    [Google Scholar]
  8. 8. 
    Bailey CJ. 2017. Metformin: historical overview. Diabetologia 60:91566–76
    [Google Scholar]
  9. 9. 
    Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y et al. 2013. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17:149–60
    [Google Scholar]
  10. 10. 
    Bokkenheuser VD, Shackleton CH, Winter J. 1987. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem. J. 248:3953–56
    [Google Scholar]
  11. 11. 
    Bondonno NP, Dalgaard F, Kyrø C, Murray K, Bondonno CP et al. 2019. Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort. Nat. Commun. 10:13651
    [Google Scholar]
  12. 12. 
    Braune A, Blaut M. 2011. Deglycosylation of puerarin and other aromatic C-glucosides by a newly isolated human intestinal bacterium. Environ. Microbiol. 13:2482–94
    [Google Scholar]
  13. 13. 
    Braune A, Blaut M. 2016. Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microbes 7:3216–34
    [Google Scholar]
  14. 14. 
    Braune A, Engst W, Blaut M. 2016. Identification and functional expression of genes encoding flavonoid O- and C-glycosidases in intestinal bacteria. Environ. Microbiol. 18:72117–29
    [Google Scholar]
  15. 15. 
    Braune A, Gütschow M, Blaut M. 2019. An NADH-dependent reductase from Eubacterium ramulus catalyzes the stereospecific heteroring cleavage of flavanones and flavanonols. Appl. Environ. Microbiol. 85:19e01233-19
    [Google Scholar]
  16. 16. 
    Braune A, Gütschow M, Engst W, Blaut M. 2001. Degradation of quercetin and luteolin by Eubacterium ramulus. Appl. Environ. Microbiol. 67:125558–67
    [Google Scholar]
  17. 17. 
    Brown JM, Hazen SL. 2015. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu. Rev. Med. 66:343–59
    [Google Scholar]
  18. 18. 
    Brown JM, Hazen SL. 2017. Targeting of microbe-derived metabolites to improve human health: the next frontier for drug discovery. J. Biol. Chem. 292:218560–68
    [Google Scholar]
  19. 19. 
    Brown MS, Goldstein JL. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:474634–47
    [Google Scholar]
  20. 20. 
    Budd J, Cusi K. 2020. Role of agents for the treatment of diabetes in the management of nonalcoholic fatty liver disease. Curr. Diabetes Rep. 20:1159
    [Google Scholar]
  21. 21. 
    Burke AC, Sutherland BG, Telford DE, Morrow MR, Sawyez CG et al. 2019. Naringenin enhances the regression of atherosclerosis induced by a chow diet in Ldlr−/− mice. Atherosclerosis 286:60–70
    [Google Scholar]
  22. 22. 
    Burke AC, Telford DE, Edwards JY, Sutherland BG, Sawyez CG, Huff MW. 2019. Naringenin supplementation to a chow diet enhances energy expenditure and fatty acid oxidation, and reduces adiposity in lean, pair-fed Ldlr−/− mice. Mol. Nutr. Food Res. 63:6e1800833
    [Google Scholar]
  23. 23. 
    Cassidy A, Minihane A-M. 2017. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am. J. Clin. Nutr. 105:110–22
    [Google Scholar]
  24. 24. 
    Castro JP, El-Atat FA, McFarlane SI, Aneja A, Sowers JR. 2003. Cardiometabolic syndrome: pathophysiology and treatment. Curr. Hypertens. Rep. 5:5393–401
    [Google Scholar]
  25. 25. 
    Chandra P, Rathore AS, Kay KL, Everhart JL, Curtis P et al. 2019. Contribution of berry polyphenols to the human metabolome. Molecules 24:234220
    [Google Scholar]
  26. 26. 
