The gut microbiota: A key factor in the therapeutic effects of (poly)phenols

Biochemical Pharmacology

Volumn 139, Issue , 2017, Pages 82-93

  Espín, Juan Carlos ^a   González Sarrías, Antonio ^a   Tomás Barberán, Francisco A ^a  

^a RESEARCH GROUP ON QUALITY   (Spain)

Author keywords

Gut microbiota; Health effects; Metabotypes; Polyphenol metabolites

Indexed keywords

CARBON; POLYPHENOL; ANTINEOPLASTIC AGENT; ANTIOXIDANT; FLAVONOID; PHENOL DERIVATIVE; PLANT MEDICINAL PRODUCT; STILBENE DERIVATIVE;

BIOLOGICAL ACTIVITY; CATABOLISM; CHEMICAL BOND; HEALTH STATUS; HUMAN; HYDROGENATION; HYDROLYSIS; HYDROXYLATION; INTESTINE FLORA; METABOLITE; NONHUMAN; PRIORITY JOURNAL; REDUCTION (CHEMISTRY); REVIEW; THERAPY EFFECT; ANIMAL; COLORECTAL NEOPLASMS; DIETARY SUPPLEMENT; DIGESTION; DYSBIOSIS; HEALTHY DIET; INTESTINE ABSORPTION; METABOLISM; MICROBIOLOGY;

ANIMALS; ANTICARCINOGENIC AGENTS; ANTIOXIDANTS; COLORECTAL NEOPLASMS; DIETARY SUPPLEMENTS; DIGESTION; DYSBIOSIS; FLAVONOIDS; GASTROINTESTINAL MICROBIOME; HEALTHY DIET; HUMANS; HYDROGENATION; HYDROLYSIS; HYDROXYLATION; INTESTINAL ABSORPTION; PHENOLS; PLANT PREPARATIONS; STILBENES;

EID: 85018884834     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2017.04.033     Document Type: Review

References (122)

1. Tomás-Barberán, F.A., Espin, J.C., Phenolic compounds and related enzymes as determinants of quality in fruits and vegetables. J. Sci. Food Agric. 81 (2000), 853–876.
2. Bonaccio, M., Pounis, G., Cerletti, C., Donati, M.B., Iacoviello, L., de Gaetano, G., et al. Mediterranean diet, dietary polyphenols and low grade inflammation: results from the MOLI-SANI study. Br. J. Clin. Pharmacol. 83 (2017), 107–113.
3. Liu, X.M., Liu, Y.J., Huang, Y., Yu, H.J., Yuan, S., Tang, B.W., et al. Dietary total flavonoids intake and risk of mortality from all causes and cardiovascular disease in the general population: a systematic review and meta-analysis of cohort studies. Mol. Nutr. Food Res., 2017, 10.1002/mnfr.201601003.
4. Mitjavila, M.T., Moreno, J.J., The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases. Biochem. Pharmacol. 84 (2012), 1113–1122.
5. Schär, M.Y., Curtis, P.J., Hazim, S., Ostertag, L.M., Kay, C.D., Potter, J.F., et al. Orange juice-derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: a randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease. Am. J. Clin. Nutr. 101 (2015), 931–938.
6. Rangel-Huerta, O.D., Pastor-Villaescusa, B., Aguilera, C.M., Gil, A.A., Systematic review of the efficacy of bioactive compounds in cardiovascular disease: phenolic compounds. Nutrients 7 (2015), 5177–5216.
7. Sahebkar, A., A systematic review and meta-analysis of randomized controlled trials investigating the effects of curcumin on blood lipid levels. Clin. Nutr. 33 (2014), 406–414.
8. Wang, D., Chen, C., Wang, Y., Liu, J., Lin, R., Effect of black tea consumption on blood cholesterol: a meta-analysis of 15 randomized controlled trials. PLoS One, 9, 2014, e107711.
