, 12:32 | Cite as

Urinary metabolomic profiling to identify biomarkers of a flavonoid-rich and flavonoid-poor fruits and vegetables diet in adults: the FLAVURS trial

  • Maria M. UlaszewskaEmail author
  • Kajetan Trost
  • Jan Stanstrup
  • Kieran M. TuohyEmail author
  • Pietro Franceschi
  • Mary Foong-Fong Chong
  • Trevor George
  • Anne Marie Minihane
  • Julie A. Lovegrove
  • Fulvio MattiviEmail author
Original Article


The present study aims to investigate the dose dependent effects of consuming diets enriched in flavonoid-rich and flavonoid-poor fruits and vegetables on the urine metabolome of adults who had a ≥1.5 fold increased risk of cardiovascular diseases. A single-blind, dose-dependent, parallel randomized controlled dietary intervention was conducted where volunteers (n = 126) were randomly assigned to one of three diets: high flavonoid diet, low flavonoid diet or habitual diet as a control for 18 weeks. High resolution LC–MS untargeted metabolomics with minimal sample cleanup was performed using an Orbitrap mass spectrometer. Putative biomarkers which characterize diets with high and low flavonoid content were selected by state-of-the-art data analysis strategies and identified by HR-MS and HR-MS/MS assays. Discrimination between diets was observed by application of two linear mixed models: one including a diet-time interaction effect and the second containing only a time effect. Valerolactones, phenolic acids and their derivatives were among sixteen biomarkers related to the high flavonoid dietary exposure. Four biomarkers related to the low flavonoid diet belonged to the family of phenolic acids. For the first time abscisic acid glucuronide was reported as a biomarker after a dietary intake, however its origins have to be examined by future hypothesis driven experiments using a more targeted approach. This metabolomic analysis has identified a number of dose dependent urinary biomarkers (i.e. proline betaine or iberin-N-acetyl cysteine), which can be used in future observation and intervention studies to assess flavonoids and non-flavonoid phenolic intakes and compliance to fruit and vegetable intervention.


Untargeted metabolomics Cardiovascular health Flavonoids Dietary intervention Urine Fruit and vegetables 



FLAVURS study group: Julie A Lovegrove (PI); Anne-Marie Minihane; Michael H Gordon, Jeremy PE Spencer, Kieran M. Tuohy, Orla B Kennedy, Trevor W George (Study Co-ordinator), Mary Foong-Fong Chong (Study Co-ordinator), Dauren Alimbetov, Yin Jin and Anna Macready. The authors would like to express their sincere thanks to all those involved in the FLAVURS project and in particular, to Orla B. Kennedy, Jeremy P.E. Spencer and Mike Gordon, for their critical reading of this article.

This metabolomic study was financially supported by the ADP2014 project, funded by the Autonomous Province of Trento, Italy. The work by Jan Stanstrup was supported by a research grant (VKR023371) from VILLUM FONDEN.

Author's contribution

MU conceived and conducted the metabolomics analyses with KT, performed metabolite annotation, and wrote the body of the paper with FM, JS, KMT and JAL; JS conceived and conducted the LC–MS data analysis with PF and MU. KT helped with the data analysis; JAL conceived, obtained funding and conducted the intervention study, of which she was coordinator, with KMT, AMM, TG, MCFF and the FLAVURS study group. FM designed and coordinated the metabolomic research and obtained funding, together with KMT. All authors reviewed, edited and approved the final version of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

FLAVURS was registered as a randomized clinical trial (ISRCTN47748735) and conducted according to the guidelines laid down in the Declaration of Helsinki. Ethical approval for the study was obtained from the Local Research Ethics Committee of the Isle of Wight, Portsmouth and South East Hampshire (REC: 07/H0501/81), and the University of Reading’s Research (REC: 07/22) Ethics Committee. Informed consent was obtained before participation.

Supplementary material

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Supplementary material 5 (DOC 68 kb)


  1. Al Janobi, A. A., Mithen, R. F., Gasper, A. V., Shaw, P. N., Middleton, R. J., Ortori, C. A., et al. (2006). Quantitative measurement of sulforaphane, iberin and their mercapturic acid pathway metabolites in human plasma and urine using liquid chromatography-tandem electrospray ionisation mass spectrometry. Journal of Chromatography B, 844(2), 223–234.CrossRefGoogle Scholar
  2. Appel, L. J., Moore, T. J., Obarzanek, E., Vollmer, W. M., Svetkey, L. P., Sacks, F. M., et al. (1997). A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. The New England Journal of Medicine, 336(16), 1117–1124.Google Scholar
  3. Appeldoorn, M. M., Vincken, J. P., Aura, A. M., Hollman, P. C., & Gruppen, H. (2009). 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. Journal of Agricultural and Food Chemistry, 57(3), 1084–1092.PubMedCrossRefGoogle Scholar
