Flavonoid metabolism: the interaction of metabolites and gut microbiota

References

• Galleano M, Calabro V, Prince PD, et al. Flavonoids and metabolic syndrome. Ann N Y Acad Sci. 2012;1259:87–94.10.1111/nyas.2012.1259.issue-1
   PubMed Web of Science ®Google Scholar
• Amiot MJ, Riva C, Vinet A. Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes Rev. 2016;17(7):573–586.10.1111/obr.v17.7
   PubMed Web of Science ®Google Scholar
• Hertog MG, Feskens EJ, Hollman PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342(8878):1007–1011.10.1016/0140-6736(93)92876-U
   PubMed Web of Science ®Google Scholar
• Knekt P, Jarvinen R, Reunanen A, et al. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312(7029):478–481.10.1136/bmj.312.7029.478
   PubMed Web of Science ®Google Scholar
• Siasos G, Tousoulis D, Tsigkou V, et al. Flavonoids in atherosclerosis: an overview of their mechanisms of action. Curr Med Chem. 2013;20(21):2641–2660.10.2174/0929867311320210003
   PubMed Web of Science ®Google Scholar
• Sacco SM, Horcajada MN, Offord E. Phytonutrients for bone health during ageing. Br J Clin Pharmacol. 2013;75(3):697–707.10.1111/bcp.12033
   PubMed Web of Science ®Google Scholar
• Formica JV, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food Chem Toxicol. 1995;33(12):1061–1080.10.1016/0278-6915(95)00077-1
   PubMed Web of Science ®Google Scholar
• Manach C, Scalbert A, Morand C, et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727–747.10.1093/ajcn/79.5.727
   PubMed Web of Science ®Google Scholar
• Manach C, Williamson G, Morand C, et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1 Suppl):230S–242S.10.1093/ajcn/81.1.230S
   PubMed Web of Science ®Google Scholar
• Morand C, Manach C, Crespy V, et al. Quercetin 3-O-β-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Radic Res. 2000;33(5):667–676.10.1080/10715760000301181
   PubMed Web of Science ®Google Scholar
• Day AJ, Mellon F, Barron D, et al. Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radic Res. 2001;35(6):941–952.10.1080/10715760100301441
   PubMed Web of Science ®Google Scholar
• Sesink AL, O’Leary KA, Hollman PC. Quercetin glucuronides but not glucosides are present in human plasma after consumption of quercetin-3-glucoside or quercetin-4′-glucoside. J Nutr. 2001;131(7):1938–1941.10.1093/jn/131.7.1938
   PubMed Web of Science ®Google Scholar
• Day AJ, Gee JM, DuPont MS, et al. Absorption of quercetin-3-glucoside and quercetin-4’-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter. Biochem Pharmacol. 2003;65(7):1199–1206.10.1016/S0006-2952(03)00039-X
   PubMed Web of Science ®Google Scholar
• Day AJ, Canada FJ, Diaz JC, et al. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett. 2000;468(2–3):166–170.10.1016/S0014-5793(00)01211-4
   PubMed Web of Science ®Google Scholar
• Day AJ, DuPont MS, Ridley S, et al. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity. FEBS Lett. 1998;436(1):71–75.10.1016/S0014-5793(98)01101-6
   PubMed Web of Science ®Google Scholar
• Walgren RA, Lin JT, Kinne RK, et al. Cellular uptake of dietary flavonoid quercetin 4’-β-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol Exp Ther. 2000;294(3):837–843.