9. Núñez-Sánchez, M.A., González-Sarrías, A., Romo-Vaquero, M., García-Villalba, R., Selma, M.V., Tomás-Barberán, F.A., et al. Dietary phenolics against colorectal cancer–From promising preclinical results to poor translation into clinical trials: Pitfalls and future needs. Mol. Nutr. Food Res. 59 (2015), 1274–1291.
10. Karuppagounder, V., Arumugam, S., Giridharan, V.V., Sreedhar, R., Bose, R.J., Vanama, J., et al. Tiny molecule, big power: Multi-target approach for curcumin in diabetic cardiomyopathy. Nutrition 34 (2017), 47–54.
11. Tomé-Carneiro, J., Larrosa, M., González-Sarrías, A., Tomás-Barberán, F.A., García-Conesa, M.T., Espín, J.C., Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr. Pharm. Des. 19 (2013), 6064–6093.
12. Sahebkar, A., Serban, C., Ursoniu, S., Wong, N.D., Muntner, P., Graham, I.M., et al. Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors–Results from a systematic review and meta-analysis of randomized controlled trials. Int. J. Cardiol. 189 (2015), 47–55.
13. Hausenblas, H.A., Schoulda, J.A., Smoliga, J.M., Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus–systematic review and meta-analysis. Mol. Nutr. Food Res. 59 (2015), 147–159.
14. Liu, Z.M., Ho, S.C., Chen, Y.M., Tomlinson, B., Ho, S., To, K., et al. Effect of whole soy and purified daidzein on ambulatory blood pressure and endothelial function–a 6-month double-blind, randomized controlled trial among Chinese postmenopausal women with prehypertension. Eur. J. Clin. Nutr. 69 (2015), 1161–1168.
15. Pusparini, Yenny, Hidayat, A., Effect of soy isoflavone supplementation on endothelial dysfunction and oxidative stress in equol-producing postmenopausal women. Endocr. Metab. Immune Disord. Drug Targets 15 (2015), 71–79.
16. Hazim, S., Curtis, P.J., Schär, M.Y., Ostertag, L.M., Kay, C.D., Minihane, A.M., et al. Acute benefits of the microbial-derived isoflavone metabolite equol on arterial stiffness in men prospectively recruited according to equol producer phenotype: a double-blind randomized controlled trial. Am. J. Clin. Nutr. 103 (2016), 694–702.
17. Yan, Z., Zhang, X., Li, C., Jiao, S., Dong, W., Association between consumption of soy and risk of cardiovascular disease: a meta-analysis of observational studies. Eur. J. Prev. Cardiol., 2017, 10.1177/2047487316686441.
18. Sreekumar, S., Sithul, H., Muraleedharan, P., Azeez, J.M., Sreeharshan, S., Pomegranate fruit as a rich source of biologically active compounds. Biomed. Res. Int., 2014, 2014, 686921.
19. Vlachojannis, C., Erne, P., Schoenenberger, A.W., Chrubasik-Hausmann, S., A critical evaluation of the clinical evidence for pomegranate preparations in the prevention and treatment of cardiovascular diseases. Phytother. Res. 29 (2015), 501–508.
20. Banihani, S., Swedan, S., Alguraan, Z., Pomegranate and type 2 diabetes. Nutr. Res. 33 (2013), 341–348.
21. Nuñez-Sánchez, M.A., Dávalos, A., González-Sarrías, A., Casas-Agustench, P., Visioli, F., Monedero-Saiz, T., et al. MicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: critical issues to discern between modulatory effects and potential artefacts. Mol. Nutr. Food Res. 59 (2015), 1973–1986.
22. Sahebkar, A., Ferri, C., Giorgini, P., Bo, S., Nachtigal, P., Grassi, D., Effects of pomegranate juice on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Pharmacol. Res. 115 (2017), 149–161.
23. Sahebkar, A., Simental-Mendía, L.E., Giorgini, P., Ferri, C., Grassi, D., Lipid profile changes after pomegranate consumption: a systematic review and meta-analysis of randomized controlled trials. Phytomedicine 23 (2016), 1103–1112.
