Regulatory Impact of Polyphenols on Intestinal Microbiota Composition and Neuroprotective Effects of These Compounds

Year 2020, Volume: 18 Issue: 2, 190 - 208, 27.06.2020

Firdevs Çimen , Havva Polat Lütfiye Ekici

https://doi.org/10.24323/akademik-gida.758838

Cited By: 2

Abstract

Intestinal microbiota consisting of trillions of microorganisms and interacting with the host from birth to old age; it varies depending on the way of birth, nutrition habits, age, disease condition, antibiotic use, environmental and cultural factors. Polyphenol-rich foods such as blackberries, grapes, apples, oranges, legumes, tea, cocoa, honey and wine can regulate the gut microbiota composition. This is explained by the fact that polyphenols exert a prebiotic effect on intestinal bacteria. In the development of intestinal and neurological diseases, the bilateral relationship between the brain and the intestine comes to the fore and this relationship is called the brain-gut axis. Dysbiosis, which can be seen as a result of negative changes in the microbiota composition, poses an important problem for brain-gut axis balance. Polyphenols offer beneficial effects in the treatment of intestinal and neurological diseases by modulating the microbiota-intestinal-brain axis. The beneficial effects of polyphenols can be explained not only by their ability to regulate intestinal microbiota, but also by their ability to reduce brain neuroinflammation, improve memory and cognitive function. These properties make polyphenols promising nutraceuticals to combat many diseases, especially neurodegenerative disorders, cardiovascular disorders. The aim of this article is to compile up-to-date information on the beneficial effects of polyphenols, which have important functions against various intestinal and neurological diseases associated with reduced microbiological diversity or undesired composition in microbiota.

Keywords

Polyphenols, Gut microbiota, Brain-gut axis, Dysbiosis, Neurodegenerative disorders

Polifenollerin Bağırsak Mikrobiyota Kompozisyonunu Düzenleyici ve Nöroprotektif Etkileri

Abstract

Trilyonlarca mikroorganizmadan oluşan ve doğumdan yaşlılığa kadar konakçı ile etkileşim halinde bulunan bağırsak mikrobiyotası; doğum şekli, beslenme alışkanlıkları, yaş, hastalık durumu, antibiyotik kullanımı, çevresel ve kültürel faktörlere bağlı olarak değişiklik göstermektedir. Böğürtlen, üzüm, elma, portakal, baklagiller, çay, kakao, bal ve şarap gibi polifenol açısından zengin gıdalar bağırsak mikrobiyota kompozisyonunu düzenleyebilmektedir. Bu durum polifenollerin bağırsak bakterileri üzerinde prebiyotik etki göstermeleri ile açıklanmaktadır. Bağırsak ve nörolojik hastalıkların gelişiminde, beyin ve bağırsak arasında çift yönlü ilişki ön plana çıkmaktadır. Bu ilişkiye beyin-bağırsak hattı denilmektedir. Mikrobiyota kompozisyonundaki olumsuz yöndeki değişiklikler sonucu görülen disbiyozis, beyin-bağırsak hattı dengesi için önemli sorun teşkil etmektedir. Polifenoller, beyin-bağırsak hattının modülasyonu yoluyla, bağırsak ve nörolojik hastalıkların tedavisinde yararlı etkiler sunmaktadır. Polifenollerin yararlı etkileri sadece bağırsak mikrobiyotasını düzenleyebilme yetenekleri ile değil, aynı zamanda beyin nöroenflamasyonunu azaltma, hafıza ve bilişsel işlevi geliştirme yetenekleriyle de açıklanabilmektedir. Bu özellikleri polifenolleri nörodejeneratif bozukluklar ve kardiyovasküler rahatsızlıklar başta olmak üzere birçok hastalıkla mücadele etmek için umut verici nutrasötikler konumuna getirmektedir. Bu makalenin amacı mikrobiyata çeşitliliğinde azalması ya da mikrobiyota kompozisyonunun arzu edilmeyen şekilde değişmesi ile ilişkilendirilen çeşitli bağırsak ve nörolojik hastalıklara karşı önemli işlevleri bulunan polifenollerin, insan sağlığına yararlı etkileri hakkında güncel bilgileri derlemektir.

Keywords

Polifenoller, Bağırsak mikrobiyotası, Beyin-bağırsak hattı, Disbiyozis, Nörodejeneratif bozukluklar