   PubMed Web of Science ®Google Scholar
• Murota K, Shimizu S, Chujo H, et al. Efficiency of absorption and metabolic conversion of quercetin and its glucosides in human intestinal cell line caco-2. Arch Biochem Biophys. 2000;384(2):391–397.10.1006/abbi.2000.2123
   PubMed Web of Science ®Google Scholar
• Olthof MR, Hollman PC, Vree TB, et al. Bioavailabilities of quercetin-3-glucoside and quercetin-4′-glucoside do not differ in humans. J Nutr. 2000;130(5):1200–1203.10.1093/jn/130.5.1200
   PubMed Web of Science ®Google Scholar
• Tamura A, Shiomi T, Hachiya S, et al. Low activities of intestinal lactase suppress the early phase absorption of soy isoflavones in Japanese adults. Clin Nutr. 2008;27(2):248–253.10.1016/j.clnu.2007.12.001
   PubMed Web of Science ®Google Scholar
• Islam MA, Punt A, Spenkelink B, et al. Conversion of major soy isoflavone glucosides and aglycones in in vitro intestinal models. Mol Nutr Food Res. 2014;58(3):503–515.10.1002/mnfr.201300390
   PubMed Web of Science ®Google Scholar
• Shi J, Zheng H, Yu J, et al. SGLT-1 transport and deglycosylation inside intestinal cells are key steps in the absorption and disposition of calycosin-7-O-β-d-glucoside in rats. Drug Metab Dispos. 2016;44(3):283–296.10.1124/dmd.115.067009
   PubMed Web of Science ®Google Scholar
• Erlund I, Kosonen T, Alfthan G, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol. 2000;56(8):545–553.10.1007/s002280000197
   PubMed Web of Science ®Google Scholar
• Jaganath IB, Mullen W, Lean ME, et al. In vitro catabolism of rutin by human fecal bacteria and the antioxidant capacity of its catabolites. Free Radic Biol Med. 2009;47(8):1180–1189.10.1016/j.freeradbiomed.2009.07.031
   PubMed Web of Science ®Google Scholar
• Rafii F. The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol. Metabolites. 2015;5(1):56–73.10.3390/metabo5010056
   PubMed Web of Science ®Google Scholar
• Duda-Chodak A, Tarko T, Satora P, et al. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review. Eur J Nutr. 2015;54(3):325–341.10.1007/s00394-015-0852-y
   PubMed Web of Science ®Google Scholar
• van der Woude H, Boersma MG, Vervoort J, et al. Identification of 14 quercetin phase II mono- and mixed conjugates and their formation by rat and human phase II in vitro model systems. Chem Res Toxicol. 2004;17(11):1520–1530.10.1021/tx049826v
   PubMed Web of Science ®Google Scholar
• Hong YJ, Mitchell AE. Identification of glutathione-related quercetin metabolites in humans. Chem Res Toxicol. 2006;19(11):1525–1532.10.1021/tx0601758
   PubMed Web of Science ®Google Scholar
• Piskula MK, Terao J. Accumulation of (−)-epicatechin metabolites in rat plasma after oral administration and distribution of conjugation enzymes in rat tissues. J Nutr. 1998;128(7):1172–1178.10.1093/jn/128.7.1172
   PubMed Web of Science ®Google Scholar
• Mullen W, Edwards CA, Crozier A. Absorption, excretion and metabolite profiling of methyl-, glucuronyl-, glucosyl- and sulpho-conjugates of quercetin in human plasma and urine after ingestion of onions. Br J Nutr. 2006;96(1):107–116.10.1079/BJN20061809
   PubMed Web of Science ®Google Scholar
• O’Leary KA, Day AJ, Needs PW, et al. Metabolism of quercetin-7- and quercetin-3-glucuronides by an in vitro hepatic model: the role of human β-glucuronidase, sulfotransferase, catechol-O-methyltransferase and multi-resistant protein 2 (MRP2) in flavonoid metabolism. Biochem Pharmacol. 2003;65(3):479–491.10.1016/S0006-2952(02)01510-1
   PubMed Web of Science ®Google Scholar
• Crozier A, Del Rio D, Clifford MN. Bioavailability of dietary flavonoids and phenolic compounds. Mol Aspects Med. 2010;31(6):446–467.10.1016/j.mam.2010.09.007
   PubMed Web of Science ®Google Scholar
• Clarke DB, Lloyd AS, Botting NP, et al. Measurement of intact sulfate and glucuronide phytoestrogen conjugates in human urine using isotope dilution liquid chromatography-tandem mass spectrometry with [13C3]isoflavone internal standards. Anal Biochem. 2002;309(1):158–172.10.1016/S0003-2697(02)00275-0
   PubMed Web of Science ®Google Scholar
• Nakamura T, Murota K, Kumamoto S, et al. Plasma metabolites of dietary flavonoids after combination meal consumption with onion and tofu in humans. Mol Nutr Food Res. 2014;58(2):310–317.10.1002/mnfr.v58.2
   PubMed Web of Science ®Google Scholar
• Arts IC, Sesink AL, Faassen-Peters M, et al. The type of sugar moiety is a major determinant of the small intestinal uptake and subsequent biliary excretion of dietary quercetin glycosides. Br J Nutr. 2004;91(6):841–847.10.1079/BJN20041123
   PubMed Web of Science ®Google Scholar
• Adlercreutz H, Hockerstedt K, Bannwart C, et al. Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG). J Steroid Biochem. 1987;27(4–6):1135–1144.10.1016/0022-4731(87)90200-7
   PubMedGoogle Scholar
• Chen J, Wang S, Jia X, et al. Disposition of flavonoids via recycling: comparison of intestinal versus hepatic disposition. Drug Metab Dispos. 2005;33(12):1777–1784.