    Chang W-C, Wu JS-B, Chen C-W, Kuo P-L, Chien H-M et al. 2015. Protective effect of vanillic acid against hyperinsulinemia, hyperglycemia and hyperlipidemia via alleviating hepatic insulin resistance and inflammation in high-fat diet (HFD)-fed rats. Nutrients 7:129946–59
    [Google Scholar]
  27. 27. 
    Chao J, Huo T-I, Cheng H-Y, Tsai J-C, Liao J-W et al. 2014. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLOS ONE 9:6e96969
    [Google Scholar]
  28. 28. 
    Cheng J-R, Liu X-M, Chen Z-Y, Zhang Y-S, Zhang Y-H. 2016. Mulberry anthocyanin biotransformation by intestinal probiotics. Food Chem 213:721–27
    [Google Scholar]
  29. 29. 
    Cueva C, Sánchez-Patán F, Monagas M, Walton GE, Gibson GR et al. 2013. In vitro fermentation of grape seed flavan-3-ol fractions by human faecal microbiota: changes in microbial groups and phenolic metabolites. FEMS Microbiol. Ecol. 83:3792–805
    [Google Scholar]
  30. 30. 
    Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A 2012. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes. Diabetes Care 35:2226–32
    [Google Scholar]
  31. 31. 
    de Ferrars RM, Cassidy A, Curtis P, Kay CD 2014. Phenolic metabolites of anthocyanins following a dietary intervention study in post-menopausal women. Mol. Nutr. Food Res. 58:3490–502
    [Google Scholar]
  32. 32. 
    de Ferrars RM, Czank C, Zhang Q, Botting NP, Kroon PA et al. 2014. The pharmacokinetics of anthocyanins and their metabolites in humans. Br. J. Pharmacol. 171:133268–82
    [Google Scholar]
  33. 33. 
    Del Rio D, Calani L, Cordero C, Salvatore S, Pellegrini N, Brighenti F. 2010. Bioavailability and catabolism of green tea flavan-3-ols in humans. Nutrition 26:11–121110–16
    [Google Scholar]
  34. 34. 
    di Gesso JL, Kerr JS, Zhang Q, Raheem S, Yalamanchili SK et al. 2015. Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes. Mol. Nutr. Food Res. 59:61143–54
    [Google Scholar]
  35. 35. 
    Doan KV, Ko CM, Kinyua AW, Yang DJ, Choi Y-H et al. 2015. Gallic acid regulates body weight and glucose homeostasis through AMPK activation. Endocrinology 156:1157–68
    [Google Scholar]
  36. 36. 
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. 2005. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 115:51343–51
    [Google Scholar]
  37. 37. 
    Eker ME, Aaby K, Budic-Leto I, Rimac Brnčić S, El SN et al. 2019. A review of factors affecting anthocyanin bioavailability: possible implications for the inter-individual variability. Foods 9:12
    [Google Scholar]
  38. 38. 
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S et al. 1999. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:54071544–48
    [Google Scholar]
  39. 39. 
    Esposito D, Damsud T, Wilson M, Grace MH, Strauch R et al. 2015. Black currant anthocyanins attenuate weight gain and improve glucose metabolism in diet-induced obese mice with intact, but not disrupted, gut microbiome. J. Agric. Food Chem. 63:276172–80
    [Google Scholar]
  40. 40. 
    Feliciano RP, Istas G, Heiss C, Rodriguez-Mateos A. 2016. Plasma and urinary phenolic profiles after acute and repetitive intake of wild blueberry. Molecules 21:91120
    [Google Scholar]
  41. 41. 
    Filippatos TD, Panagiotopoulou TV, Elisaf MS. 2014. Adverse effects of GLP-1 receptor agonists. Rev. Diabet. Stud. 11:3202–30
    [Google Scholar]
  42. 42. 
    Ford ES, Li C, Zhao G. 2010. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J. Diabetes 2:3180–93
    [Google Scholar]
  43. 43. 