References

• [1] Pandey, K.B., Rizvi, S.I. (2009). Plant polyphenols as dietary antioxidants in human health and disease. Oxidative Medicine and Cellular Longevity, 2(5), 270-278.
• [2] Oksana, S., Marian, B., Mahendra, R., Hong B.S. (2012). Plant phenolic compounds for food, pharmaceutical and cosmetiсs production. Journal of Medicinal Plants Research, 6(13), 2526-2539.
• [3] Talay, R., Erdoğan, Ü. (2018). Fenolik bileşenler ve bağırsak bakterileri arasında karşılıklı etkileşim. Türk Tarım - Gıda Bilim ve Teknoloji Dergisi, 6 (11), 1562-1568.
• [4] Selamoğlu, Z. (2017). Polyphenolic compounds in human health with pharmacological properties. Journal of Traditional Medicine & Clinical Naturopathy, 6(4).
• [5] Filosa, S., Di Meo, F., Crispi, S. (2018). Polyphenols-gut microbiota interplay and brain neuromodulation. Neural Regeneration Research, 13(12), 2055-2059.
• [6] Di Meo, F., Donato, S., Di Pardo, A., Maglione, V., Filosa, S., Crispi, S. (2018). New therapeutic drugs from bioactive natural molecules: The role of gut microbiota metabolism in neurodegenerative diseases. Current Drug Metabolism, 19(6), 478-489.
• [7] Özer, M., Özyurt, G., Tellioğlu Harsa, Ş. (2019). Probiyotik ve prebiyotiklerin bağırsak-beyin aksına etkisi. Akademik Gıda, 17 (2), 269–280.
• [8] Şahin, A. (2011). Hastalıkta ve sağlıkta gastrointestinal flora: Mikrobiyota. Güncel Gastroenteroloji, 22(3),156-166.
• [9] Cueva, C., Sánchez, G.-I., Moreno-Arribas, M.V., Sualdea, B.B. (2016). Interactions between wine polyphenols and gut microbiota. In: Wine Safety, Consumer Preference, and Human Health, Edited by M.V. Moreno-Arribas, B. Bartolomé Sualdea, Springer International Publishing Switzerland, 259-278p.
• [10] Dueñas, M., Muñoz-González, I., Cueva, C., Jiménez-Girón, A., Sánchez-Patán, F., Santos-Buelga, C., M. Moreno-Arribas, V., Bartolomé, Begoña. (2015). A survey of modulation of gut microbiota by dietary polyphenols. BioMed Research International, 2015, 1-15.
• [11] Bonaccio, M., Pounis, G., Cerletti, C., Donati, M.B., Iacoviello, L., de Gaetano, G. (2017). Mediterranean diet, dietary polyphenols and low grade inflammation: Results from the MOLI-SANI study. British Journal of Clinical Pharmacology, 83(1), 107-113.
• [12] Liu, X.M., Liu, Y.J., Huang, Y., Yu, H.J., Yuan, S., Tang, B.W., Wang, P.G., He, Q.Q. (2017). 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. Molecular Nutrition and Food Research, 61(6), 12-30.
• [13] Mitjavila, M.T., Moreno, J.J. (2012). The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases. Biochemical Pharmacology, 84(9), 1113-1122.
• [14] Özenoğlu, A. (2018). Duygu durumu, besin ve beslenme ilişkisi. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi, 9(4), 357-365.
• [15] Alagöz, A.N. (2017). Mikrobiyota ve nörodejenerasyon. Journal of Biotechnology and Strategic Health Research, 1, 115-122.
• [16] Collins, S.M., Surette, M., Bercik, P. (2012). The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology, 10(11), 735-742.
• [17] Adak, A., Khan, M.R. (2019). An insight into gut microbiota and its functionalities. Cellular and Molecular Life Sciences, 76(3), 473-493.
• [18] Shahidi, F., Ho, C.T. (2005). Phenolics in food and natural health products: An overview. ACS Symposium Series, 2, 1-8.
• [19] Vermerris, W., Nicholson, R. (2006). Phenolic compound biochemistry. Springer, Dordrecht, The Netherlands.
• [20] Rahman, I., Biswas, S.K., Kirkham, P.A. (2006). Regulation of inflammation and redox signaling by dietary polyphenols. Biochemical Pharmacology, 72(11), 1439-1452. [21] Romier, B., Schneider, Y.J., Larondelle, Y., During, A. (2009). Dietary polyphenols can modulate the intestinal inflammatory response. Nutrition Reviews, 67(7), 363-378.
• [22] Del Rio, D., Rodriguez-Mateos, A., Spencer, J.P.E., Tognolini, M., Borges, G., Crozier, A. (2013). Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxidants and Redox Signaling, 18(14), 1818-1892.
• [23] Manach, C., Scalbert, A., Morand, C., Rémésy, C., Jiménez, L. (2004). Polyphenols: Food sources and bioavailability. American Journal of Clinical Nutrition, 79(5), 727-747.
• [24] Acar, J., Gökmen, V. (2014). Fenolik Bileşikler ve Doğal Renk Maddeleri. İçinde Gıda Kimyası, Editör Saldamlı, İ. Hacettepe Üniversitesi Yayınları, Ankara, 557-587p.
• [25] Cemeroğlu, B. (2016). Meyve ve Sebze İşleme Teknolojisi. Bizim Grup Basımevi, Ankara.
• [26] Campos, P.B., Paulsen, B.S., Rehen, S.K. (2014). Accelerating neuronal aging in in vitro model brain disorders: A focus on reactive oxygen species. Frontiers in Aging Neuroscience, 6(292), 1-10.
• [27] Gu, F., Chauhan, V., Chauhan, A. (2015). Glutathione redox imbalance in brain disorders. Current Opinion in Clinical Nutrition and Metabolic Care, 18(1), 89-95.
• [28] Moldovan, L., Moldovan, N.I. (2004). Oxygen free radicals and redox biology of organelles. Histochemistry and Cell Biology, 122(4), 395-412.
• [29] Duthie, G., Crozier, A. (2000). Plant-derived phenolic antioxidants. Current Opinion in Lipidology, 11(1), 43-47.
• [30] Akagawa, M., Shigemitsu, T., Suyama, K. (2003). Production of hydrogen peroxide by polyphenols and polyphenol-rich beverages under quasi-physiological conditions. Bioscience, Biotechnology and Biochemistry, 67(12), 2632-2640.