   PubMed Web of Science ®Google Scholar
• Murota K, Terao J. Quercetin appears in the lymph of unanesthetized rats as its phase II metabolites after administered into the stomach. FEBS Lett. 2005;579(24):5343–5346.10.1016/j.febslet.2005.08.060
   PubMed Web of Science ®Google Scholar
• Murota K, Cermak R, Terao J, et al. Influence of fatty acid patterns on the intestinal absorption pathway of quercetin in thoracic lymph duct-cannulated rats. Br J Nutr. 2013;109(12):2147–2153.10.1017/S0007114512004564
   PubMed Web of Science ®Google Scholar
• de Boer VC, Dihal AA, van der Woude H, et al. Tissue distribution of quercetin in rats and pigs. J Nutr. 2005;135(7):1718–1725.10.1093/jn/135.7.1718
   PubMed Web of Science ®Google Scholar
• Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995;155(4):381–386.10.1001/archinte.1995.00430040053006
   PubMed Web of Science ®Google Scholar
• Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992;339(8808):1523–1526.10.1016/0140-6736(92)91277-F
   PubMed Web of Science ®Google Scholar
• Yamamoto N, Moon JH, Tsushida T, et al. Inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein. Arch Biochem Biophys. 1999;372(2):347–354.10.1006/abbi.1999.1516
   PubMed Web of Science ®Google Scholar
• Murota K, Hotta A, Ido H, et al. Antioxidant capacity of albumin-bound quercetin metabolites after onion consumption in humans. J Med Invest. 2007;54(3–4):370–374.10.2152/jmi.54.370
   PubMedGoogle Scholar
• Moon JH, Nakata R, Oshima S, et al. Accumulation of quercetin conjugates in blood plasma after the short-term ingestion of onion by women. Am J Physiol Regul Integr Comp Physiol. 2000;279(2):R461–467.10.1152/ajpregu.2000.279.2.R461
   PubMed Web of Science ®Google Scholar
• Murota K, Mitsukuni Y, Ichikawa M, et al. Quercetin-4′-glucoside is more potent than quercetin-3-glucoside in protection of rat intestinal mucosa homogenates against iron ion-induced lipid peroxidation. J Agric Food Chem. 2004;52(7):1907–1912.10.1021/jf035151a
   PubMed Web of Science ®Google Scholar
• Day AJ, Bao Y, Morgan MRA, et al. Conjugation position of quercetin glucuronides and effect on biological activity. Free Radic Biol Med. 2000;29(12):1234–1243.10.1016/S0891-5849(00)00416-0
   PubMed Web of Science ®Google Scholar
• Gimenez-Bastida JA, Gonzalez-Sarrias A, Vallejo F, et al. Hesperetin and its sulfate and glucuronide metabolites inhibit TNF-α induced human aortic endothelial cell migration and decrease plasminogen activator inhibitor-1 (PAI-1) levels. Food Func. 2016;7(1):118–126.10.1039/C5FO00771B
   PubMed Web of Science ®Google Scholar
• Kinjo J, Tsuchihashi R, Morito K, et al. Interactions of phytoestrogens with estrogen receptors α and β (III). Estrogenic activities of soy isoflavone aglycones and their metabolites isolated from human urine. Biol Pharm Bull. 2004;27(2):185–188.10.1248/bpb.27.185
   PubMed Web of Science ®Google Scholar
• Pugazhendhi D, Watson KA, Mills S, et al. Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells. J Endocrinol. 2008;197(3):503–515.10.1677/JOE-07-0384
   PubMed Web of Science ®Google Scholar
• Shimoi K, Saka N, Nozawa R, et al. Deglucuronidation of a flavonoid, luteolin monoglucuronide, during inflammation. Drug Metab Dispos. 2001;29(12):1521–1524.