    Friend A, Craig L, Turner S 2013. The prevalence of metabolic syndrome in children: a systematic review of the literature. Metab. Syndr. Relat. Disord. 11:271–80
    [Google Scholar]
  44. 44. 
    Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y et al. 2004. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Investig. 114:121752–61
    [Google Scholar]
  45. 45. 
    Gao K, Xu A, Krul C, Venema K, Liu Y et al. 2006. Of the major phenolic acids formed during human microbial fermentation of tea, citrus, and soy flavonoid supplements, only 3,4-dihydroxyphenylacetic acid has antiproliferative activity. J. Nutr. 136:152–57
    [Google Scholar]
  46. 46. 
    Glowacki RWP, Martens EC. 2020. In sickness and health: effects of gut microbial metabolites on human physiology. PLOS Pathogens 16:4e1008370
    [Google Scholar]
  47. 47. 
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD et al. 2013. Heart disease and stroke statistics—2013 update. Circulation 127:1e6–6
    [Google Scholar]
  48. 48. 
    Golomb BA, Evans MA. 2008. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs 8:6373–418
    [Google Scholar]
  49. 49. 
    Gonzales GB, Smagghe G, Grootaert C, Zotti M, Raes K, Van Camp J. 2015. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab. Rev. 47:2175–90
    [Google Scholar]
  50. 50. 
    Grundy SM, Brewer HB Jr., Cleeman JI, Smith SC Jr., Lenfant C. 2004. Definition of metabolic syndrome. Circulation 109:3433–38
    [Google Scholar]
  51. 51. 
    Ham JR, Lee H-I, Choi R-Y, Sim M-O, Seo K-I, Lee M-K. 2016. Anti-steatotic and anti-inflammatory roles of syringic acid in high-fat diet-induced obese mice. Food Funct 7:2689–97
    [Google Scholar]
  52. 52. 
    Han X, Guo J, You Y, Yin M, Liang J et al. 2018. Vanillic acid activates thermogenesis in brown and white adipose tissue. Food Funct 9:84366–75
    [Google Scholar]
  53. 53. 
    Hanske L, Engst W, Loh G, Sczesny S, Blaut M, Braune A. 2013. Contribution of gut bacteria to the metabolism of cyanidin 3-glucoside in human microbiota-associated rats. Br. J. Nutr. 109:81433–41
    [Google Scholar]
  54. 54. 
    Herles C, Braune A, Blaut M. 2004. First bacterial chalcone isomerase isolated from Eubacterium ramulus. Arch. Microbiol 181:6428–34
    [Google Scholar]
  55. 55. 
    Hidalgo M, Oruna-Concha MJ, Kolida S, Walton GE, Kallithraka S et al. 2012. Metabolism of anthocyanins by human gut microflora and their influence on gut bacterial growth. J. Agric. Food Chem. 60:153882–90
    [Google Scholar]
  56. 56. 
    Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, Swarts HJM, van Vliet M et al. 2015. Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice. Genes Nutr 10:23
    [Google Scholar]
  57. 57. 
    Hollman PCH. 2004. Absorption, bioavailability, and metabolism of flavonoids. Pharm. Biol. 42:Suppl. 174–83
    [Google Scholar]
  58. 58. 
    Hur H-G, Beger RD, Heinze TM, Lay JO, Freeman JP et al. 2002. Isolation of an anaerobic intestinal bacterium capable of cleaving the C-ring of the isoflavonoid daidzein. Arch. Microbiol. 178:18–12
    [Google Scholar]
  59. 59. 
    Ivey KL, Chan AT, Izard J, Cassidy A, Rogers GB, Rimm EB. 2019. Role of dietary flavonoid compounds in driving patterns of microbial community assembly. mBio 10:5e01205-19
    [Google Scholar]
  60. 60. 
    Jaganath IB, Mullen W, Edwards CA, Crozier A. 2006. The relative contribution of the small and large intestine to the absorption and metabolism of rutin in man. Free Radic. Res. 40:101035–46
    [Google Scholar]
  61. 61. 