• [31] Ikigai, H., Nakae, T., Hara, Y., Shimamura, T. (1993). Bactericidal catechins damage the lipid bilayer. BBA - Biomembranes, 1147(1), 132-136.
• [32] Fraga, C.G., Galleano, M., Verstraeten, S. V., Oteiza, P.I. (2010). Basic biochemical mechanisms behind the health benefits of polyphenols. Molecular Aspects of Medicine, 31(6), 435-445.
• [33] Colin, D., Limagne, E., Jeanningros, S., Jacquel, A., Lizard, G., Athias, A., Gambert, P., Hichami, A., Latruffe, N., Solary, E., Delmas, D. (2011). Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells. Cancer Prevention Research, 4(7), 1095-1106.
• [34] Tomás-Barberán, F.A., Selma, M. V., Espín, J.C. (2016). Interactions of gut microbiota with dietary polyphenols and consequences to human health. Current Opinion in Clinical Nutrition and Metabolic Care, 19(6), 471-476.
• [35] Costabile, A., Klinder, A., Fava, F., Napolitano, A., Fogliano, V., Leonard, C., Gibson, G.R., Tuohy, K.M. (2008). Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: A double-blind, placebo-controlled, crossover study. British Journal of Nutrition, 99(1), 110-120.
• [36] Martínez, I., Lattimer, J.M., Hubach, K.L., Case, J.A., Yang, J., Weber, C.G., Louk, J.A., Rose, D.J., Kyureghian G., Peterson D.A., Haub M.D., Walter J. (2013). Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME Journal, 7(2), 269-280.
• [37] Tanaka, S., Yamamoto, K., Yamada, K., Furuya, K., Uyeno, Y. (2016). Relationship of enhanced butyrate production by colonic butyrate-producing bacteria to immunomodulatory effects in normal mice fed an insoluble fraction of Brassica rapa L. Applied and Environmental Microbiology, 82(9), 2693-2699.
• [38] Uyeno, Y., Katayama, S., Nakamura, S. (2014). Changes in mouse gastrointestinal microbial ecology with ingestion of kale. Beneficial Microbes, 5(3), 345-349.
• [39] Vaiserman, A.M., Koliada, A.K., Marotta, F. (2017). Gut microbiota: A player in aging and a target for anti-aging intervention. Ageing Research Reviews, 35(2007), 36-45.
• [40] Buddington, R.K., Sangild, P.T. (2011). Companion animals symposium: Development of the mammalian gastrointestinal tract, the resident microbiota, and the role of diet in early life. Journal of Animal Science, 89(5), 1506-1519.
• [41] Tremaroli, V., Bäckhed, F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature, 489(7415), 242-249.
• [42] Mariat, D., Firmesse, O., Levenez, F., Guimarǎes, V.D., Sokol, H., Doré, J., Corthier, G., Furet, J.P. (2009). The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiology, 9(123), 1-6.
• [43] Tiihonen, K., Ouwehand, A.C., Rautonen, N. (2010). Human intestinal microbiota and healthy ageing. Ageing Research Reviews, 9(2), 107-116.
• [44] Lepage, P., Leclerc, M.C., Joossens, M., Mondot, S., Blottière, H.M., Raes, J., Ehrlich, D., Dore, J. (2013). A metagenomic insight into our gut’s microbiome. Gut, 62(1), 146-158.
• [45] Zimmer, J., Lange, B., Frick, J.S., Sauer, H., Zimmermann, K., Schwiertz, A., Rusch, K., Klosterhalfen, S., Enck, P. (2012). A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. European Journal of Clinical Nutrition, 66(1), 53-60.
• [46] Sekirov, I., Russell, S.L., Caetano M Antunes, L., Finlay, B.B. (2010). Gut microbiota in health and disease. Physiological Reviews, 90(3), 859-904.
• [47] Chung, H., Pamp, S.J., Hill, J.A., Surana, N.K., Edelman, S.M., Troy, E.B., Reading, N.C., Villablanca, E.J., Wang, S., Mora, J.R., Umesaki, Y., Mathis, D., Benoist, C., Relman, D.A., Kasper, D.L. (2012). Gut immune maturation depends on colonization with a host-specific microbiota. Cell, 149(7), 1578-1593.
• [48] Rowland, I., Gibson, G., Heinken, A., Scott, K., Swann, J., Thiele, I., Tuohy, K. (2018). Gut microbiota functions: metabolism of nutrients and other food components. European Journal of Nutrition, 57(1), 1-24.
• [49] Collino, S., Montoliu, I., Martin, F.P.J., Scherer, M., Mari, D., Salvioli, S., Bucci, L., Ostan, R., Monti, D., Biagi, E., Brigidi, P., Franceschi, C., Rezzi, S. (2013). Metabolic signatures of extreme longevity in northern İtalian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PLoS ONE, 8(3), 1-12.
• [50] Cario, E., Gerken, G., Podolsky, D.K. (2007). Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology, 132(4), 1359-1374.
• [51] Espín, J.C., González-Sarrías, A.,Tomás-Barberán, F.A. (2017). The gut microbiota: A key factor in the therapeutic effects of (poly)phenols. Biochemical Pharmacology, 139, 82-93.
• [52] Conlon, M.A., Bird, A.R. (2015). The impact of diet and lifestyle on gut microbiota and human health. Nutrients, 7(1), 17-44.
• [53] Krishnan, S., Alden, N., Lee, K. (2015). Pathways and functions of gut microbiota metabolism impacting host physiology. Current Opinion in Biotechnology, 36, 137-145.
• [54] Dominguez-Bello, M.G., Costello, E.K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N., Knight, R. (2010). Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proceedings of the National Academy of Sciences of the United States of America, 107(26), 11971-11975.