   PubMed Web of Science ®Google Scholar
• Kawai Y, Nishikawa T, Shiba Y, et al. Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids. J Biol Chem. 2008;283(14):9424–9434.10.1074/jbc.M706571200
   PubMed Web of Science ®Google Scholar
• Kawai Y. beta-Glucuronidase activity and mitochondrial dysfunction: the sites where flavonoid glucuronides act as anti-inflammatory agents. J Clin Biochem Nutr. 2014;54(3):145–150.10.3164/jcbn.14-9
   PubMed Web of Science ®Google Scholar
• Ishisaka A, Kawabata K, Miki S, et al. Mitochondrial dysfunction leads to deconjugation of quercetin glucuronides in inflammatory macrophages. PLoS One. 2013;8(11):e80843.10.1371/journal.pone.0080843
   PubMed Web of Science ®Google Scholar
• Lodi F, Jimenez R, Moreno L, et al. Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta. Atherosclerosis. 2009;204(1):34–39.10.1016/j.atherosclerosis.2008.08.007
   PubMed Web of Science ®Google Scholar
• Kaneko A, Matsumoto T, Matsubara Y, et al. Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β-glucuronidase in macrophages. Immun Inflamm Dis. 2017;5(3):265–279.10.1002/iid3.163
   PubMed Web of Science ®Google Scholar
• Menendez C, Duenas M, Galindo P, et al. Vascular deconjugation of quercetin glucuronide: the flavonoid paradox revealed? Mol Nutr Food Res. 2011;55(12):1780–1790.10.1002/mnfr.v55.12
   PubMed Web of Science ®Google Scholar
• Ikushiro S, Nishikawa M, Masuyama Y, et al. Biosynthesis of drug glucuronide metabolites in the budding Yeast Saccharomyces cerevisiae. Mol Pharm. 2016;13(7):2274–2282.10.1021/acs.molpharmaceut.5b00954
   PubMedGoogle Scholar
• Hervert-Hernández D, Goñi I. Dietary polyphenols and human gut microbiota: a review. Food Rev Int. 2011;27(2):154–169.10.1080/87559129.2010.535233
   Web of Science ®Google Scholar
• Högger P. Nutrition-derived bioactive metabolites produced by gut microbiota and their potential impact on human health. Nutr Med. 2013;1(1):1.
   Google Scholar
• Meng X, Sang S, Zhu N, et al. Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats. Chem Res Toxicol. 2002;15(8):1042–1050.10.1021/tx010184a
   PubMed Web of Science ®Google Scholar
• Takagaki A, Kato Y, Nanjo F. Isolation and characterization of rat intestinal bacteria involved in biotransformation of (−)-epigallocatechin. Arch Microbiol. 2014;196(10):681–695.10.1007/s00203-014-1006-y
   PubMed Web of Science ®Google Scholar
• Appeldoorn MM, Vincken J-P, Aura A-M, et al. Procyanidin dimers are metabolized by human microbiota with 2-(3,4-dihydroxyphenyl)acetic acid and 5-(3,4-dihydroxyphenyl)-γ-valerolactone as the major metabolites. J Agric Food Chem. 2009;57(3):1084–1092.10.1021/jf803059z
   PubMed Web of Science ®Google Scholar
• Faria A, Fernandes I, Norberto S, et al. Interplay between anthocyanins and gut microbiota. J Agric Food Chem. 2014;62(29):6898–6902.10.1021/jf501808a
   PubMed Web of Science ®Google Scholar
• Konishi Y, Kobayashi S. Microbial metabolites of ingested caffeic acid are absorbed by the monocarboxylic acid transporter (MCT) in intestinal caco-2 cell monolayers. J Agric Food Chem. 2004;52(21):6418–6424.10.1021/jf049560y