  4. Babior, B. M., & Bloch, K. (1966). Aromatization of cyclohexanecarboxylic acid. The Journal of Biological Chemistry, 241(16), 3643–3651.PubMedGoogle Scholar
  5. Badenhorst, C. P., Erasmus, E., van der Sluis, R., Nortje, C., & van Dijk, A. A. (2014). A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. Drug Metabolism Review, 46(3), 343–361.CrossRefGoogle Scholar
  6. Ban, K., Noyan-Ashraf, M. H., Hoefer, J., Bolz, S. S., Drucker, D. J., & Husain, M. (2008). Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation, 117, 2340–2350.PubMedCrossRefGoogle Scholar
  7. Beer, C. T., Dickens, F., & Pearson, J. (1951). The aromatization of hydrogenated derivatives of benzoic acid in animal tissues. Journal of Biochemistry, 48(2), 222–237.CrossRefGoogle Scholar
  8. Benjamini, Y., Krieger, A. M., & Yekutieli, D. (2006). Adaptive linear step-up procedures that control the false discovery rate. Biometrika, 93(3), 491–507.CrossRefGoogle Scholar
  9. Blakely, E. R., & Papish, B. (1982). The metabolism of 3-cyclohexenecarboxylic acid by Alcaligenes faecalis. Canadian Journal of Microbiology, 28, 1037–1046.CrossRefGoogle Scholar
  10. Blake, G. J., & Ridker, P. M. (2002). Inflammatory bio-markers and cardiovascular risk prediction. Journal of Internal Medicine, 252(4), 283–294.Google Scholar
  11. Bodrato, N., Franco, L., Fresia, C., Guida, L., Usai, C., Salis, A., et al. (2009). Abscisic acid activates the murine microglial cell line N9 through the second messenger cyclic ADP-ribose. The Journal of Biological Chemistry, 284(22), 14777–14787.PubMedCentralPubMedCrossRefGoogle Scholar
  12. Bolling, B. W., Ji, L. L., Lee, C. H., & Parkin, K. C. (2011). Dietary supplementation of ferulic acid and ferulic acid ethyl ester induces quinone reductase and glutathione-S-transferase in rats. Food Chemistry, 124, 1–6.CrossRefGoogle Scholar
  13. Bonaccio, M., Di Castelnuovo, A., Bonanni, A., Costanzo, S., De Lucia, F., Pounic, G., et al. (2013). Adherence to a Mediterranean diet is associated with a better health-related quality of life: A possible role of high dietary antioxidant content. British Medical Journal, 3(8), 1–11.Google Scholar
  14. Borges, G., Lean, M. E. J., Roberts, S. A., & Crozier, A. (2013). Bioavailability of dietary (poly)phenols: A study with ileostomists to discriminate between absorption in small and large intestine. Food and Function, 4, 754.PubMedCrossRefGoogle Scholar
  15. Brewster, D., Jones, R. S., & Parke, D. (1976). Aromatization of Shikimic Acid in the Rat and the Role of Gastrointestinal Micro-Organisms. Biochemical Society Transactions, 4, 518–521.PubMedCrossRefGoogle Scholar
  16. Brewster, D., Jones, R. S., & Parke, D. V. (1978). The metabolism of shikimate in the rat. Journal of Biochemistry, 170(2), 257–264.CrossRefGoogle Scholar
  17. Brindle, J. T., Antti, H., Holmes, E., Tranter, G., Nicholson, J. K., Bethell, H. W., et al. (2002). Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nature Medicine, 8(12), 1439–1444.PubMedCrossRefGoogle Scholar
  18. Bruzzone, S., Bodrato, N., Usai, C., Guida, L., Moreschi, I., Nano, R., et al. (2008). Abscisic acid is an endogenous stimulator of insulin release from human pancreatic islets with cyclic adp ribose as second messenger. Journal of Biological Chemistry, 283, 32188–32197.PubMedCrossRefGoogle Scholar
  19. Bruzzone, S., Moreschi, I., Usai, C., Guida, L., Damonte, G., Salis, A., et al. (2007). Abscisic acid is an endogenous cytokine in human granulocytes with cyclic ADP-ribose as second messenger. Proceedings of the National Academy of Sciences, 104(14), 5759–5764.CrossRefGoogle Scholar
  20. Cassidy, A., Hanley, B., & Lamuela-Raventos, R. M. (2000). Isoflavones: Lignans and stilbenes; origins, metabolism and potential importance to human health. Journal of the Science of Food and Agriculture, 80(7), 1044–1062.CrossRefGoogle Scholar
  21. Chambers, M. C., Maclean, B., Burke, R., et al. (2012). A cross-platform toolkit for mass spectrometry and proteomics. Nature Biotechnology, 30(10), 918–920.PubMedCentralPubMedCrossRefGoogle Scholar
  22. Chiva-Blanch, G., Badimon, L., & Estruch, R. (2014). Latest evidence of the effects of the Mediterranean diet in prevention of cardiovascular disease. Current Atherosclerosis Reports, 16(446), 1–7.Google Scholar
  23. Chong, M. F., George, T. W., Alimbetov, D., Jin, Y., Weech, M., Macready, A. L., et al. (2013). Impact of the quantity and flavonoid content of fruits and vegetables on markers of intake in adults with an increased risk of cardiovascular disease: The FLAVURS trial. European Journal of Nutrition, 52(1), 361–378.PubMedCrossRefGoogle Scholar
  24. Claudino, W. M., Goncalves, P. H., di Leo, A., Philip, P. A., & Sarkar, F. H. (2012). Metabolomics in cancer: A bench-to-bedside intersection. Critical Reviews in Oncology/Hematology, 84(1), 1–7.PubMedCrossRefGoogle Scholar
  25. Cuparencu, C. S., Schmidt Andersen, M. B., Gurdeniz, G., Schou, S. S., Wichmann Mortensen, M., Raben, A., et al. (2015). Identification of urinary biomarkers after consumption of sea buckthorn and strawberry, by untargeted LC-MS metabolomics: A meal study in adult men. Metabolomics. doi: 10.1007/s11306-015-0934-0.