• [55] Azad, M.B., Konya, T., Maughan, H., Guttman, D.S., Field, C.J., Chari, R.S., Sears, M.R., Becker, A.B., Scott, J.A., Kozyrskyj, A.L. (2013). Gut microbiota of healthy Canadian infants: Profiles by mode of delivery and infant diet at 4 months. Canadian Medical Association Journal, 185 (5), 373-374.
• [56] Roger, L.C., Costabile, A., Holland, D.T., Hoyles, L., McCartney, A.L. (2010). Examination of faecal Bifidobacterium populations in breast- and formula-fed infants during the first 18 months of life. Microbiology, 156(11), 3329-3341.
• [57] De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J.B., Massart, S., Collini, S., Pieraccini, G., Lionetti, P. (2010). Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences of the United States of America, 107(33), 14691-14696.
• [58] Young, V.B., Schmidt, T.M. (2004). AAD accompanied by large-scale alterations in the composition of the fecal microbiota. Journal of Clinical Microbiology, 42(3), 1203-1206.
• [59] Jernberg, C., Löfmark, S., Edlund, C., Jansson, J.K. (2007). Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME Journal, 1(1), 56-66.
• [60] Claesson, M.J., Jeffery, I.B., Conde, S., Power, S.E., O'Connor, E.M., Cusack, S., Harris, H.M., Coakley, M., Lakshminarayanan, B., O'Sullivan, O., Fitzgerald, G.F., Deane, J., O'Connor, M., Harnedy, N., O'Connor, K., O'Mahony, D., van Sinderen, D., Wallace, M., Brennan, L., Stanton, C., Marchesi, J.R., Fitzgerald, A.P., Shanahan, F., Hill, C., Ross, R.P., O'Toole, P.W. (2012). Gut microbiota composition correlates with diet and health in the elderly. Nature, 488(7410), 178-184.
• [61] Moon, C., Baldridge, M.T., Wallace, M.A., Burnham, C.A.D., Virgin, H.W., Stappenbeck, T.S. (2015). Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature, 521(7550), 90-93.
• [62] Bengmark, S. (2013). Gut microbiota, immune development and function. Pharmacological Research, 69(1), 87-113.
• [63] Zhu, X., Han, Y., Du, J., Liu, R., Jin, K., Yi, W. (2017). Microbiota-gut-brain axis and the central nervous system. Oncotarget, 8(32), 53829-53838.
• [64] Iyer, L.M., Aravind, L., Coon, S.L., Klein, D.C., Koonin, E.V. (2004). Evolution of cell-cell signaling in animals: Did late horizontal gene transfer from bacteria have a role? Trends in Genetics, 20(7), 292-299.
• [65] Yunes, R.A., Poluektova, E.U., Dyachkova, M.S., Klimina, K.M., Kovtun, A.S., Averina, O.V., Orlova, V.S., Danilenko, V.N. (2016). GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota. Anaerobe, 42, 197-204.
• [66] Lyte, M. (2011). Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. BioEssays, 33(8), 574-581.
• [67] Nzakizwanayo, J., Dedi, C., Standen, G., Macfarlane, W.M., Patel, B.A., Jones, B.V. (2015). Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance. Scientific Reports, 5(17324), 1-13.
• [68] Higuchi, T., Hayashi, H., Abe, K. (1997). Exchange of glutamate and γ-aminobutyrate in a Lactobacillus strain. Journal of Bacteriology, 179(10), 3362-3364.
• [69] Ting Wong, C.G., Bottiglieri, T., Snead, O.C. (2003). GABA,  γ-hydroxybutyric acid, and neurological disease. Annals of Neurology, 54(6), 3-12.
• [70] Möhler, H. (2012). The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology, 62(1), 42-53.
• [71] Auteri, M., Zizzo, M.G., Serio, R. (2015). GABA and GABA receptors in the gastrointestinal tract: From motility to inflammation. Pharmacological Research, 93, 11-21.
• [72] Kalueff, A.V., Nutt, D.J. (2007). Role of GABA in anxiety and depression. Depression and Anxiety, 24, 495-517.
• [73] Boonstra, E., de Kleijn, R., Colzato, L.S., Alkemade, A., Forstmann, B.U., Nieuwenhuis, S. (2015). Neurotransmitters as food supplements: The effects of GABA on brain and behavior. Frontiers in Psychology, 6, 6-11.
• [74] Shiah, I.S., Yatham, L.N. (1998). GABA function in mood disorders: An update and critical review. Life Sciences, 63(15), 1289-1303.
• [75] Yalçınkaya, S., Başyiğit, G., Gül, Ç. (2019). The importance of gamma aminobutyric acid produced by lactic acid bacteria. Turkish Journal of Agriculture - Food Science and Technology, 7(8), 1094-1099.
• [76] Zhang, R., Miller, R.G., Gascon, R., Champion, S., Katz, J., Lancero, M., Narvaez, A., Honrada, R., Ruvalcaba, D., McGrath, M.S. (2009). Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). Journal of Neuroimmunology, 206(1-2), 121-124.
• [77] Tack, J., Broekaert, D., Fischler, B., Van Oudenhove, L., Gevers, A.M., Janssens, J. (2006). A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut, 55(8), 1095-1103.
• [78] White, B.A., Horwath, C.C., Conner, T.S. (2013). Many apples a day keep the blues away - daily experiences of negative and positive affect and food consumption in young adults. British Journal of Health Psychology, 18(4), 782-798.
• [79] Brown, A.J., Goldsworthy, S.M., Barnes, A.A., Eilert, M.M., Tcheang, L., Daniels, D., Muir, A.I., Wigglesworth, M.J. Kinghorn, I., Fraser, N.J., Pike, N.B., Strum, J.C., Steplewski, K.M., Murdock, P.R., Holder, J.C., Marshall, F.H., Szekeres, P.G., Wilson, S., Ignar, D.M., Foord, S.M., Wise, A., Dowell, S.J. (2003). The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. Journal of Biological Chemistry, 278(13), 11312-11319.