   PubMed Web of Science ®Google Scholar
• Tsushida T, Suzuki M. Isolation of flavonoid-glycosides in onion and identification by chemical synthesis of the glycosides (flavonoids in fruits and vegetables part 1) (in Japanese). J Jpn Soc Food Sci Technol. 1995;42(2):100–108.10.3136/nskkk.42.100
   Web of Science ®Google Scholar
• Mullen W, Rouanet J-M, Auger C, et al. Bioavailability of [2-14C]Quercetin-4ʹ-glucoside in Rats. J Agric Food Chem. 2008;56(24):12127–12137.10.1021/jf802754s
   PubMed Web of Science ®Google Scholar
• Rios LY, Gonthier M-P, Rémésy C, et al. Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects. Am J Clin Nutr. 2003;77(4):912–918.10.1093/ajcn/77.4.912
   PubMed Web of Science ®Google Scholar
• Aura AM, O’Leary KA, Williamson G, et al. Quercetin derivatives are deconjugated and converted to hydroxyphenylacetic acids but not methylated by human fecal flora in vitro. J Agric Food Chem. 2002;50(6):1725–1730.10.1021/jf0108056
   PubMed Web of Science ®Google Scholar
• Yang J, Qian D, Guo J, et al. Identification of the major metabolites of hyperoside produced by the human intestinal bacteria using the ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. J Ethnopharmacol. 2013;147(1):174–179.10.1016/j.jep.2013.02.029
   PubMed Web of Science ®Google Scholar
• Peng X, Zhang Z, Zhang N, et al. In vitro catabolism of quercetin by human fecal bacteria and the antioxidant capacity of its catabolites. Food Nutr Res. 2014;58(1):23406.10.3402/fnr.v58.23406
   Web of Science ®Google Scholar
• Gesi M, Santinami A, Ruffoli R, et al. Novel aspects of dopamine oxidative metabolism (confounding outcomes take place of certainties). Pharmacol Toxicol. 2001;89(5):217–224.10.1034/j.1600-0773.2001.d01-151.x
   PubMedGoogle Scholar
• Tang Y, Nakashima S, Saiki S, et al. 3,4-Dihydroxyphenylacetic acid is a predominant biologically-active catabolite of quercetin glycosides. Food Res Int. 2016;89(Pt 1):716–723.10.1016/j.foodres.2016.09.034
   PubMedGoogle Scholar
• Monagas M, Khan N, Andrés-Lacueva C, et al. Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. Br J Nutr. 2009;102(2):201–206.10.1017/S0007114508162110
   PubMed Web of Science ®Google Scholar
• Rechner AR, Kroner C. Anthocyanins and colonic metabolites of dietary polyphenols inhibit platelet function. Thromb Res. 2005;116(4):327–334.10.1016/j.thromres.2005.01.002
   PubMed Web of Science ®Google Scholar
• Verzelloni E, Pellacani C, Tagliazucchi D, et al. Antiglycative and neuroprotective activity of colon-derived polyphenol catabolites. Mol Nutr Food Res. 2011;55(Suppl 1):S35–43.10.1002/mnfr.v55.5s
   PubMedGoogle Scholar
• Liu Y, Kurita A, Nakashima S, et al. 3,4-Dihydroxyphenylacetic acid is a potential aldehyde dehydrogenase inducer in murine hepatoma Hepa1c1c7 cells. Biosci Biotechnol Biochem. 2017;81(10):1978–1983.10.1080/09168451.2017.1361809
   PubMed Web of Science ®Google Scholar
• Nakashima S, Liu Z, Yamaguchi Y, et al. A novel tag-free probe for targeting molecules interacting with a flavonoid catabolite. Biochem Biophys Rep. 2016;7:240–245.