    Jin L, Piao ZH, Sun S, Liu B, Kim GR et al. 2017. Gallic acid reduces blood pressure and attenuates oxidative stress and cardiac hypertrophy in spontaneously hypertensive rats. Sci. Rep. 7:15607
    [Google Scholar]
  62. 62. 
    Jung Y, Park J, Kim H-L, Sim J-E, Youn D-H et al. 2018. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro. FASEB J 32:31388–402
    [Google Scholar]
  63. 63. 
    Kay CD. 2010. The future of flavonoid research. Br. J. Nutr. 104:Suppl. 3S91–91
    [Google Scholar]
  64. 64. 
    Kay CD, Clifford MN, Mena P, McDougall GJ, Andres-Lacueva C et al. 2020. Recommendations for standardizing nomenclature for dietary (poly)phenol catabolites. Am. J. Clin. Nutr. 112:41051–68
    [Google Scholar]
  65. 65. 
    Keppler K, Humpf H-U. 2005. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorg. Med. Chem. 13:175195–205
    [Google Scholar]
  66. 66. 
    Kirk EP, Klein S. 2009. Pathogenesis and pathophysiology of the cardiometabolic syndrome. J. Clin. Hypertens. 11:12761–65
    [Google Scholar]
  67. 67. 
    Koeth RA, Wang Z, Levison BS, Buffa JA, Org E et al. 2013. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19:5576–85
    [Google Scholar]
  68. 68. 
    Koh A, Molinaro A, Ståhlman M, Khan MT, Schmidt C et al. 2018. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175:4947–61.e17
    [Google Scholar]
  69. 69. 
    Kolodziejczyk AA, Zheng D, Elinav E. 2019. Diet-microbiota interactions and personalized nutrition. Nat. Rev. Microbiol. 17:12742–53
    [Google Scholar]
  70. 70. 
    Kris-Etherton PM, Lefevre M, Beecher GR, Gross MD, Keen CL, Etherton TD. 2004. Bioactive compounds in nutrition and health-research methodologies for establishing biological function: the antioxidant and anti-inflammatory effects of flavonoids on atherosclerosis. Annu. Rev. Nutr. 24:511–38
    [Google Scholar]
  71. 71. 
    Kumar S, Pandey AK. 2013. Chemistry and biological activities of flavonoids: an overview. Sci. World J. 2013 162750
    [Google Scholar]
  72. 72. 
    Lang S, Schnabl B. 2020. Microbiota and fatty liver disease—the known, the unknown, and the future. Cell Host Microbe 28:2233–44
    [Google Scholar]
  73. 73. 
    Lee SK. 2018. Sex as an important biological variable in biomedical research. BMB Rep 51:4167–73
    [Google Scholar]
  74. 74. 
    Liao C-C, Ou T-T, Wu C-H, Wang C-J. 2013. Prevention of diet-induced hyperlipidemia and obesity by caffeic acid in C57BL/6 mice through regulation of hepatic lipogenesis gene expression. J. Agric. Food Chem. 61:4611082–88
    [Google Scholar]
  75. 75. 
    Liu W-H, Lin C-C, Wang Z-H, Mong M-C, Yin M-C. 2010. Effects of protocatechuic acid on trans fat induced hepatic steatosis in mice. J. Agric. Food Chem. 58:1810247–52
    [Google Scholar]
  76. 76. 
    Manach C, Milenkovic D, Van de Wiele T, Rodriguez-Mateos A, de Roos B et al. 2017. Addressing the inter-individual variation in response to consumption of plant food bioactives: towards a better understanding of their role in healthy aging and cardiometabolic risk reduction. Mol. Nutr. Food Res. 61:61600557
    [Google Scholar]
  77. 77. 
    Manach C, Williamson G, Morand C, Scalbert A, Rémésy C. 2005. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 81:1230S–42S
    [Google Scholar]
  78. 78. 