• [80] Macfarlane, G.T., Macfarlane, S. (2012). Probiotic and prebiotic applications for vaginal health. Journal of AOAC International, 95(1), 5-24.
• [81] Adams, J.B., Johansen, L.J., Powell, L.D., Quig, D., Rubin, R.A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism - comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11(22), 1-13.
• [82] Sherwin, E., Rea, K., Dinan, T.G., Cryan, J.F. (2016). A gut (microbiome) feeling about the brain. Current Opinion in Gastroenterology, 32(2), 96-102.
• [83] Williamson, G., Clifford, M.N. (2010). Colonic metabolites of berry polyphenols: The missing link to biological activity? British Journal of Nutrition, 104(3), 48-66.
• [84] Manach, C., Williamson, G., Morand, C., Scalbert, A., Rémésy, C. (2005). Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. The American Journal of Clinical Nutrition, 81(1), 230-242.
• [85] Bowey, E., Adlercreutz, H., Rowland, I. (2003). Metabolism of isoflavones and lignans by the gut microflora: A study in germ-free and human flora associated rats. Food and Chemical Toxicology, 41(5), 631-636.
• [86] Aura, A.M., Martin-Lopez, P., O’Leary, K.A., Williamson, G., Oksman-Caldentey, K.M., Poutanen, K., Santos-Buelga, C. (2005). In vitro metabolism of anthocyanins by human gut microflora. European Journal of Nutrition, 44(3), 133-142.
• [87] Guergoletto, K.B., Costabile, A., Flores, G., Garcia, S., Gibson, G.R. (2016). In vitro fermentation of juçara pulp (Euterpe edulis) by human colonic microbiota. Food Chemistry, 196, 251-258.
• [88] Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X.N., Kubo, C., Koga, Y. (2004). Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. Journal of Physiology, 558(1), 263-275.
• [89] Savignac, H.M., Corona, G., Mills, H., Chen, L., Spencer, J.P., Tzortzis, G., Burnet, PW. (2013). Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochemistry International, 63(8), 756-764.
• [90] Alherz, F., Alherz, M., Almusawi, H. (2017). NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia. Schizophrenia Research: Cognition, 8(2017), 1-6.
• [91] Petschow, B., Doré, J., Hibberd, P., Dinan, T., Reid, G., Blaser, M., Cani, P.D., Degnan, F.H., Foster, J., Gibson, G., Hutton, J., Klaenhammer, T.R., Ley, R., Nieuwdorp, M., Pot, B., Relman, D., Serazin, A., Sanders, M.E. (2013). Probiotics, prebiotics, and the host microbiome: The science of translation. Annals of the New York Academy of Sciences, 1306(1), 1-17.
• [92] Özkay, Ü.D., Öztürk, Y., Can, Ö.D. (2011). Yaşlanan dünyanın hastalığı: Alzheimer hastalığı. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, 18(8), 35-42.
• [93] Ertekin-Taner, N. (2007). Genetics of Alzheimer’s disease: A centennial review. NIH Public Access, 28(3), 1-43.
• [94] Friedland, R.P. (2015). Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. Journal of Alzheimer’s Disease, 45(2), 349-362.
• [95] Clarke, J.R., Lyra E Silva, N.M., Figueiredo, C.P., Frozza, R.L., Ledo, J.H., Beckman, D., Katashima, C.K., Razolli, D., Carvalho, B.M., Frazão, R., Silveira, M.A., Ribeiro, F.C., Bomfim, T.R., Neves, F.S., Klein, W.L., Medeiros, R., LaFerla, F.M., Carvalheira, J.B., Saad, M.J., Munoz, D.P., Velloso, L.A., Ferreira, S.T., De Felice, F.G. (2015). Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Molecular Medicine, 7(2), 190-210.
• [96] Cirrito, J.R., Disabato, B.M., Restivo, J.L., Verges, D.K., Goebel, W.D., Sathyan, A., Hayreh, D., D'Angelo, G., Benzinger, T., Yoon, H., Kim, J., Morris, J.C., Mintun, M.A., Sheline, Y.I. (2011). Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 108(36), 14968-14973.
• [97] Gareau, M.G., Wine, E., Rodrigues, D.M., Cho, J.H., Whary, M.T., Philpott, D.J., Macqueen, G., Sherman, P.M. (2011). Bacterial infection causes stress-induced memory dysfunction in mice. Gut, 60(3), 307-317.
• [98] Mancuso, C., Santangelo, R. (2018). Alzheimer’s disease and gut microbiota modifications: The long way between preclinical studies and clinical evidence. Pharmacological Research, 129, 329-336.
• [99] Clavel, T., Fallani, M., Lepage, P., Levenez, F., Mathey, J., Rochet, V., Sérézat, M., Sutren, M., Henderson, G., Bennetau-Pelissero, C., Tondu, F., Blaut, M., Doré, J., Coxam, V. (2005). Isoflavones and functional foods alter the dominant intestinal microbiota in postmenopausal women. The Journal of Nutrition, 135(12), 2786-2792.
• [100] Cuervo, A., Valdés, L., Salazar, N., De Los Reyes-Gavilán, C.G., Ruas-Madiedo, P., Gueimonde, M., González, S. (2014). Pilot study of diet and microbiota: Interactive associations of fibers and polyphenols with human intestinal bacteria. Journal of Agricultural and Food Chemistry, 62(23), 5330-5336.
• [101] Shinohara, K., Ohashi, Y., Kawasumi, K., Terada, A., Fujisawa, T. (2010). Effect of apple intake on fecal microbiota and metabolites in humans. Anaerobe, 16(5), 510-515.
• [102] Tzounis, X., Rodriguez-Mateos, A., Vulevic, J., Gibson, G.R., Kwik-Uribe, C., Spencer, J.P. (2011). Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study. The American Journal of Clinical Nutrition, 91, 62-72.