24. Sahebkar, A., Gurban, C., Serban, A., Andrica, F., Serban, M.C., Effects of supplementation with pomegranate juice on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Phytomedicine 23 (2016), 1095–1102.
25. Ioannidis, J.P., The mass production of redundant, misleading, and conflicted systematic reviews and meta-analyses. Milbank Q. 94 (2016), 485–514.
26. Tomás-Barberán, F.A., Selma, M.V., Espín, J.C., Interactions of gut microbiota with dietary polyphenols and consequences to human health. Curr. Opin. Clin. Nutr. Metab. Care 19 (2016), 471–476.
27. González-Sarrías, A., García-Villalba, R., Romo-Vaquero, M., Alasalvar, C., Örem, A., Zafrilla, P., et al. Clustering according to urolithin metabotype explains the interindividual variability in the improvement of cardiovascular risk biomarkers in overweight-obese individuals consuming pomegranate: a randomised clinical trial. Mol. Nutr. Food Res., 2017, 10.1002/mnfr.201600830.
28. Manach, C., Milenkovic, D., Van de Wiele, T., Rodriguez-Mateos, A., de Roos, B., Garcia-Conesa, M.T., et al. Addressing the inter-individual variation in response to consumption of plant food bioactives – towards a better understanding of their role in healthy ageing and cardiometabolic risk reduction. Mol. Nut. Food Res., 2017, 10.1002/mnfr.201600557.
29. Bohn, T., McDougall, G.J., Alegría, A., Alminger, M., Arrigoni, E., Aura, A.M., et al. Mind the gap-deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites–a position paper focusing on carotenoids and polyphenols. Mol. Nutr. Food Res. 59 (2015), 1307–1323.
30. Anhê, F.F., Varin, T.V., Le Barz, M., Desjardins, Y., Levy, E., Roy, D., et al. Gut microbiota dysbiosis in obesity-linked metabolic diseases and prebiotic potential of polyphenol-rich extracts. Curr. Obes. Rep. 4 (2015), 389–400.
31. Selma, M.V., Espín, J.C., Tomás-Barberán, F.A., Interaction between phenolics and gut microbiota: role in human health. J. Agric. Food Chem. 57 (2009), 6485–6501.
32. Vaiserman, A.M., Koliada, A.K., Marotta, F., Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Res. Rev. 35 (2017), 36–45.
33. Lynch, S.V., Pedersen, O., The human intestinal microbiome in health and disease. N. Engl. J. Med. 375 (2016), 2369–2379.
34. Turnbaugh, P.J., Quince, C., Faith, J.J., McHardy, A.C., Yatsunenko, T., Niazi, F., et al. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 7503–7508.
35. Sonnenburg, J.L., Bäckhed, F., Diet-microbiota interactions as moderators of human metabolism. Nature 535 (2016), 56–64.
36. Bindels, L.B., Delzenne, N.M., Cani, P.D., Walter, J., Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol. 12 (2015), 303–310.
37. Marchesi, J.R., Adams, D.H., Fava, F., Hermes, G.D., Hirschfield, G.M., Hold, G., et al. The gut microbiota and host health: a new clinical frontier. Gut 65 (2016), 330–339.
38. Arranz, S., Silván, J.M., Saura-Calixto, F., Nonextractable polyphenols, usually ignored, are the major part of dietary polyphenols: a study on the Spanish diet. Mol. Nutr. Food Res. 54 (2010), 1646–1658.
39. Dueñas, M., Muñoz-González, I., Cueva, C., Jiménez-Girón, A., Sánchez-Patán, F., Santos-Buelga, C., et al. A survey of modulation of gut microbiota by dietary polyphenols. Biomed. Res. Int., 2015, 2015, 850902.
40. Larrosa, M., González-Sarrías, A., Yáñez-Gascón, M.J., Selma, M.V., Azorín-Ortuño, M., Toti, S., et al. Antiinflammatory properties of a pomegranate extract and its metabolite urolithin A in a colitis rat model and the effect of colon inflammation on the phenolic metabolism. J. Nutr. Biochem. 21 (2010), 717–725.