  26. Curtis, P., Sampson, M., Potter, J., Dhatariya, K., Kroon, P., & 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. A 1-year, double-blind, randomized, controlled trial. Diabetes Care, 35(2), 226–232.PubMedCentralPubMedCrossRefGoogle Scholar
  27. Dall’Asta, M., Calani, L., Tedeschi, M., Jechiu, L., Brighenti, F., & Del Rio, D. (2012). Identification of microbial metabolites derived from in vitro fecal fermentation of different polyphenolic food sources. Nutrition, 28(2), 197–203.PubMedCrossRefGoogle Scholar
  28. Devore, E. E., Kang, J. H., Breteler, M. M., & Grodstein, F. (2012). Dietary intakes of berries and flavonoids in relation to cognitive decline. Annals of Neurology, 72(1), 135–143.PubMedCentralPubMedCrossRefGoogle Scholar
  29. Duenas, M., Hernandez, T., & Estrella, I. (2007). Influence of the action of exogenous enzymes on the polyphenolic composition of pea: Effect on the antioxidant activity. European Food Research and Technology, 225(3), 493–500.CrossRefGoogle Scholar
  30. Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M. I., Corella, D., Arós, F., et al. (2013). PREDIMED Study investigators: Primary prevention of cardiovascular disease with a Mediterranean diet. The New England Journal of Medicine, 368(14), 1279–1290.Google Scholar
  31. Fernandez-Peralbo, M. A., & Luque de Castro, M. D. (2012). Preparation of urine samples prior to targeted or untargeted metabolomics mass-spectrometry analysis. Trends in Analytical Chemistry, 41, 75–85.CrossRefGoogle Scholar
  32. Feskanich, D., Ziegler, R. G., Michaud, D. S., Giovannucci, E. L., Speizer, F. E., Willett, W. C., & Colditz, G. A. (2000). Prospective study of fruit and vegetable consumption and risk of lung cancer among men and women. Journal of the National Cancer Institute, 92(22), 1812–1823.PubMedCrossRefGoogle Scholar
  33. Gallus, S., Talamini, R., Giacosa, A., Montella, M., Ramazzotti, V., Franceschi, S., & La Vecchia, C. (2005). Does an apple a day keep the oncologist away? Annals of Oncology, 16(11), 1841–1844.PubMedCrossRefGoogle Scholar
  34. Garcia-Aloy, M., Llorach, R., Urpi-Sarda, M., Tulipani, S., Salas-Salvadó, J., Martínez González, M. A., et al. (2015) Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort. Metabolomics, 11, 155–165.Google Scholar
  35. Garrido, I., Urpi-Sarda, M., Monagas, M., Gómez-Cordovés, C., Martín-Alvarez, P. J., Llorach, R., et al. (2010). Targeted analysis of conjugated and microbial-derived phenolic metabolites in human urine after consumption of an almond skin phenolic extract. Journal of Nutrition, 140(10), 1799–1807.PubMedCrossRefGoogle Scholar
  36. Gasperotti, M., Masuero, D., Guella, G., Mattivi, F., & Vrhovsek, U. (2014). Development of a targeted method for twenty-three metabolites related to polyphenol gut microbial metabolism in biological samples, using SPE and UHPLC-ESI-MS/MS. Talanta, 128, 221–230.PubMedCrossRefGoogle Scholar
  37. Gerlich, M., & Neumann, S. (2013). MetFusion: Integration of compound identification strategies. Journal of Mass Spectrometry, 48(3), 291–298.PubMedCrossRefGoogle Scholar
  38. Giuliano, G., Al-Babili, S., & von Lintig, J. (2003). Carotenoid oxygenases: Cleave it or leave it. Trends in Plant Science, 8(4), 145–149.PubMedCrossRefGoogle Scholar
  39. Gostner, J. M., Becker, K., Croft, K. D., Woodman, R. J., Puddey, I. B., Fuchs, D., & Hodgson, J. M. (2015). Regular consumption of black tea increases circulating kynurenine concentrations: A randomized controlled trial. BBA Clinical, 3, 31–35.PubMedCentralPubMedCrossRefGoogle Scholar
  40. Guillot, E., Vaugelade, P., Lemarchal, P., & Rérat, A. (1993). Intestinal absorption and liver uptake of medium-chain fatty acids in non-anaesthetized pigs. Britsh Journal of nutrition, 69(2), 431–442.CrossRefGoogle Scholar
  41. Guri, A. J., Hontecillas, R., Ferrer, G., Casagran, O., Wankhade, U., Noble, A. M., & Bassaganya-Riera, J. (2007a). The loss of PPAR gamma in immune cells abrogates the ability of abscisic acid to improve insulin sensitivity through a mechanism involving suppression of MCP-1 expression and macrophage infiltration into white adipose tissue. Journal of the Federation of American Societies for Experimental Biology., 21(5), 64–67.Google Scholar
  42. Guri, A. J., Hontecillas, R., Si, H., Liu, D., & Bassaganya-Riera, J. (2007b). Dietary abscisic acid ameliorates glucose tolerance and obesity-related inflammation in db/db mice fed high-fat diets. Clinical Nutrition, 26(1), 107–116.PubMedCrossRefGoogle Scholar
  43. Guri, A. J., Misyak, S., Hontecillas, R., Hasty, A., Liu, D., Si, H., & Bassaganya-Riera, J. (2010). Abscisic acid ameliorates atherosclerosis by suppressing macrophage and CD4+ T cell recruitment into the aortic wall. J Nutritional Biochemistry, 21(12), 1178–1185.CrossRefGoogle Scholar
  44. Hansen, L., Dragsted, L. O., Olsen, A., Christensen, J., Tjonneland, A., Schmidt, E. B., & Overvad, K. (2010). Fruit and vegetable intake and risk of acute coronary syndrome. British Journal of Nutrition, 104(2), 248–255.PubMedCrossRefGoogle Scholar