   PubMedGoogle Scholar
• Heinonen S, Wähälä K, Adlercreutz H. Identification of isoflavone metabolites dihydrodaidzein, dihydrogenistein, 6ʹ-OH-O-DMA, and cis-4-OH-equol in human urine by gas chromatography–mass spectroscopy using authentic reference compounds. Anal Biochem. 1999;274(2):211–219.10.1006/abio.1999.4279
   PubMed Web of Science ®Google Scholar
• Setchell KDR, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol—a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002;132(12):3577–3584.10.1093/jn/132.12.3577
   PubMed Web of Science ®Google Scholar
• Atkinson C, Frankenfeld CL, Lampe JW. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med. 2005;230(3):155–170.10.1177/153537020523000302
   Web of Science ®Google Scholar
• Ingram D, Sanders K, Kolybaba M, et al. Case-control study of phyto-oestrogens and breast cancer. Lancet. 1997;350(9083):990–994.10.1016/S0140-6736(97)01339-1
   PubMed Web of Science ®Google Scholar
• Heinonen S-M, Hoikkala A, Wähälä K, et al. Metabolism of the soy isoflavones daidzein, genistein and glycitein in human subjects: identification of new metabolites having an intact isoflavonoid skeleton. J Steroid Biochem Mol Biol. 2003;87(4):285–299.10.1016/j.jsbmb.2003.09.003
   PubMed Web of Science ®Google Scholar
• Coldham NG, Darby C, Hows M, et al. Comparative metabolism of genistin by human and rat gut microflora: detection and identification of the end-products of metabolism. Xenobiotica. 2002;32(1):45–62.10.1080/00498250110085809
   PubMed Web of Science ®Google Scholar
• Hur H-G, Rafii F. Biotransformation of the isoflavonoids biochanin A, formononetin, and glycitein by Eubacterium limosum. FEMS Microbiol Lett. 2000;192(1):21–25.10.1111/fml.2000.192.issue-1
   PubMed Web of Science ®Google Scholar
• Setchell KD, Clerici C, Lephart ED, et al. 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. 2005;81(5):1072–1079.10.1093/ajcn/81.5.1072
   PubMed Web of Science ®Google Scholar
• Lundh T. Metabolism of estrogenic isoflavones in domestic animals. Proc Soc Exp Biol Med. 1995;208(1):33–39.10.3181/00379727-208-43828
   PubMed Web of Science ®Google Scholar
• Adlercreutz H, Musey PI, Fotsis T, et al. Identification of lignans and phytoestrogens in urine of chimpanzees. Clin Chim Acta. 1986;158(2):147–154.10.1016/0009-8981(86)90230-5
   PubMed Web of Science ®Google Scholar
• Ohta A, Uehara M, Sakai K, et al. A combination of dietary fructooligosaccharides and isoflavone conjugates increases femoral bone mineral density and equol production in ovariectomized mice. J Nutr. 2002;132(7):2048–2054.10.1093/jn/132.7.2048
   PubMed Web of Science ®Google Scholar
• Kelly GE, Joannou GE, Reeder AY, et al. The variable metabolic response to dietary isoflavones in humans. Proc Soc Exp Biol Med. 1995;208(1):40–43.10.3181/00379727-208-43829
   PubMed Web of Science ®Google Scholar
• Lampe JW, Karr SC, Hutchins AM, et al. Urinary equol excretion with a soy challenge: influence of habitual diet. Proc Soc Exp Biol Med. 1998;217(3):335–339.10.3181/00379727-217-44241
   PubMed Web of Science ®Google Scholar
• Arai Y, Uehara M, Sato Y, et al. Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. J Epidemiol. 2000;10(2):127–135.10.2188/jea.10.127
   PubMedGoogle Scholar
• Frankenfeld CL, McTiernan A, Tworoger SS, et al. Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes. J Steroid Biochem Mol Biol. 2004;88(4):399–408.10.1016/j.jsbmb.2004.01.006
   PubMed Web of Science ®Google Scholar
• Ueno T, Uchiyama S. Identification of the specific intestinal bacteria capable of metabolising soy isoflavone to equol. Ann Nutr Metab. 2001;45(Suppl):114 (abs).