41. Remely, M., Tesar, I., Hippe, B., Gnauer, S., Rust, P., Haslberger, A.G., Gut microbiota composition correlates with changes in body fat content due to weight loss. Benef. Microbes. 6 (2015), 431–439.
42. Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J.P., Druart, C., Bindels, L.B., et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 110 (2013), 9066–9071.
43. Anhê, F.F., Roy, D., Pilon, G., Dudonné, S., Matamoros, S., Varin, T.V., et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 64 (2015), 872–883.
44. Roopchand, D.E., Carmody, R.N., Kuhn, P., Moskal, K., Rojas-Silva, P., Turnbaugh, P.J., et al. Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes 64 (2015), 2847–2858.
45. Etxeberria, U., Arias, N., Boqué, N., Macarulla, M.T., Portillo, M.P., Martínez, J.A., et al. Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats. J. Nutr. Biochem. 26 (2015), 651–660.
46. Zhang, Z., Wu, X., Cao, S., Wang, L., Wang, D., Yang, H., et al. Caffeic acid ameliorates colitis in association with increased Akkermansia population in the gut microbiota of mice. Oncotarget 7 (2016), 31790–31799.
47. Neyrinck, A.M., Etxeberria, U., Taminiau, B., Daube, G., Van Hul, M., Everard, A., et al. Rhubarb extract prevents hepatic inflammation induced by acute alcohol intake, an effect related to the modulation of the gut microbiota. Mol. Nutr. Food Res., 61, 2017, 10.1002/mnfr.201500899.
48. Heyman-Lindén, L., Kotowska, D., Sand, E., Bjursell, M., Plaza, M., Turner, C., et al. Lingonberries alter the gut microbiota and prevent low-grade inflammation in high-fat diet fed mice. Food Nutr. Res., 60, 2016, 29993.
49. Song, H., Chu, Q., Yan, F., Yang, Y., Han, W., Zheng, X., Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice. J. Gastroenterol. Hepatol. 31 (2016), 1462–1469.
50. Power, K.A., Lepp, D., Zarepoor, L., Monk, J.M., Wu, W., Tsao, R., et al. Dietary flaxseed modulates the colonic microenvironment in healthy C57Bl/6 male mice which may alter susceptibility to gut-associated diseases. J. Nutr. Biochem. 28 (2016), 61–69.
51. Cho, S.Y., Kim, J., Lee, J.H., Sim, J.H., Cho, D.H., Bae, I.H., et al. Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice. Sci Rep., 6, 2016, 39026.
52. Li, Z., Henning, S.M., Lee, R.P., Lu, Q.Y., Summanen, P.H., Thames, G., et al. Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in healthy volunteers. Food Funct. 6 (2015), 2487–2495.
53. Henning, S.M., Summanen, P.H., Lee, R.P., Yang, J., Finegold, S.M., Heber, D., et al. Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo. Anaerobe 43 (2017), 56–60.
54. Plovier, H., Everard, A., Druart, C., Depommier, C., VanHul, M., Geurts, L., et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23 (2017), 107–113.
55. Moreno-Indias, I., Sánchez-Alcoholado, L., Pérez-Martínez, P., Andrés-Lacueva, C., Cardona, F., Tinahones, F., et al. Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients. Food Funct. 7 (2016), 1775–1787.
56. Magistrelli, D., Zanchi, R., Malagutti, L., Galassi, G., Canzi, E., Rosi, F., Effects of docoa husk feeding on the composition of swine intestinal microbiota. J. Agric. Food Chem. 64 (2016), 2046–2052.
57. Miquel, S., Martín, R., Rossi, O., Bermúdez-Humarán, L.G., Chatel, J.M., Sokol, H., et al. Faecalibacterium prausnitzii and human intestinal health. Curr. Opin. Microbiol. 16 (2013), 255–261.
58. Barbieri, R., Coppo, E., Marchese, A., Daglia, M., Sobarzo-Sánchez, E., Nabavi, S.F., et al. Phytochemicals for human disease: an update on plant-derived compounds antibacterial activity. Microbiol. Res. 196 (2017), 44–68.