  45. Haug, K., Salek, R. M., Conesa, P., et al. (2013). MetaboLights–an open-access general-purpose repository for metabolomics studies and associated meta-data. Nucleic Acids Research, 41, 781–786.CrossRefGoogle Scholar
  46. Heinzmann, S. S., Brown, I. J., Chan, Q., Bictash, M., Dumas, M. E., Kochhar, S., et al. (2010). Metabolic profiling strategy for discovery of nutritional biomarkers: Proline betaine as a marker of citrus consumption. The American Journal of Clinical Nutrition, 92(2), 436–443.PubMedCentralPubMedCrossRefGoogle Scholar
  47. Hoek-van den Hil, E. F., Keijer, J., Bunschoten, A., Vervoort, J. J., Stankova, B., Bekkenkamp, M., et al. (2013). Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice. PLoS One, 8, 1.CrossRefGoogle Scholar
  48. Hooper, L., Kroon, P. A., Rimm, E. B., Cohn, J. S., Harvey, I., Le Cornu, K. A., et al. (2008). Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. The American Journal of Clinical Nutrition, 88, 38–50.PubMedGoogle Scholar
  49. Horai, H., Arita, M., Kanaya, S., Nihei, Y., Ikeda, T., Suwa, K., et al. (2010). MassBank: A public repository for sharing mass spectral data for life sciences. Journal of Mass Spectrometry, 45(7), 703–714.Google Scholar
  50. Houston, M. C. (2005). Nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension. Progress in Cardiovascular Diseases, 47(6), 396–449.PubMedCrossRefGoogle Scholar
  51. Howard, B. V., Van Horn, L., Hsia, J., Manson, J. E., Stefanick, M. L., Wassertheil-Smoller, S., et al. (2006). Low-fat dietary pattern and risk of cardiovascular disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA, 295(6), 655–666.Google Scholar
  52. Huang, J., Sun, J., Chen, Y., Song, Y., Dong, L., et al. (2012). Analysis of multiplex endogenous estrogen metabolites in human urine using ultra-fast liquid chromatography–tandem mass spectrometry: A case study for breast cancer. Analica Chimica Acta, 711, 60–68.CrossRefGoogle Scholar
  53. Ignarro, L. J., Balestrieri, M. L., & Napoli, C. (2007). Nutrition, physical activity, and cardiovascular disease: An update. Cardiovascular Research, 73(2), 326–340.PubMedCrossRefGoogle Scholar
  54. Ito, H., Gonthier, M. P., Manach, C., Morand, C., Mennen, L., Rémésy, C., & Scalbert, A. (2005). Polyphenol levels in human urine after intake of six different polyphenol-rich beverages. British Journal of Nutrition, 94(4), 500–509.PubMedCrossRefGoogle Scholar
  55. Jacobs, D. M., Fuhrmann, J. C., van Dorsten, F. A., Rein, D., Peters, S., van Velzen, E. J. J., et al. (2012). Impact of short-term intake of red wine and grape polyphenol extract on the human metabolome. Journal of Agricultural and Food Chemistry, 60, 3078–3085.PubMedCrossRefGoogle Scholar
  56. Jenab, M., Slimani, N., Bictash, M., Ferrari, P., & Bingham, S. A. (2009). Biomarkers in nutritional epidemiology: Applications, needs and new horizons. Human Genetics, 125(5–6), 507–525.PubMedCrossRefGoogle Scholar
  57. Jin, Y., Gordon, M. H., Alimbetov, D., Chong, M. F., George, T. W., Spencer, J. P., et al. (2014). A novel combined biomarker including plasma carotenoids, vitamin C, and ferric reducing antioxidant power is more strongly associated with fruit and vegetable intake than the individual components. Journal of Nutrition, 144(11), 1866–1872.PubMedCrossRefGoogle Scholar
  58. Kang, S. H., Shin, H. J., Lee, & K. W., (2011). Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis. Pharmacology and Therapeutics, 130(3), 310–324.PubMedCrossRefGoogle Scholar
  59. Keppler, K., & Humpf, H. U. (2005). Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorganic and Medicinal Chemistry, 13(17), 5195–5205.PubMedCrossRefGoogle Scholar
  60. Khan, F., Raya, S., Craigie, A. M., Kennedy, G., Hill, A., Barton, K. L., et al. (2014). Lowering of oxidative stress improves endothelial function in healthy subjects with habitually low intake of fruit and vegetables: A randomized controlled trial of antioxidant- and polyphenol-rich blackcurrant juice. Free Radical Biology and Medicine, 72, 232–237.PubMedCrossRefGoogle Scholar
  61. Kris-Etherton, P. M., Hecker, K. D., Bonanome, A., Coval, S. M., Binkoski, A. E., Hilpert, K. F., et al. (2002). Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer. American Journal of Medicine, 113(9), 71–88.CrossRefGoogle Scholar
  62. Krogholm, K. S., Bysted, A., Brantsæter, A. L., Jakobsen, J., Rasmussen, S. E., Kristoffersen, L., & Toft, U. (2012). Evaluation of flavonoids and enterolactone in overnight urine as intake biomarkers of fruits, vegetables and beverages in the Inter99 cohort study using the method of triads. British Journal of Nutrition, 108(10), 1904–1912.PubMedCrossRefGoogle Scholar
  63. Krupp, D., Doberstein, N., Shi, L., & Remer, T. (2012). Hippuric acid in 24-hour urine collections is a potential biomarker for fruit and vegetable consumption in healthy children and adolescents. Journal of Nutrition, 142(7), 1314–1320.PubMedCrossRefGoogle Scholar