    Márquez Campos E, Stehle P, Simon M-C 2019. Microbial metabolites of flavan-3-ols and their biological activity. Nutrients 11:102260
    [Google Scholar]
  79. 79. 
    Meselhy MR, Nakamura N, Hattori M. 1997. Biotransformation of (−)-epicatechin 3-O-gallate by human intestinal bacteria. Chem. Pharm. Bull. 45:5888–93
    [Google Scholar]
  80. 80. 
    Miyake Y, Yamamoto K, Osawa T. 1997. Metabolism of antioxidant in lemon fruit (Citrus limon BURM. f.) by human intestinal bacteria. J. Agric. Food Chem. 45:103738–42
    [Google Scholar]
  81. 81. 
    Monagas M, Urpi-Sarda M, Sánchez-Patán F, Llorach R, Garrido I et al. 2010. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food Funct 1:3233–53
    [Google Scholar]
  82. 82. 
    Morrow NM, Burke AC, Samsoondar JP, Seigel KE, Wang A et al. 2020. The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK. J. Lipid Res. 61:3387–402
    [Google Scholar]
  83. 83. 
    Mozaffarian D. 2016. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity—a comprehensive review. Circulation 133:2187–225
    [Google Scholar]
  84. 84. 
    Najmanová I, Pourová J, Vopršalová M, Pilařová V, Semecký V et al. 2016. Flavonoid metabolite 3-(3-hydroxyphenyl)propionic acid formed by human microflora decreases arterial blood pressure in rats. Mol. Nutr. Food Res. 60:5981–91
    [Google Scholar]
  85. 85. 
    Nemet I, Saha PP, Gupta N, Zhu W, Romano KA et al. 2020. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell 180:5862–77.e22
    [Google Scholar]
  86. 86. 
    Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM et al. 2004. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27:1256–63
    [Google Scholar]
  87. 87. 
    Neveu V, Perez-Jiménez J, Vos F, Crespy V, du Chaffaut L et al. 2010. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database 2010 bap024
    [Google Scholar]
  88. 88. 
    Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S et al. 2008. Comparison of pioglitazone versus glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 299:131561–73
    [Google Scholar]
  89. 89. 
    Ohue-Kitano R, Taira S, Watanabe K, Masujima Y, Kuboshima T et al. 2019. 3-(4-hydroxy-3-methoxyphenyl)propionic acid produced from 4-hydroxy-3-methoxycinnamic acid by gut microbiota improves host metabolic condition in diet-induced obese mice. Nutrients 11:51036
    [Google Scholar]
  90. 90. 
    Orabi D, Osborn LJ, Fung K, Aucejo F, Choucair I et al. 2020. A novel surgical method for continuous intra-portal infusion of gut microbial metabolites in mice. bioRxiv 2020.10.29.360628. https://doi.org/10.1101/2020.10.29.360628
    [Crossref]
  91. 91. 
    Ormazabal P, Scazzocchio B, Varì R, Santangelo C, D'Archivio M et al. 2018. Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B. Int. J. Obes. 42:122012–21
    [Google Scholar]
  92. 92. 
    Ottaviani JI, Borges G, Momma TY, Spencer JPE, Keen CL et al. 2016. The metabolome of [2-14C](−)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci. Rep. 6:29034
    [Google Scholar]
  93. 93. 
    Panche AN, Diwan AD, Chandra SR. 2016. Flavonoids: an overview. J. Nutr. Sci. 5:e47
    [Google Scholar]
  94. 94. 
    Pathak P, Helsley RN, Brown AL, Buffa JA, Choucair I et al. 2020. Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism. Am. J. Physiol. Heart Circ. Physiol. 318:6H1474–1474
    [Google Scholar]
  95. 95. 