59. Daglia, M., Di Lorenzo, A., Nabavi, S.F., Talas, Z.S., Nabavi, S.M., Polyphenols: well beyond the antioxidant capacity: gallic acid and related compounds as neuroprotective agents: you are what you eat!. Curr. Pharm. Biotechnol. 15 (2014), 362–372.
60. Marín, L., Miguélez, E.M., Villar, C.J., Lombó, F., Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. BioMed Res. Int., 2015, 2015, 905215.
61. Slobodníková, L., Fialová, S., Rendeková, K., Kováč, J., Mučaji, P., Antibiofilm activity of plant polyphenols. Molecules, 21, 2016 pii: E1717.
62. Truchado, P., Giménez-Bastida, J.A., Larrosa, M., Castro-Ibáñez, I., Espín, J.C., Tomás-Barberán, F.A., et al. Inhibition of Quorum Sensing (QS) in Yersinia enterocolitica by orange extract rich in glycosylated flavanones. J. Agric. Food Chem. 60 (2012), 8885–8894.
63. Braune, A., Blaut, M., Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microbes 7 (2016), 216–234.
64. Martinez-Zapata, M.J., Vernooij, R.W., Uriona Tuma, S.M., Stein, A.T., Moreno, R.M., Vargas, E., et al. Phlebotonics for venous insufficiency. Cochrane Database Syst. Rev., 4, 2016, CD003229.
65. Quartieri, A., García-Villalba, R., Amaretti, A., Raimondi, S., Leonardi, A., Rossi, M., et al. Detection of novel metabolites of flaxseed lignans in vitro and in vivo. Mol. Nut. Food Res. 60 (2016), 1590–1601.
66. Raimondi, S., Anighoro, A., Quartieri, A., Amaretti, A., Tomás-Barberán, F.A., Rastelli, G., et al. Role of bifidobacteria in the hydrolysis of chlorogenic acid. Micriobiol. Open 4 (2015), 41–52.
67. Aguilera-Carbo, A., Augur, C., Prado-Barragan, L.A., Favela-Torres, E., Aguilar, C.N., Microbial production of ellagic acid and biodegradation of ellagitannins. Appl. Microbiol. Biotechnol. 78 (2008), 189–199.
68. Gill, S.R., Pop, M., Deboy, R.T., Eckburg, P.B., Turnbaugh, P.J., Samuel, B.S., et al. Metagenomic analysis of the human distal gut microbiome. Science 312 (2006), 1355–1359.
69. Louis, P., Hold, G.L., Flint, H.J., The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12 (2014), 661–672.
70. Gonzalez-Sarrías, A., Espin, J.C., Tomás-Barberán, F.A., Non-extractable polyphenols produce gut microbiota metabolites that persist in circulation and show anti-inflammatory and free radical-scavenging effects. Trends Food Sci. Technol., 2017.
71. Tomás-Barberán, F.A., Garcia-Villalba, R., Quartieri, A., Raimondi, S., Amaretti, A., Leonardi, A., et al. In vitro transformations of chlorogenic acid by human gut microbiota. Mol. Nut. Food Res. 58 (2014), 1122–1131.
72. Selma, M.V., Beltrán, D., García-Villalba, R., Espín, J.C., Tomás-Barberán, F.A., Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species. Food Funct. 5 (2014), 1779–1784.
73. Tomás-Barberán, F.A., González-Sarrías, A., García-Villalba, R., Núñez-Sánchez, M.A., Selma, M.V., García-Conesa, M.T., et al. Urolithins, the rescue of ‘old’ metabolites to understand a ‘new’ concept: metabotypes as a nexus between phenolic metabolism, microbiota dysbiosis and host health status. Mol. Nutr. Food Res., 61, 2017, 10.1002/mnfr.201500901.
74. Tomás-Barberán, F.A., García-Villalba, R., González-Sarrías, A., Selma, M.V., Espín, J.C., Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J. Agric. Food Chem. 62 (2014), 6535–6538.