  64. Kuhl, C., Tautenhahn, R., Böttcher, C., Larson, T. R., & Neumann, S. (2012). CAMERA: An integrated strategy for compound spectra extraction and annotation of liquid chromatography/mass spectrometry data sets. Analytical Chemistry, 84(1), 283.PubMedCentralPubMedCrossRefGoogle Scholar
  65. Lee, H. C., Jenner, A. M., Lowa, C. S., & Lee, Y. K. (2006). Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Research in Microbiology, 157, 876–884.PubMedCrossRefGoogle Scholar
  66. Lee, H. C., Lai, C. K., Yau, K. C., Siu, T. S., Mak, C. M., et al. (2012). Non-invasive urinary screening for aromatic L-amino acid decarboxylase deficiency in high-prevalence areas: A pilot study. Clinica Chimica Acta, 413, 126–130.CrossRefGoogle Scholar
  67. Lees, H. J., Swann, J. R., Wilson, I. D., Nicholson, J. K., & Holmes, E. (2013). Hippurate: The natural history of a mammalian-microbial cometabolite. Journal or Proteome Research, 12(4), 1527–1546.PubMedCrossRefGoogle Scholar
  68. Lin, L.-Z., & Harnly, J. M. (2008). Phenolic compounds and chromatographic profiles of pear skins (Pyrus spp.). Journal pf Agricultural Food Chemistry, 56(19), 9094–9101.CrossRefGoogle Scholar
  69. Liu, R. H. (2013). Health-promoting components of fruits and vegetables in the diet. Advances in Nutrition: An International Review Journal, 4(3), 384–392.CrossRefGoogle Scholar
  70. Llorach, R., Garrido, I., Monagas, M., Urpi-Sarda, M., Tulipani, S., Bartolome, B., & Andres-Lacueva, C. (2010). Metabolomics study of human urinary metabolome modifications after intake of almond (Prunus dulcis (Mill.) D.A. Webb) skin polyphenols. Journal of Proteome Research, 9(11), 5859–5866.PubMedCrossRefGoogle Scholar
  71. Llorach, R., Urpi-Sarda, M., Jauregui, O., Monagas, M., & Andres-Lacueva, C. (2009). An LC-MS-based metabolomics approach for exploring urinary metabolome modifications after cocoa consumption. Journal of Proteome Research, 8(11), 5060–5068.PubMedCrossRefGoogle Scholar
  72. Llorach, R., Urpi-Sarda, M., Tulipani, S., Garcia-Aloy, M., Monagas, M., & Andres-Lacueva, C. (2013). Metabolomic fingerprint in patients at high risk of cardiovascular disease by cocoa intervention. Molecular Nutrition and Food Research, 57(6), 962–973.PubMedCrossRefGoogle Scholar
  73. Lloyd, A. J., Beckmann, M., Favé, G., Mathers, J. C., & Draper, J. (2011). Proline betaine and its biotransformation products in fasting urine samples are potential biomarkers of habitual citrus fruit consumption. British Journal of Nutrition, 106(6), 812–824.PubMedCrossRefGoogle Scholar
  74. Lloyd, A. J., Beckmann, M., Haldar, S., Seal, C., Brandt, K., & Draper, J. (2012). Data-driven strategy for the discovery of potential urinary biomarkers of habitual dietary exposure. The American Journal of Clinical Nutrition, 97(2), 377–389.PubMedCrossRefGoogle Scholar
  75. Lourida, I., Soni, M., Thompson-Coon, J., Purandare, N., Lang, I., Ukoumunne, O. C., & Llewellyn, D. J. (2013). Mediterranean diet, cognitive function, and dementia: A systematic review. Epidemiology, 24(4), 479–489.PubMedCrossRefGoogle Scholar
  76. Macready, A. L., George, T. W., Chong, M. F., Alimbetov, D. S., Jin, Y., Vidal, A., et al. (2014). Flavonoid-rich fruit and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease—FLAVURS: A randomized controlled trial. The American Journal of Clinical Nutrition, 99(3), 479–489.PubMedCrossRefGoogle Scholar
  77. Magnone, M., Bruzzone, S., Guida, L., Damonte, G., Millo, E., Scarfì, S., et al. (2009). Abscisic acid released by human monocytes activates monocytes and vascular smooth muscle cell responses involved in atherogenesis. Journal of Biological Chemistry, 284(26), 17808–17818.PubMedCentralPubMedCrossRefGoogle Scholar
  78. Mamas, M., Dunn, W. B., Neyses, L., & Goodacre, R. (2011). The role of metabolites and metabolomics in clinically applicable biomarkers of disease. Archives of Toxicology, 85(1), 5–17.PubMedCrossRefGoogle Scholar
  79. May, D. H., Navarro, S. L., Ruczinski, I., Hogan, J., Ogata, Y., Schwarz, Y., et al. (2013). Metabolomic profiling of urine: Response to a randomised, controlled feeding study of select fruits and vegetables, and application to an observational study. British Journal of Nutrition, 110(10), 1760–1770.PubMedCrossRefGoogle Scholar
  80. Medina, S., Domínguez-Perles, R., Ferreres, F., Tomás-Barberán, F. A., & Gil-Izquierdo, A. (2013). The effects of the intake of plant foods on the human metabolome. Trends in Analytical Chemistry, 52, 88–99.CrossRefGoogle Scholar
  81. Mendes-Pinto, M. M. (2009). Carotenoid breakdown products the-norisoprenoidsin wine aroma. Archives of Biochemistry and Biophysics, 483, 236–245.PubMedCrossRefGoogle Scholar
  82. Mendis, S. (2014). Global status report on noncommunicable diseases 2014. Switzerland: World Health Organization.Google Scholar
  83. Mitoma, C., Posner, H., & Leonard, F. (1958). Aromatization of hexahydrobenzoic acid by mamalian liver mitochondria. Biochimica et Biophysica Acta, 27(1), 156–160.PubMedCrossRefGoogle Scholar