   Google Scholar
• Yokoyama S-i, Oshima K, Nomura I, et al. Complete genomic sequence of the equol-producing bacterium Eggerthella sp. strain YY7918, isolated from adult human intestine. J Bacteriol. 2011;193(19):5570–5571.10.1128/JB.05626-11
   PubMed Web of Science ®Google Scholar
• Maruo T, Sakamoto M, Ito C, et al. Adlercreutzia equolifaciens gen. nov., sp. nov., an equol-producing bacterium isolated from human faeces, and emended description of the genus Eggerthella. Int J Syst Evol Microbiol. 2008;58(Pt 5):1221–1227.10.1099/ijs.0.65404-0
   PubMedGoogle Scholar
• Tamura M, Tsushida T, Shinohara K. Isolation of an isoflavone-metabolizing, Clostridium-like bacterium, strain TM-40, from human faeces. Anaerobe. 2007;13(1):32–35.10.1016/j.anaerobe.2006.10.001
   PubMed Web of Science ®Google Scholar
• Wang XL, Kim HJ, Kang SI, et al. Production of phytoestrogen S-equol from daidzein in mixed culture of two anaerobic bacteria. Arch Microbiol. 2007;187(2):155–160.10.1007/s00203-006-0183-8
   PubMed Web of Science ®Google Scholar
• Decroos K, Vanhemmens S, Cattoir S, et al. Isolation and characterisation of an equol-producing mixed microbial culture from a human faecal sample and its activity under gastrointestinal conditions. Arch Microbiol. 2005;183(1):45–55.10.1007/s00203-004-0747-4
   PubMed Web of Science ®Google Scholar
• Schoefer L, Mohan R, Braune A, et al. Anaerobic C-ring cleavage of genistein and daidzein by Eubacterium ramulus. FEMS Microbiol Lett. 2002;208(2):197–202.10.1111/fml.2002.208.issue-2
   PubMed Web of Science ®Google Scholar
• Blaut Schoefer. Braune. Transformation of flavonoids by intestinal microorganisms. Int J Vitamin Nutr Res. 2003;73(2):79–87.
   PubMed Web of Science ®Google Scholar
• Hur H-G, Beger RD, Heinze TM, et al. Isolation of an anaerobic intestinal bacterium capable of cleaving the C-ring of the isoflavonoid daidzein. Arch Microbiol. 2002;178(1):8–12.10.1007/s00203-002-0414-6
   PubMed Web of Science ®Google Scholar
• Ohtomo T, Uehara M, Peñalvo JL, et al. Comparative activities of daidzein metabolites, equol and O-desmethylangolensin, on bone mineral density and lipid metabolism in ovariectomized mice and in osteoclast cell cultures. Eur J Nutr. 2008;47(5):273–279.10.1007/s00394-008-0723-x
   PubMed Web of Science ®Google Scholar
• Frankenfeld CL. O-Desmethylangolensin: the importance of equol’s lesser known cousin to human health. Adv Nutr. 2011;2(4):317–324.10.3945/an.111.000539
   PubMed Web of Science ®Google Scholar
• Uchiyama S, Ueno T, Suzuki T. Identification of a newly isolated equol-producing lactic acid bacterium from the human feces. J Intest Microbiol. 2007;21(3):217–220.
   Google Scholar
• Uchiyama S, Kimura H, Ueno T, et al. Detection of Lactococcus garvieae in foods and its existence in the human intestine (in Japanese). J Intest Microbiol. 2007;21(3):221–225.
   Google Scholar
• Wang X-L, Hur H-G, Lee JH, et al. Enantioselective synthesis of S-equol from dihydrodaidzein by a newly isolated anaerobic human intestinal bacterium. Appl Environ Microbiol. 2005;71(1):214–219.10.1128/AEM.71.1.214-219.2005
   PubMed Web of Science ®Google Scholar
• Muthyala RS, Ju YH, Sheng S, et al. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors α and β. Bioorg Med Chem. 2004;12(6):1559–1567.10.1016/j.bmc.2003.11.035
   PubMed Web of Science ®Google Scholar
• Rowland I, Wiseman H, Sanders T, et al. Metabolism of oestrogens and phytoestrogens: role of the gut microflora. Biochem Soc Trans. 1999;27(2):304.10.1042/bst0270304
   PubMed Web of Science ®Google Scholar
• Minamida K, Tanaka M, Abe A, et al. Production of equol from daidzein by gram-positive rod-shaped bacterium isolated from rat intestine. J Biosci Bioeng. 2006;102(3):247–250.10.1263/jbb.102.247
   PubMed Web of Science ®Google Scholar