• [103] Houser, M.C., Chang, J., Factor, S.A., Molho, E.S., Zabetian, C.P., Hill-Burns, E.M., Payami, H., Hertzberg, V.S., Tansey, M.G. (2018). Stool immune profiles evince gastrointestinal inflammation in Parkinson’s disease. Movement Disorders, 33(5), 793-804.
• [104] Ojetti, V., Ianiro, G., Tortora, A., D‘Angelo, G., Di Rienzo, T.A., Bibbò, S., Migneco, A., Gasbarrini, A. (2014). The effect of Lactobacillus reuteri supplementation in adults with chronic functional constipation: A randomized, double-blind, placebo-controlled trial. Journal of Gastrointestinal and Liver Diseases, 23(4), 387-391.
• [105] Wu, X., Chen, P.S., Dallas, S., Wilson, B., Block, M.L., Wang, C.C., Kinyamu, H., Lu, N., Gao, X., Leng, Y., Chuang, D.M., Zhang, W., Lu, R.B., Hong, J.S. (2008). Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. International Journal of Neuropsychopharmacology, 11(8), 1123-1134.
• [106] Achour, I., Arel-Dubeau, A.M., Renaud, J., Legrand, M., Attard, E., Germain, M., Martinoli, M.G. (2016). Oleuropein prevents neuronal death, mitigates mitochondrial superoxide production and modulates autophagy in a dopaminergic cellular model. International Journal of Molecular Sciences, 17(8), 1-17.
• [107] Lord, C., Elsabbagh, M., Baird, G., Veenstra-Vanderweele, J. (2018). Autism spectrum disorder. The Lancet, 392(10146), 508-520.
• [108] Serra, D., Almeida, L.M., Dinis, T.C.P. (2019). Polyphenols in the management of brain disorders: Modulation of the microbiota-gut-brain axis, Advances in Food and Nutrition Research, 1043-4526.
• [109] Berding, K., Donovan, S.M. (2016). Microbiome and nutrition in autism spectrum disorder: Current knowledge and research needs. Nutrition Reviews, 74(12), 723-736.
• [110] Hsiao, E.Y. (2014). Gastrointestinal issues in autism spectrum disorder. Harvard Review of Psychiatry, 22(2), 104-111.
• [111] De Magistris, L., Familiari, V., Pascotto, A., Sapone, A., Frolli, A., Iardino, P., Carteni, M., De Rosa, M., Francavilla, R., Riegler, G., Militerni, R., Bravaccio, C. (2010). Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. Journal of Pediatric Gastroenterology and Nutrition, 51(4), 418-424.
• [112] Marler, S., Ferguson, B.J., Lee, E.B., Peters, B., Williams, K.C., McDonnell, E., Macklin, E.A., Levitt, P., Gillespie, C.H., Anderson, G.M., Margolis, K.G., Beversdorf, D.Q., Veenstra-VanderWeele, J. (2016). Brief report: Whole blood serotonin levels and gastrointestinal symptoms in autism spectrum disorder. Journal of Autism and Developmental Disorders, 46(3), 1124-1130.
• [113] Serra, D., Almeida, L.M., Dinis, T.C.P. (2019). Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review. Neuroscience and Biobehavioral Reviews, 102 (July), 290-298.
• [114] Jardim, F.R., De Rossi, F.T., Nascimento, M.X., Da Silva Barros, R.G., Borges, P.A., Prescilio, I.C., De Oliveira, M.R. (2018). Resveratrol and brain mitochondria: A review. Molecular Neurobiology, 55(3), 2085-2101.
• [115] Taliou, A., Zintzaras, E., Lykouras, L., Francis, K. (2013). An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clinical Therapeutics, 35(5), 592-602.
• [116] Cryan, J.F., Dinan, T.G. (2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13(10), 701-712.
• [117] O’Mahony, S.M., Clarke, G., Borre, Y.E., Dinan, T.G., Cryan, J.F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural Brain Research, 277, 32-48.
• [118] Kennedy, D.O. (2014). Polyphenols and the human brain: Plant “secondary metabolite” ecologic roles and endogenous signaling functions drive benefits. Advances in Nutrition, 5(5), 515-533.
• [119] Spencer, J.P.E. (2008). Flavonoids: Modulators of brain function? British Journal of Nutrition, 99(1), 60-77.
• [120] Torres-Pérez, M., Tellez-Ballesteros, R.I., Ortiz-López, L., Ichwan, M., Vega-Rivera, N.M., Castro-García, M., Gómez-Sánchez, A., Kempermann, G., Ramirez-Rodriguez, G.B. (2015). Resveratrol enhances neuroplastic changes, including hippocampal neurogenesis, and memory in Balb/C mice at six months of age. PLoS ONE, 10(12), 1-21.
• [121] Witte, A.V., Kerti, L., Margulies, D.S., Flöel, A. (2014). Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. Journal of Neuroscience, 34(23), 7862-7870.
• [122] Rendeiro, C., Rhodes, J.S., Spencer, J.P. (2015). The mechanisms of action of flavonoids in the brain: Direct versus indirect effects. Neurochemistry International, 89, 126-139.
• [123] Zhang, Y.J., Gan, R.Y., Li, S., Zhou, Y., Li, A.N., Xu, D.P., Li, H.B. (2015). Antioxidant phytochemicals for the prevention and treatment of chronic diseases. Molecules, 20(12), 21138-21156.
• [124] Zhao, C.N., Meng, X., Li, Y., Li, S., Liu, Q., Tang, G.Y., Li, H.B. (2017). Fruits for prevention and treatment of cardiovascular diseases. Nutrients, 9(6), 1-29.
• [125] Klinder, A., Shen, Q., Heppel, S., Lovegrove, J.A., Rowland, I., Tuohy, K.M. (2016). Impact of increasing fruit and vegetables and flavonoid intake on the human gut microbiota. Food and Function, 7(4), 1788-1796.
• [126] Zhang, Y.J., Li, S., Gan, R.Y., Zhou, T., Xu, D.P., Li, H.B. (2015). Impacts of gut bacteria on human health and diseases. International Journal of Molecular Sciences, 16(4), 7493-7519.