  84. Murata, S., Miniati, D. N., Kown, M. H., Koransky, M. L., Balsam, L. B., Lijkwan, M. A., et al. (2003). Elevated cyclic adenosine monophosphate ameliorates ischemia-reperfusion injury in rat cardiac allografts. Journal of Heart and Lung Transplantation, 22, 802–809.PubMedCrossRefGoogle Scholar
  85. Norskov, N. P., Hedemann, M. S., Lærke, H. N., & Knudsen, K. E. (2013). Multicompartmental nontargeted LC-MS metabolomics: Explorative study on the metabolic responses of rye fiber versus refined wheat fiber intake in plasma and urine of hypercholesterolemic pigs. Journal of Proteome Research, 12(6), 2818–2832.PubMedCrossRefGoogle Scholar
  86. Obarzanek, E., Sacks, F. M., Vollmer, W. M., et al. (2001). Effects on blood lipids of a blood pressure-lowering diet: The dietary approaches to stop hypertension (DASH) trial. The American Journal of Clinical Nutrition, 74, 80–89.PubMedGoogle Scholar
  87. Olthof, M. R., Hollman, P. C., Buijsman, M. N., van Amelsvoort, J. M., & Katan, M. B. (2003). Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans. Journal of Nutrition, 133(6), 1806–1814.PubMedGoogle Scholar
  88. Papamandjaris, A. A., MacDougall, D. E., & Jones, P. J. (1998). Medium chain fatty acid metabolism and energy expenditure: Obesity treatment implications. Life Science, 62(14), 1203–1215.CrossRefGoogle Scholar
  89. Pekkinen, J., Rosa, N. N., Savolainen, O. I., Keski-Rahkonen, P., Mykkänen, H., Poutanen, K., et al. (2014). Disintegration of wheat aleurone structure has an impact on the bioavailability of phenolic compounds and other phytochemicals as evidenced by altered urinary metabolite profile of diet-induced obese mice. Nutrition & Metabolism., 11(1), 1–15.CrossRefGoogle Scholar
  90. Piazzon, A., Vrhovsek, U., Masuero, D., Mattivi, F., Mandoj, F., & Nardini, M. (2012). Antioxidant activity of phenolic acids and their metabolites: Synthesis and antioxidant properties of the sulfate derivatives of ferulic and caffeic acids and of the acyl glucuronide of ferulic acid. Journal of Agricultural and Food Chemistry, 60(50), 12312–12322.PubMedCrossRefGoogle Scholar
  91. Pojer, E., Mattivi, F., Johnson, D., & Stockley, C. S. (2013). The Case for Anthocyanin Consumptionto Promote Human Health: A Review. Comprehensive Reviews in Food Science and Food Safety, 12(5), 483–508.CrossRefGoogle Scholar
  92. Possemiers, S., Bolca, S., Eeckhaut, E., Depypere, H., & Verstraete, W. (2007). Metabolism of isofavones, lignans and prenylfavonoids by intestinal bacteria: Producer phenotyping and relation with intestinal community. FEMS Microbiology Ecology, 61(2), 1372–1383.CrossRefGoogle Scholar
  93. Pujos-Guillot, E., Hubert, J., Martin, J. F., et al. (2013). Mass spectrometry-based metabolomics for the discovery of biomarkers of fruit and vegetable intake: Citrus fruit as a case study. Journal of Proteome Research, 12(4), 1645–1659.PubMedCrossRefGoogle Scholar
  94. Rago, D., Gurdeniz, G., Ravn-Haren, G., & Dragsted, L. (2015). An explorative study of the effect of apple and apple products on the human plasma metabolome investigated by LC–MS profiling. Metabolomics, 11, 27–39.CrossRefGoogle Scholar
  95. Rechner, A. R., Pannala, A. S., & Rice-Evans, C. A. (2001a). Caffeic acid derivatives in artichoke extract are metabolized to phenolic acids in vivo. Free Radical Research, 35, 195–202.PubMedCrossRefGoogle Scholar
  96. Rechner, A. R., Spencer, J. P., Kuhnle, G., Hahn, U., & Rice- Evans, C. A. (2001b). Novel biomarkers of the metabolism of caffeic acid derivatives in vivo. Free Radical Biology and Medicine, 30(11), 1213–1222.PubMedCrossRefGoogle Scholar
  97. Russell, W., & Duthie, G. (2011). Plant secondary metabolites and gut health: The case for phenolic acids. Proceedings of the Nutrition Society, 70(3), 389–396.PubMedCrossRefGoogle Scholar
  98. Saha, S., Hollands, W., Teucher, B., Needs, P. W., Narbad, A., Ortori, C. A., et al. (2012). Isothiocyanate concentrations and interconversion of sulforaphane to erucin in human subjects after consumption of commercial frozen broccoli compared to fresh broccoli. Molecular Nutrition & Food Research, 56(12), 1906–1916.CrossRefGoogle Scholar
  99. Sanchez-Patan, F., Chioua, M., Garrido, I., Cueva, C., Samadi, A., Marco-Contelles, J., et al. (2011). Synthesis, analytical features, and biological relevance of 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone, a microbial metabolite derived from the catabolism of dietary flavan-3-ols. Journal of Agricultural and Food Chemistry, 59(13), 7083–7091.PubMedCrossRefGoogle Scholar
  100. Sang, S., Lee, M. J., Yang, I., Buckley, B., & Yang, C. S. (2008). Human urinary metabolite profile of tea polyphenols analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry with data-dependent acquisition. Rapid Communications in Mass Spectrometry, 22(10), 1567–1578.Google Scholar
  101. Scalbert, A., Brennan, L., Manach, C., Andres-Lacueva, C., Dragsted, L. O., Draper, J., et al. (2014). The food metabolome: A window over dietary exposure. The American Journal of Clinical Nutrition, 99(6), 1286–1308.PubMedCrossRefGoogle Scholar