    Peng X, Zhang Z, Zhang N, Liu L, Li S, Wei H 2014. In vitro catabolism of quercetin by human fecal bacteria and the antioxidant capacity of its catabolites. Food Nutr. Res. 58:123406
    [Google Scholar]
  96. 96. 
    Pereira-Caro G, Fernández-Quirós B, Ludwig IA, Pradas I, Crozier A, Moreno-Rojas JM. 2018. Catabolism of citrus flavanones by the probiotics Bifidobacterium longum and Lactobacillus rhamnosus. Eur. J. Nutr. 57:1231–42
    [Google Scholar]
  97. 97. 
    Pond SM, Tozer TN. 1984. First-pass elimination basic concepts and clinical consequences. Clin. Pharmacokinet. 9:11–25
    [Google Scholar]
  98. 98. 
    Rechner AR, Smith MA, Kuhnle G, Gibson GR, Debnam ES et al. 2004. Colonic metabolism of dietary polyphenols: influence of structure on microbial fermentation products. Free Radic. Biol. Med. 36:2212–25
    [Google Scholar]
  99. 99. 
    Rena G, Hardie DG, Pearson ER. 2017. The mechanisms of action of metformin. Diabetologia 60:91577–85
    [Google Scholar]
  100. 100. 
    Rice-Evans CA, Miller NJ, Paganga G. 1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20:7933–56
    [Google Scholar]
  101. 101. 
    Rienks J, Barbaresko J, Nöthlings U. 2017. Association of polyphenol biomarkers with cardiovascular disease and mortality risk: a systematic review and meta-analysis of observational studies. Nutrients 9:4415
    [Google Scholar]
  102. 102. 
    Rizos CV, Elisaf MS, Mikhailidis DP, Liberopoulos EN. 2009. How safe is the use of thiazolidinediones in clinical practice?. Expert Opin. Drug Saf. 8:115–32
    [Google Scholar]
  103. 103. 
    Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z et al. 2018. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24:91407–17
    [Google Scholar]
  104. 104. 
    Roowi S, Stalmach A, Mullen W, Lean MEJ, Edwards CA, Crozier A. 2010. Green tea flavan-3-ols: colonic degradation and urinary excretion of catabolites by humans. J. Agric. Food Chem. 58:21296–304
    [Google Scholar]
  105. 105. 
    Rothwell JA, Perez-Jimenez J, Neveu V, Medina-Remón A, M'Hiri N et al. 2013. Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content. Database 2013:bat070
    [Google Scholar]
  106. 106. 
    Salomone F, Ivancovsky-Wajcman D, Fliss-Isakov N, Webb M, Grosso G et al. 2020. Higher phenolic acid intake independently associates with lower prevalence of insulin resistance and non-alcoholic fatty liver disease. JHEP Rep. 2:2100069
    [Google Scholar]
  107. 107. 
    Sánchez-Patán F, Cueva C, Monagas M, Walton GE, Gibson GR et al. 2012. Gut microbial catabolism of grape seed flavan-3-ols by human faecal microbiota. Targetted analysis of precursor compounds, intermediate metabolites and end-products. Food Chem 131:1337–47
    [Google Scholar]
  108. 108. 
    Schneider H, Blaut M. 2000. Anaerobic degradation of flavonoids by Eubacterium ramulus. Arch. Microbiol. 173:171–75
    [Google Scholar]
  109. 109. 
    Schneider H, Simmering R, Hartmann L, Pforte H, Blaut M. 2000. Degradation of quercetin-3-glucoside in gnotobiotic rats associated with human intestinal bacteria. J. Appl. Microbiol. 89:61027–37
    [Google Scholar]
  110. 110. 
    Schoefer L, Braune A, Blaut M. 2004. Cloning and expression of a phloretin hydrolase gene from Eubacterium ramulus and characterization of the recombinant enzyme. Appl. Environ. Microbiol. 70:106131–37
    [Google Scholar]
  111. 111. 