• [127] Qiao, Y., Sun, J., Xia, S., Tang, X., Shi, Y., Le, G. (2014). Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food and Function, 5(6), 1241-1249.
• [128] Pozuelo, M.J., Agis-Torres, A., Hervert-Hernández, D., López-Oliva, M.E., Muñoz-Martínez, E., Rotger, R., Goñi, I. (2012). Grape antioxidant dietary fiber stimulates Lactobacillus growth in rat cecum. Journal of Food Science, 77(2), 59-62.
• [129] Kahouli, I., Malhotra, M., Tomaro-Duchesneau, C., Saha, S., Marinescu, D., Rodes, L.S., Alaoui-Jamali, M.A., Prakash, S. (2015). Screening and in-vitro analysis of Lactobacillus reuteri strains for short chain fatty acids production, stability and therapeutic potentials in colorectal cancer. Journal of Bioequivalence & Bioavailability, 7(1), 39-50.
• [130] Viveros, A., Chamorro, S., Pizarro, M., Arija, I., Centeno, C., Brenes, A. (2011). Effects of dietary polyphenol-rich grape products on intestinal microflora and gut morphology in broiler chicks. Poultry Science, 90(3), 566-578.
• [131] Ashok, P.K., Upadhyaya, K. (2012). Tannins are astringent. Journal of Pharmacognosy and Phytochemistry, 1(3), 45-50.
• [132] Condezo-Hoyos, L., Mohanty, I.P., Noratto, G.D. (2014). Assessing non-digestible compounds in apple cultivars and their potential as modulators of obese faecal microbiota in vitro. Food Chemistry, 161, 208-215.
• [133] Jiang, T., Gao, X., Wu, C., Tian, F., Lei, Q., Bi, J., Xie, B., Wang, H.Y., Chen, S., Wang, X. (2016). Apple-derived pectin modulates gut microbiota, improves gut barrier function, and attenuates metabolic endotoxemia in rats with diet-induced obesity. Nutrients, 8(3), 2-20.
• [134] Masumoto, S., Terao, A., Yamamoto, Y., Mukai, T., Miura, T., Shoji, T. (2016). Non-absorbable apple procyanidins prevent obesity associated with gut microbial and metabolomic changes. Scientific Reports, 6, 1-10.
• [135] Heyman-Lindén, L., Kotowska, D., Sand, E., Bjursell, M., Plaza, M., Turner, C., Holm, C., Fåk, F., Berger, K. (2016). Lingonberries alter the gut microbiota and prevent low-grade inflammation in high-fat diet fed mice. Food and Nutrition Research, 60, 1-14.
• [136] Lee, S., Keirsey, K.I., Kirkland, R., Grunewald, Z.I., Fischer, J.G., de La Serre, C.B. (2018). Blueberry supplementation influences the gut microbiota, inflammation, and insulin resistance in high-fat-diet-fed rats. Journal of Nutrition, 148(2), 209-219.
• [137] Pan, P., Lam, V., Salzman, N., Huang, Y.W., Yu, J., Zhang, J., Wang, L.S. (2017). Black raspberries and their anthocyanin and fiber fractions alter the composition and diversity of gut microbiota in F-344 rats. Nutrition and Cancer, 69(6), 943-951.
• [138] Ojo, B., El-Rassi, G.D., Payton, M.E., Perkins-Veazie, P., Clarke, S., Smith, B.J., Lucas, E.A. (2016). Mango supplementation modulates gut microbial dysbiosis and short-chain fatty acid production independent of body weight reduction in C57BL/6 mice fed a high-fat diet. The Journal of Nutrition, 146(8), 1483-1491.
• [139] Tung, Y.C., Chang, W.T., Li, S., Wu, J.C., Badmeav, V., Ho, C.T., Pan, M.H. (2018). Citrus peel extracts attenuated obesity and modulated gut microbiota in mice with high-fat diet-induced obesity. Food and Function, 9(6), 3363-3373.
• [140] Stenblom, E.L., Weström, B., Linninge, C., Bonn, P., Farrell, M., Rehfeld, J.F., Montelius, C. (2016). Dietary green-plant thylakoids decrease gastric emptying and gut transit, promote changes in the gut microbial flora, but does not cause steatorrhea. Nutrition and Metabolism, 13(1), 1-9.
• [141] Carrera-Quintanar, L., Roa, R.I.L., Quintero-Fabián, S., Sánchez-Sánchez, M.A., Vizmanos, B., Ortuño-Sahagún, D. (2018). Phytochemicals that influence gut microbiota as prophylactics and for the treatment of obesity and inflammatory diseases. Mediators of Inflammation, 2018, 1-18.
• [142] Di Meo, F., Filosa, S., Madonna, M., Giello, G., Di Pardo, A., Maglione, V., Baldi, A., Crispi, S. (2019). Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: An in vitro and in vivo analysis. Journal of Experimental and Clinical Cancer Research, 38(1), 1-11.
• [143] Zhang, Z., Chen, Y., Xiang, L., Wang, Z., Xiao, G.G., Hu, J. (2017). Effect of curcumin on the diversity of gut microbiota in ovariectomized rats. Nutrients, 9(10), 1-11.
• [144] Ohno, M., Nishida, A., Sugitani, Y., Nishino, K., Inatomi, O., Sugimoto, M., Kawahara, M., Andoh, A. (2017). Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells. PLoS ONE, 12(10), 1-16.
• [145] Amic, D., Davidovic-Amic, D., Beslo, D., Rastija, V., Lucic, B., Trinajstic, N. (2007). SAR and QSAR of the antioxidant activity of flavonoids. Current Medicinal Chemistry, 14(7), 827-845.
• [146] Bors, W., Heller, W., Michel, C., Saran, M. (1990). Flavonoids as antioxidants: Determination of radical-scavenging efficiencies. Methods in Enzymology, 186, 343-355.
• [147] Smolensky, D., Rhodes, D., McVey, D.S., Fawver, Z., Perumal, R., Herald, T., Noronha, L. (2018). High-polyphenol sorghum bran extract inhibits cancer cell growth through ROS induction, cell cycle arrest, and apoptosis. Journal of Medicinal Food, 21(10), 990-998.
• [148] Di Meo, F., Margarucci, S., Galderisi, U., Crispi, S., Peluso, G. (2019). Curcumin, gut microbiota, and neuroprotection. Nutrients, 11(10), 1-14.