75. Clavel, T., Henderson, G., Engst, W., Doré, J., Blaut, M., Phylogeny of human intestinal bacteria that activate the dietary lignan secoisolariciresinol diglucoside. FEMS Microbiol. Ecol. 55 (2006), 471–478.
76. Clavel, T., Lippman, R., Gavini, F., Doré, J., Blaut, M., Clostridium saccharogumia sp. nov. and Lactonifactor longoviformis gen. nov., sp. nov., two novel human faecal bacteria involved in the conversion of the dietary phytoestrogen secoisolariciresinol diglucoside. Syst. Appl. Microbiol. 30 (2007), 16–26.
77. Larrosa, M., García-Conesa, M.T., Espín, J.C., Tomás-Barberán, F.A., Ellagitannins, ellagic acid and vascular health. Mol. Aspects Med. 31 (2010), 513–539.
78. Espín, J.C., Larrosa, M., García-Conesa, M.T., Tomás-Barberán, F.A., Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid. Based Complement. Alternat. Med., 2013, 2013, 270418.
79. Garcia-Muñoz, C., Vaillant, F., Metabolic fate of ellagitannins: implications for health, and research perspectives for innovative functional foods. Crit. Rev. Food Sci. Nutr. 54 (2014), 1584–1598.
80. González-Sarrías, A., Núñez-Sánchez, M.A., Tomás-Barberán, F.A., Espín, J.C., Neuroprotective effects of bioavailable polyphenol-derived metabolites against oxidative stress-induced Cytotoxicity in human neuroblastoma SH-SY5Y cells. J. Agric. Food Chem. 65 (2017), 752–758.
81. Yuan, T., Ma, H., Liu, W., Niesen, D.B., Shah, N., Crews, R., et al. Pomegranate's neuroportective effects against Alzheimer's disease are mediated by urolithins, its ellagitannin-gut microbial metabolites. ACS Chem. Neurosci. 7 (2016), 26–33.
82. Adolphe, J.L., Whiting, S.J., Juurlink, B.H., Thorpe, L.U., Alcorn, J., Health effects with consumption of the flax lignan secoisolariciresinol diglucoside. Br. J. Nutr. 103 (2010), 929–938.
83. During, A., Debouche, C., Raas, T., Larondelle, Y., Among plant lignans, pinoresinol has the strongest antiinflammatory properties in human intestinal Caco-2 cells. J. Nutr. 142 (2012), 1798–1805.
84. Durazzo, A., Turfani, V., Azzini, E., Maiani, G., Carcea, M., Phenols, lignans and antioxidant properties of legume and sweet chestnut flours. Food Chem. 140 (2013), 666–671.
85. Imran, M., Ahmad, N., Anjum, F.M., Khan, M.K., Mushtaq, Z., Nadeem, M., et al. Potential protective properties of flax lignan secoisolariciresinol diglucoside. Nutr. J., 14, 2015, 71.
86. Davis, C.D., Milner, J.A., Gastrointestinal microflora, food components and colon cancer prevention. J. Nutr. Biochem. 20 (2009), 743–752.
87. Landete, J.M., Arqués, J., Medina, M., Gaya, P., de Las Rivas, B., Muñoz, R., Bioactivation of phytoestrogens: intestinal bacteria and health. Crit. Rev. Food Sci. Nutr. 56 (2016), 1826–1843.
88. Ganai, A.A., Farooqi, H., Bioactivity of genistein: a review of in vitro and in vivo studies. Biomed. Pharmacother. 76 (2015), 30–38.
89. Rahman Mazumder, M.A., Hongsprabhas, P., Genistein as antioxidant and antibrowning agents in in vivo and in vitro: a review. Biomed. Pharmacother. 82 (2016), 379–392.
90. Mahmoud, A.M., Yang, W., Bosland, M.C., Soy isoflavones and prostate cancer: a review of molecular mechanisms. J. Steroid Biochem. Mol. Biol. 140 (2014), 116–132.