    Schoefer L, Mohan R, Schwiertz A, Braune A, Blaut M. 2003. Anaerobic degradation of flavonoids by Clostridium orbiscindens. Appl. Environ. Microbiol. 69:105849–54
    [Google Scholar]
  112. 112. 
    Schröder C, Matthies A, Engst W, Blaut M, Braune A. 2013. Identification and expression of genes involved in the conversion of daidzein and genistein by the equol-forming bacterium Slackia isoflavoniconvertens. Appl. Environ. Microbiol. 79:113494–502
    [Google Scholar]
  113. 113. 
    Sekikawa A, Ihara M, Lopez O, Kakuta C, Lopresti B et al. 2019. Effect of S-equol and soy isoflavones on heart and brain. Curr. Cardiol. Rev. 15:2114–35
    [Google Scholar]
  114. 114. 
    Serra A, Macià A, Romero M-P, Reguant J, Ortega N, Motilva M-J. 2012. Metabolic pathways of the colonic metabolism of flavonoids (flavonols, flavones and flavanones) and phenolic acids. Food Chem 130:2383–93
    [Google Scholar]
  115. 115. 
    Setchell KDR, Clerici C. 2010. Equol: history, chemistry, and formation. J. Nutr. 140:71355S–62S
    [Google Scholar]
  116. 116. 
    Setchell KDR, Clerici C, Lephart ED, Cole SJ, Heenan C et al. 2005. S-equol, a potent ligand for estrogen receptor β, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am. J. Clin. Nutr. 81:51072–79
    [Google Scholar]
  117. 117. 
    Setchell KDR, Cole SJ. 2006. Method of defining equol-producer status and its frequency among vegetarians. J. Nutr. 136:82188–93
    [Google Scholar]
  118. 118. 
    Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C et al. 2011. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat. Genet. 43:9883–86
    [Google Scholar]
  119. 119. 
    Sonnenburg JL, Bäckhed F. 2016. Diet-microbiota interactions as moderators of human metabolism. Nature 535:761056–64
    [Google Scholar]
  120. 120. 
    Sousa JN, Paraíso AF, Andrade JMO, Lelis DF, Santos EM et al. 2020. Oral gallic acid improve liver steatosis and metabolism modulating hepatic lipogenic markers in obese mice. Exp. Gerontol. 134:110881
    [Google Scholar]
  121. 121. 
    Suez J, Elinav E. 2017. The path towards microbiome-based metabolite treatment. Nat. Microbiol. 2:617075
    [Google Scholar]
  122. 122. 
    Sun R, Kang X, Zhao Y, Wang Z, Wang R et al. 2020. Sirtuin 3-mediated deacetylation of acyl-CoA synthetase family member 3 by protocatechuic acid attenuates non-alcoholic fatty liver disease. Br. J. Pharmacol. 177:184166–80
    [Google Scholar]
  123. 123. 
    Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB et al. 2013. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368:171575–84
    [Google Scholar]
  124. 124. 
    Thaiss CA, Itav S, Rothschild D, Meijer MT, Levy M et al. 2016. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540:7634544–51
    [Google Scholar]
  125. 125. 
    Thilakarathna SH, Rupasinghe HPV. 2013. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5:93367
    [Google Scholar]
  126. 126. 
    Trošt K, Ulaszewska MM, Stanstrup J, Albanese D, De Filippo C et al. 2018. Host: microbiome co-metabolic processing of dietary polyphenols – an acute, single blinded, cross-over study with different doses of apple polyphenols in healthy subjects. Food Res. Int. 112:108–28
    [Google Scholar]
  127. 127. 
    UK Prospect. Diabetes Study (UKPDS) Group 1998. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:9131854–65
    [Google Scholar]
  128. 128. 
    Vitaglione P, Donnarumma G, Napolitano A, Galvano F, Gallo A et al. 2007. Protocatechuic acid is the major human metabolite of cyanidin-glucosides. J. Nutr. 137:92043–48
    [Google Scholar]
  129. 129. 