  102. Scarfì, S., Fresia, C., Ferraris, C., Bruzzone, S., Fruscione, F., Usai, C., et al. (2009). The plant hormone abscisic acid stimulates the proliferation of human hemopoietic progenitors through the second messenger cyclic ADP-ribose. Stem Cells, 27(10), 2469–2477.PubMedCrossRefGoogle Scholar
  103. Schmidt-Andersen, M. J., Reinbach, H. C., Rinnan, A., Barri, T., Mithril, C., & Dragsted, L. O. (2013). Discovery of exposure markers in urine for Brassica-containing meals served with different protein sources by UPLC-qTOF-MS untargeted metabolomics. Metabolomics, 9(5), 984–997.CrossRefGoogle Scholar
  104. Sesso, H. D., Gaziano, J. M., Liu, S., & Buring, J. E. (2003). Flavonoid intake and the risk of cardiovascular disease in women. The American Journal of Clinical Nutrition, 77(6), 1400–1408.PubMedGoogle Scholar
  105. Smith, C., Maille, G., Want, E., et al. (2005) METLIN: A metabolite mass spectral database. Therapeutic Drug Monitoring, 27, 747–751.Google Scholar
  106. Smith, C. A., Want, E. J., O’Maille, G., Abagyan, R., & Siuzdak, G. (2006). XCMS: Processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Analytical Chemistry, 78(3), 779–787.PubMedCrossRefGoogle Scholar
  107. Stalmach, A., Mullen, W., Barron, D., Uchida, K., Yokota, T., Cavin, C., et al. (2009). Metabolite profiling of hydroxycinnamate derivatives in plasma and urine after the ingestion of coffee by humans: Identification of biomarkers of coffee consumption. Drug Metabolism and Disposition, 37(8), 1749–1758.PubMedCrossRefGoogle Scholar
  108. Stanstrup, J., Schou, S. S., Holmer-Jensen, J., Hermansen, K., & Dragsted, L. O. (2014). Whey protein delays gastric emptying and suppresses plasma fatty acids and their metabolites compared to casein, gluten, and fish protein. Journal of Proteome Research, 13(5), 2396–2408.PubMedCrossRefGoogle Scholar
  109. Stephens, N. G., Parsons, A., Schofield, P. M., Kelly, F., Cheeseman, K., Mitchinson M. J. (1996). Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet, 347(9004):781–786.Google Scholar
  110. Sturla, L., Fresia, C., Guida, L., Bruzzone, S., Scarfì, S., Usai, C., et al. (2009). LANCL2 is necessary for abscisic acid binding and signaling in human granulocytes and in rat insulinoma cells. The Journal of biological chemistry, 284(41), 28045–28057.PubMedCentralPubMedCrossRefGoogle Scholar
  111. Sturm, M., Bertsch, A., Gröpl, C., Hildebrandt, A., Hussong, R., Lange, E., et al. (2008). OpenMS—an open-source software framework for mass spectrometry. BMC Bioinformatics, 9(163), 1–11.Google Scholar
  112. Sud, Fahy E., Cotter, D., Brown, A., Dennis, E. A., Glass, C. K., Merrill, A. H., et al. (2006). LMSD: Lipid maps structure database. Nucleic Acids Research, 35, 527–532.CrossRefGoogle Scholar
  113. Theodoratou, E., Kyle, J., Cetnarskyj, R., Farrington, S. M., Tenesa, A., Barnetson, R., & Campbell, H. (2007). Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiology, Biomarkers and Prevention, 16(4), 684–693.PubMedCrossRefGoogle Scholar
  114. Tomas-Barberan, F. A., Cienfuegos-Jovellanos, E., Marín, A., Muguerza, B., Gil-Izquierdo, A., Cerda, B., et al. (2007). A new process to develop a cocoa powder with higher flavonoid monomer content and enhanced bioavailability in healthy humans. Journal of Agricultural and Food Chemistry, 55(10), 3926–3935.Google Scholar
  115. Tremaroli, V., & Bäckhed, F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature, 489(7415), 242–249.PubMedCrossRefGoogle Scholar
  116. Tulipani, S., Urpi-Sarda, M., García-Villalba, R., et al. (2012). Urolithins are the main urinary microbial-derived phenolic metabolites discriminating a moderate consumption of nuts in free-living subjects with diagnosed metabolic syndrome. Journal of Agricultural and Food Chemistry, 60(36), 8930–8940.PubMedCrossRefGoogle Scholar
  117. Urpi-Sarda, M., Garrido, I., Monagas, M., Gómez-Cordovés, C., Medina-Remón, A., Andres-Lacueva, C., & Bartolomé, B. (2009a). Profile of plasma and urine metabolites after the intake of almond [Prunus dulcis (Mill.) D.A. Webb] polyphenols in humans. Journal of Agricultural and Food Chemistry, 57(21), 10134–10142.PubMedCrossRefGoogle Scholar
  118. Urpi-Sarda, M., Monagas, M., Khan, N., Llorach, R., Lamuela-Raventós, R. M., Jáuregui, O., et al. (2009b). Targeted metabolic profiling of phenolics in urine and plasma after regular consumption of cocoa by liquid chromatography-tandem mass spectrometry. Journal Chromatography A, 1216(43), 7258–7267.CrossRefGoogle Scholar
  119. Vallverdú-Queralt, A., Jáuregui, O., Medina-Remón, A., Andrés-Lacueva, C., & Lamuela-Raventós, R. M. (2010). Improved characterization of tomato polyphenols using liquid chromatography/electrospray ionization linear ion trap quadrupole Orbitrap mass spectrometry and liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Communications in Mass Spectrometry, 24, 2986–2992.PubMedCrossRefGoogle Scholar