91. Choi, E.J., Kim, G.H., The antioxidant activity of daidzein metabolites, O desmethylangolensin and equol, in HepG2 cells. Mol. Med. Rep. 9 (2014), 328–332.
92. Kinjo, J., Tsuchihashi, R., Morito, K., Hirose, T., Aomori, T., Nagao, T., et al. Interactions of phytoestrogens with estrogen receptors alpha and beta (III). Estrogenic activities of soy isoflavone aglycones and their metabolites isolated from human urine. Biol. Pharm. Bull. 27 (2004), 185–188.
93. Yu, J., Bi, X., Yu, B., Chen, D., Isoflavones: anti-inflammatory benefit and possible caveats. Nutrients, 8, 2016 pii: E361.
94. Frankenfeld, C.L., O-desmethylangolensin: the importance of equol's lesser known cousin to human health. Adv. Nutr. 2 (2011), 317–324.
95. Frankenfeld, C.L., Cardiometabolic risk and gut microbial phytoestrogen metabolite phenotypes. Mol. Nutr. Food Res., 61, 2017, 10.1002/mnfr.201500900.
96. Bharti, S., Rani, N., Krishnamurthy, B., Arya, D.S., Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 80 (2014), 437–451.
97. Roohbakhsh, A., Parhiz, H., Soltani, F., Rezaee, R., Iranshahi, M., Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci. 124 (2015), 64–74.
98. Parhiz, H., Roohbakhsh, A., Soltani, F., Rezaee, R., Iranshahi, M., Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res. 29 (2015), 323–331.
99. Koosha, S., Alshawsh, M.A., Looi, C.Y., Seyedan, A., Mohamed, Z., An association map on the effect of flavonoids on the signaling pathways in colorectal cancer. Int. J. Med. Sci. 13 (2016), 374–385.
100. Kay, C.D., Pereira-Caro, G., Ludwig, I.A., Clifford, M.N., Crozier, A., Anthocyanins and flavanones are more bioavailable than previously perceived: a review of recent evidence. Annu. Rev. Food Sci. Technol., 2017, 10.1146/annurev-food-030216-025636.
101. Dall'Asta, M., Derlindati, E., Curella, V., Mena, P., Calani, L., Ray, S., et al. Effects of naringenin and its phase II metabolites on in vitro human macrophage gene expression. Int. J. Food Sci. Nutr. 64 (2013), 843–849.
102. Chanet, A., Milenkovic, D., Claude, S., Maier, J.A., Kamran Khan, M., Rakotomanomana, N., et al. Flavanone metabolites decrease monocyte adhesion to TNF-α-activated endothelial cells by modulating expression of atherosclerosis-related genes. Br. J. Nutr. 110 (2013), 587–598.
103. Yamamoto, M., Jokura, H., Hashizume, K., Ominami, H., Shibuya, Y., Suzuki, A., et al. Hesperidin metabolite hesperetin-7-O-glucuronide, but not hesperetin-3’-O-glucuronide, exerts hypotensive, vasodilatory, and anti-inflammatory activities. Food Funct. 4 (2013), 1346–1351.
104. Giménez-Bastida, J.A., González-Sarrías, A., Vallejo, F., Espín, J.C., Tomás-Barberán, F.A., 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 Funct. 7 (2016), 118–126.
105. Núñez-Sánchez, M.A., González-Sarrías, A., García-Villalba, R., Monedero-Saiz, T., García-Talavera, N., Gómez-Sánchez, M.B., et al. Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J. Nutr. Biochem. 42 (2017), 126–133.
106. Manach, C., Williamson, G., Morand, C., Scalbert, A., Rémésy, C., Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 81 (2005), 230S–242S.
107. González-Sarrías, A., García-Villalba, R., Núñez-Sánchez, M.A., Tomé-Carneiro, J., Zafrilla, P., Mulero, J., et al. Identifying the limits of ellagic acid bioavailability: a crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. J. Funct. Foods 19 (2015), 225–235.