    Wang D, Wei X, Yan X, Jin T, Ling W 2010. Protocatechuic acid, a metabolite of anthocyanins, inhibits monocyte adhesion and reduces atherosclerosis in apolipoprotein E-deficient mice. J. Agric. Food Chem. 58:2412722–28
    [Google Scholar]
  130. 130. 
    Wang D, Xia M, Yan X, Li D, Wang L et al. 2012. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ. Res. 111:8967–81
    [Google Scholar]
  131. 131. 
    Wang P, Gao J, Ke W, Wang J, Li D et al. 2020. Resveratrol reduces obesity in high-fat diet-fed mice via modulating the composition and metabolic function of the gut microbiota. Free Radic. Biol. Med. 156:83–98
    [Google Scholar]
  132. 132. 
    Wang X, Ouyang YY, Liu J, Zhao G. 2014. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies. Br. J. Nutr. 111:11–11
    [Google Scholar]
  133. 133. 
    Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS et al. 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:734157–63
    [Google Scholar]
  134. 134. 
    Warner EF, Zhang Q, Raheem KS, O'Hagan D, O'Connell MA, Kay CD 2016. Common phenolic metabolites of flavonoids, but not their unmetabolized precursors, reduce the secretion of vascular cellular adhesion molecules by human endothelial cells. J. Nutr. 146:3465–73
    [Google Scholar]
  135. 135. 
    Wei Y, Gao J, Kou Y, Liu M, Meng L et al. 2020. The intestinal microbial metabolite desaminotyrosine is an anti-inflammatory molecule that modulates local and systemic immune homeostasis. FASEB J 34:1216117–28
    [Google Scholar]
  136. 136. 
    WHO (World Health Organ.) 2000. Obesity: preventing and managing the global epidemic. Report of a WHO consultation WHO Tech. Rep. Ser. 894 WHO, Geneva:
    [Google Scholar]
  137. 137. 
    Williamson G, Kay CD, Crozier A. 2018. The bioavailability, transport, and bioactivity of dietary flavonoids: a review from a historical perspective. Compr. Rev. Food Sci. Food Saf. 17:51054–112
    [Google Scholar]
  138. 138. 
    Winter J, Moore LH, Dowell VR, Bokkenheuser VD. 1989. C-ring cleavage of flavonoids by human intestinal bacteria. Appl. Environ. Microbiol. 55:51203–8
    [Google Scholar]
  139. 139. 
    Winter J, Popoff MR, Grimont P, Bokkenheuser VD. 1991. Clostridium orbiscindens sp. nov., a human intestinal bacterium capable of cleaving the flavonoid C-ring. Int. J. Syst. Bacteriol. 41:3355–57
    [Google Scholar]
  140. 140. 
    Xu J, Ge J, He X, Sheng Y, Zheng S et al. 2020. Caffeic acid reduces body weight by regulating gut microbiota in diet-induced-obese mice. J. Funct. Foods 74:104061
    [Google Scholar]
  141. 141. 
    Yin J, Yang L, Mou L, Dong K, Jiang J et al. 2019. A green tea-triggered genetic control system for treating diabetes in mice and monkeys. Sci. Transl. Med. 11:515eaav8826
    [Google Scholar]
  142. 142. 
    Zheng J, Li Q, He L, Weng H, Su D et al. 2020. Protocatechuic acid inhibits vulnerable atherosclerotic lesion progression in older Apoe−/− mice. J. Nutr. 150:51167–77
    [Google Scholar]
  143. 143. 
    Zhu W, Gregory JC, Org E, Buffa JA, Gupta N et al. 2016. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165:1111–24
    [Google Scholar]
  144. 144. 
    Zmora N, Suez J, Elinav E. 2019. You are what you eat: diet, health and the gut microbiota. Nat. Rev. Gastroenterol. Hepatol. 16:135–56
    [Google Scholar]
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