• Minamida K, Ota K, Nishimukai M, et al. Asaccharobacter celatus gen. nov., sp. nov., isolated from rat caecum. Int J Syst Evol Microbiol. 2008;58(Pt 5):1238–1240.10.1099/ijs.0.64894-0
   PubMedGoogle Scholar
• Yokoyama S-i. Suzuki, T. Isolation and characterization of a novel equol-producing cacterium from human feces. Biosci Biotechnol Biochem. 2008;72(10):2660–2666.10.1271/bbb.80329
   PubMed Web of Science ®Google Scholar
• Yu Z-T, Yao W, Zhu W-Y. Isolation and identification of equol-producing bacterial strains from cultures of pig faeces. FEMS Microbiol Lett. 2008;282(1):73–80.10.1111/fml.2008.282.issue-1
   PubMed Web of Science ®Google Scholar
• Tamura M, Hori S, Nakagawa H. Lactobacillus rhamnosus JCM 2771: impact on metabolism of isoflavonoids in the fecal flora from a male equol producer. Curr Microbiol. 2011;62(5):1632–1637.10.1007/s00284-011-9904-6
   PubMed Web of Science ®Google Scholar
• Shimada Y, Yasuda S, Takahashi M, et al. Cloning and expression of a novel NADP(H)-Ddependent daidzein reductase, an enzyme involved in the metabolism of daidzein, from equol-producing Lactococcus Strain 20-92. Appl Environ Microbiol. 2010;76(17):5892–5901.10.1128/AEM.01101-10
   PubMed Web of Science ®Google Scholar
• Shimada Y, Takahashi M, Miyazawa N, et al. Identification of two novel reductases involved in equol biosynthesis in lactococcus strain 20–92. J Mol Microbiol Biotechnol. 2011;21(3–4):160–172.10.1159/000335049
   PubMed Web of Science ®Google Scholar
• Shimada Y, Takahashi M, Miyazawa N, et al. Identification of a novel dihydrodaidzein racemase essential for biosynthesis of equol from daidzein in Lactococcus sp. strain 20-92. Appl Environ Microbiol. 2012;78(14):4902–4907.10.1128/AEM.00410-12
   PubMed Web of Science ®Google Scholar
• Tsuji H, Moriyama K, Nomoto K, et al. Isolation and characterization of the equol-producing bacterium Slackia sp. strain NATTS. Arch Microbiol. 2010;192(4):279–287.10.1007/s00203-010-0546-z
   PubMed Web of Science ®Google Scholar
• Tsuji H, Moriyama K, Nomoto K, et al. Identification of an enzyme system for daidzein-to-equol conversion in Slackia sp. Strain NATTS. Appl Environ Microbiol. 2012;78(4):1228–1236.10.1128/AEM.06779-11
   PubMed Web of Science ®Google Scholar
• Kawada Y, Yokoyama S, Yanase E, et al. The production of S-equol from daidzein is associated with a cluster of three genes in Eggerthella sp. YY7918. Biosci Microbiota Food Health. 2016;35(3):113–121.
   PubMedGoogle Scholar
• Abiru Y, Kumemura M, Ueno T, et al. Discovery of an S-equol rich food stinky tofu, a traditional fermented soy product in Taiwan. Int J Food Sci Nutr. 2012;63(8):964–970.10.3109/09637486.2012.687369
   PubMed Web of Science ®Google Scholar
• Tousen Y, Uehara M, Kruger MC, et al. Effects of dietary fibre and tea catechin, ingredients of the Japanese diet, on equol production and bone mineral density in isoflavone-treated ovariectomised mice. J Nutr Sci. 2012;1:e13.10.1017/jns.2012.14
   PubMedGoogle Scholar
• Fujii S, Takahashi N, Inoue H, et al. A combination of soy isoflavones and cello-oligosaccharides changes equol/O-desmethylangolensin production ratio and attenuates bone fragility in ovariectomized mice. Biosci Biotechnol Biochem. 2016;80(8):1632–1635.10.1080/09168451.2016.1184559
   PubMed Web of Science ®Google Scholar
• Tousen Y, Abe F, Ishida T, et al. Resistant starch promotes equol production and inhibits tibial bone loss in ovariectomized mice treated with daidzein. Metabolism. 2011;60(10):1425–1432.10.1016/j.metabol.2011.02.009
   PubMed Web of Science ®Google Scholar
• Clavel T, Fallani M, Lepage P, et al. Isoflavones and functional foods alter the dominant intestinal microbiota in postmenopausal women. J Nutr. 2005;135(12):2786–2792.10.1093/jn/135.12.2786
   PubMed Web of Science ®Google Scholar