108. Hollebeeck, S., Winand, J., Hérent, M.F., During, A., Leclercq, J., Larondelle, Y., et al. Anti-inflammatory effects of pomegranate (Punica granatum L.) husk ellagitannins in Caco-2 cells, an in vitro model of human intestine. Food Funct. 3 (2012), 875–885.
109. Adams, L.S., Seeram, N.P., Aggarwal, B.B., Takada, Y., Sand, D., Heber, D., Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J. Agric. Food Chem. 54 (2006), 980–985.
110. González-Sarrías, A., Larrosa, M., Tomás-Barberán, F.A., Dolara, P., Espín, J.C., NF-kappaB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts. Br. J. Nutr. 104 (2010), 503–512.
111. González-Sarrías, A., Giménez-Bastida, J.A., Núñez-Sánchez, M.A., Larrosa, M., García-Conesa, M.T., Tomás-Barberán, F.A., et al. Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells. Eur. J. Nutr. 53 (2014), 853–864.
112. Perez-Martinez, P., Garcia-Rios, A., Delgado-Lista, J., Perez-Jimenez, F., Lopez-Miranda, J., Metabolic syndrome: evidences for a personalized Nutrition. Mol. Nutr. Food Res. 56 (2012), 67–76.
113. Bolca, S., Van de Wiele, T., Possemiers, S., Gut metabotypes govern health effects of dietary polyphenols. Curr. Opin. Biotechnol. 24 (2013), 220–225.
114. Clavel, T., Lagkouvardos, I., Hiergeist, A., Microbiome sequencing: challenges and opportunities for molecular medicine. Expert. Rev. Mol. Diagn. 16 (2016), 795–805.
115. Lagkouvardos, I., Kläring, K., Heinzmann, S.S., Platz, S., Scholz, B., Engel, K.H., et al. Gut metabolites and bacterial community networks during a pilot intervention study with flaxseeds in healthy adult men. Mol. Nutr. Food Res. 59 (2015), 1614–1628.
116. Takagaki, A., Nanjo, F., Bioconversion of (−)-epicatechin, (+)-epicatechin, (−)-catechin, and (+)-catechin by (−)-epigallocatechin-metabolizing bacteria. Biol. Pharm. Bull. 38 (2015), 789–794.
117. Kang, C., Zhang, Y., Zhu, X., Liu, K., Wang, X., Chen, M., et al. Healthy subjects differentially respond to dietary capsaicin correlating with specific gut enterotypes. J. Clin. Endocrinol. Metab. 101 (2016), 4681–4689.
118. Vázquez-Fresno, R., Llorach, R., Perera, A., Mandal, R., Feliz, M., Tinahones, F.J., et al. Clinical phenotype clustering in cardiovascular risk patients for the identification of responsive metabotypes after red wine polyphenol intake. J. Nutr. Biochem. 28 (2016), 114–120.
119. Sánchez-Patán, F., Cueva, C., Monagas, M., Walton, G.E., Gibson, G.R., Quintanilla-López, J.E., et al. In vitro fermentation of a red wine extract by human gut microbiota: changes in microbial groups and formation of phenolic metabolites. J. Agric. Food Chem. 60 (2012), 2136–2147.
120. Sun, Q., Wedick, N.M., Pan, A., Townsend, M.K., Cassidy, A., Franke, A.A., et al. Gut microbiota metabolites of dietary lignans and risk of type 2 diabetes: a prospective investigation in two cohorts of U.S. women. Diabetes Care 37 (2014), 1287–1295.
121. Reverri, E.J., Slupsky, C.M., Mishchuk, D.O., Steinberg, F.M., Metabolomics reveals differences between three daidzein metabolizing phenotypes in adults with cardiometabolic risk factors. Mol. Nutr. Food Res., 61, 2017, 10.1002/mnfr.201600132.
122. Selma, M.V., González-Sarrías, A., Salas-Salvadó, J., Andrés-Lacueva, C., Alasalvar, C., Örem, A., et al. The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: comparison between normoweight, overweight-obesity and metabolic syndrome. Clin. Nutr., 2017, 10.1016/j.clnu.2017.03.012.