  120. van der Hooft, J. J., de Vos, R. C., Mihaleva, V., Bino, R. J., Ridder, L., de Roo, N., et al. (2012). Structural elucidation and quantification of phenolic conjugates present in human urine after tea intake. Analytical Chemistry, 84(16), 7263–7271.PubMedCrossRefGoogle Scholar
  121. van Duynhoven, J., van der Hooft, J. J., van Dorsten, F. A., Peters, S., Foltz, M., Gomez-Roldan, V., et al. (2014). Rapid and sustained systemic circulation of conjugated gut microbial catabolites after single-dose black tea extract consumption. Journal of Proteome Research, 13(5), 2668–2678.PubMedCrossRefGoogle Scholar
  122. Vermeulen, M., van den Berg, R., Freidig, A. P., van Bladeren, P. J., & Vaes, W. H. (2006). Association between consumption of cruciferous vegetables and condiments and excretion in urine of isothiocyanate mercapturic acids. Journal of Agricultural and Food Chemistry, 54(15), 5350–5358.PubMedCrossRefGoogle Scholar
  123. Vrhovsek, U., Masuero, D., Gasperotti, M., Franceschi, P., Caputi, L., Viola, R., & Mattivi, F. (2012). Versatile targeted metabolomics method for the rapid quantification of multiple classes of phenolics in fruits and beverages. Journal of Agricultural and Food Chemistry, 60(36), 8831–8840.PubMedCrossRefGoogle Scholar
  124. Walle, T. (2004). Absorption and metabolism of flavonoids. Free Radical Biology and Medicine, 36(7), 829–837.PubMedCrossRefGoogle Scholar
  125. Wang, S., Melnyk, J. P., Tsao, R., & Marcone, M. F. (2011). How natural dietary antioxidants in fruits, vegetables and legumes promote vascular health. Food Research International, 44(1), 14–22.CrossRefGoogle Scholar
  126. Want, E. J., Masson, P., Michopoulos, F., Wilson, I. D., Theodoridis, G., Plumb, R. S., et al. (2013). Global metabolic profiling of animal and human tissues via UPLC-MS. Nature Protocols, 8(1), 17–32.PubMedCrossRefGoogle Scholar
  127. Wheeler, L. A., Halula, M., De Meo, M., Sutter, V. L., & Finegold, S. M. (1979). Metabolism of shikimic, quinic and cyclohexanecabooxylic acid in germfree, conventional and gnotobiotic rats. Current Microbiology, 2, 85–90.CrossRefGoogle Scholar
  128. Williams, R. J., & Spencer, J. P. (2012). Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimerdisease. Free Radical Biology and Medicine, 52(1), 35–45.PubMedCrossRefGoogle Scholar
  129. Wishart, D. S., Knox, C., Guo, A. C., et al. (2009). HMDB: A knowledgebase for the human metabolome. Nucleic Acids Research, 37, 603–610.CrossRefGoogle Scholar
  130. Yasuda, T., Inaba, A., Ohmori, M., Endo, T., Kubo, S., & Ohsawa, K. (2000). Urinary metabolites of gallic acid in rats and their radical-scavenging effects on 1,1-diphenyl-2-picrylhydrazyl radical. Journal of Natural Products, 63(10), 1444–1446.PubMedCrossRefGoogle Scholar
  131. Yun, J. M., Jialal, I., & Devaraj, S. (2010). Effects of epigallocatechin gallate on regulatory T cell number and function in obese v. lean volunteers. British Journal of Nutrition, 103, 1771–1777.PubMedCrossRefGoogle Scholar
  132. Zamora-Ros, R., Knaze, V., Luján-Barroso, L., et al. (2013). Differences in dietary intakes, food sources and determinants of total flavonoids between Mediterranean and non-Mediterranean countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. British Journal of Nutrition, 109(8), 1498–1507.PubMedCrossRefGoogle Scholar
  133. Zamora-Ros, R., Touillaud, M., Rothwell, J. A., Romieu, I., & Scalbert, A. (2014). Measuring exposure to the polyphenol metabolome in observational epidemiologic studies: Current tools and applications and their limits. The American Journal of Clinical Nutrition, 100(1), 11–26.PubMedCentralPubMedCrossRefGoogle Scholar
  134. Zhang, A., Sun, H., Wang, P., Han, Y., & Wang, X. (2012). Recent and potential developments of biofluid analyses in metabolomics. Journal of Proteomics., 75, 1079–1088.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Maria M. Ulaszewska
    • 1
    Email author
  • Kajetan Trost
    • 1
    • 2
  • Jan Stanstrup
    • 1
  • Kieran M. Tuohy
    • 1
    Email author
  • Pietro Franceschi
    • 1
  • Mary Foong-Fong Chong
    • 3
    • 4
  • Trevor George
    • 3
    • 5
  • Anne Marie Minihane
    • 3
    • 6
  • Julie A. Lovegrove
    • 3
  • Fulvio Mattivi
    • 1
    Email author
  1. 1.Department of Food Quality and Nutrition, Research and Innovation CentreFondazione Edmund Mach (FEM)San Michele all’AdigeItaly
  2. 2.Wine Research CentreUniversity of Nova GoricaNova GoricaSlovenia
  3. 3.Hugh Sinclair Unit of Human Nutrition and the Institute for Cardiovascular and Metabolic Research (ICMR), Department of Food and Nutritional SciencesUniversity of ReadingReadingUK
  4. 4.Singapore Institute for Clinical SciencesBrenner CentreSingaporeSingapore
  5. 5.Department of Applied Sciences, Faculty of Health and Life SciencesNorthumbria UniversityNewcastle upon TyneUK
  6. 6.Department of Nutrition, Norwich Medical SchoolUniversity of East AngliaNorwichUK

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