• [149] Samarghandian, S., Azimi-Nezhad, M., Farkhondeh, T., Samini, F. (2017). Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomedicine and Pharmacotherapy, 87, 223-229.
• [150] Rajeswari, A., Sabesan, M. (2008). Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice. Inflammopharmacology, 16(2), 96-99.
• [151] Singh, C., Bortolato, M., Bali, N., Godar, S.C., Scott, A.L., Chen, K., Thompson, R.F., Shih, J.C. (2013). Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 110(31), 12816-12821.
• [152] Begum, A.N., Jones, M.R., Lim, G.P., Morihara, T., Kim, P., Heath, D.D., Rock, C.L., Pruitt, M.A., Yang, F., Hudspeth, B., Hu, S., Faull, K.F., Teter, B., Cole, G.M., Frautschy, S.A. (2008). Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. Journal of Pharmacology and Experimental Therapeutics, 326(1), 196-208.
• [153] Mishra, S., Mishra, M., Seth, P., Sharma, S.K. (2011). Tetrahydrocurcumin confers protection against amyloid β-induced toxicity. NeuroReport, 22(1), 23-27.
• [154] Shen, W., Shen, M., Zhao, X., Zhu, H., Yang, Y., Lu, S., Tan, Y., Li, G., Li, M., Wang, J., Hu, F., Le, S. (2017). Anti-obesity effect of capsaicin in mice fed with high-fat diet is associated with an increase in population of the gut bacterium Akkermansia muciniphila. Frontiers in Microbiology, 8, 1-10.
• [155] Kang, C., Zhang, Y., Zhu, X., Liu, K., Wang, X., Chen, M., Wang, J., Chen, H., Hui, S., Huang, L., Zhang, Q., Zhu, J., Wang, B., Mi, M. (2016). Healthy subjects differentially respond to dietary capsaicin correlating with specific gut enterotypes. Journal of Clinical Endocrinology and Metabolism, 101(12), 4681-4689.
• [156] Song, J.X., Ren, H., Gao, Y.F., Lee, C.Y., Li, S.F., Zhang, F., Li, L., Chen, H. (2017). Dietary capsaicin improves glucose homeostasis and alters the gut microbiota in obese diabetic ob/ob mice. Frontiers in Physiology, 8, 1-12.
• [157] Cao, S.Y., Zhao, C.N., Xu, X.Y., Tang, G.Y., Corke, H., Gan, R.Y., Li, H.B. (2019). Dietary plants, gut microbiota, and obesity: Effects and mechanisms. Trends in Food Science and Technology, 92, 194-204.
• [158] Wang, W., Wu, N., Zu, Y.G., Fu, Y.J. (2008). Antioxidative activity of Rosmarinus officinalis L. essential oil compared to its main components. Food Chemistry, 108(3), 1019-1022.
• [159] Aslan-Öz, M.N. (2017). Balıkesir yöresinde doğal olarak yetişen biberiye ve fesleğen bitkilerine ait uçucu yağların antioksidan ve antimikotik özelliklerinin belirlenmesi. Yüksek Lisans Tezi, Tekirdağ.
• [160] Romo-Vaquero, M., Selma, M.V., Larrosa, M., Obiol, M., García-Villalba, R., González-Barrio, R., Issaly, N., Flanagan, J., Roller, M., Tomás-Barberán, F.A., García-Conesa, M.T. (2014). A rosemary extract rich in carnosic acid selectively modulates caecum microbiota and inhibits β-glucosidase activity, altering fiber and short chain fatty acids fecal excretion in lean and obese female rats. PLoS ONE, 9(4), 1-11.
• [161] Kim, Y.A., Keogh, J.B., Clifton, P.M. (2016). Polyphenols and glycémie control. Nutrients, 8(1),1-27.
• [162] Taher, M., Abdul Majid, F.A., Sarmidi, M.R. (2004). Cinnamtannin B1 activity on adipocyte formation. The Medical Journal of Malaysia, 59, 97-98.
• [163] Van Hul, M., Geurts, L., Plovier, H., Druart, C., Everard, A., Ståhlman, M., Rhimi, M., Chira, K., Teissedre, P.L., Delzenne, N.M., Maguin, E., Guilbot, A., Brochot, A., Gérard, P., Bäckhed, F., Cani, P.D. (2018). Reduced obesity, diabetes, and steatosis upon cinnamon and grape pomace are associated with changes in gut microbiota and markers of gut barrier. American Journal of Physiology- Endocrinology and Metabolism, 314(4), 334-352.
• [164] Tomaand́s-Barberaand́n, F.A., Martos, I., Ferreres, F., Radovic, B.S., Anklam, E. (2001). HPLC flavonoid profiles as markers for the botanical origin of European unifloral honeys. Journal of the Science of Food and Agriculture, 81(5), 485-496.
• [165] Al-Mamary, M., Al-Meeri, A., Al-Habori, M. (2002). Antioxidant activities and total phenolics of different types of honey. Nutrition Research, 22(9), 1041-1047.
• [166] Kenjerić, D., Mandić, M.L., Primorac, L., Bubalo, D., Perl, A. (2007). Flavonoid profile of Robinia honeys produced in Croatia. Food Chemistry, 102(3), 683-690.
• [167] Inanami, O., Watanabe, Y., Syuto, B., Nakano, M., Tsuji, M., Kuwabara, M. (1998). Oral administration of (-) catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radical Research, 29(4), 359-365.
• [168] Luo, Y., Smith, J. V., Paramasivam, V., Burdick, A., Curry, K.J., Buford, J.P., Khan, I., Netzer, W.J., Xu, H., Butko, P. (2002). Inhibition of amyloid-β aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proceedings of the National Academy of Sciences of the United States of America, 99(19), 12197-12202.
• [169] Bastianetto, S., Zheng, W.H., Quirion, R. (2000). The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: Involvement of its flavonoid constituents and protein kinase C. Journal of Neurochemistry, 74(6), 2268-2277.
• [170] Vauzour, D., Vafeiadou, K., Rice-Evans, C., Williams, R.J., Spencer, J.P.E. (2007). Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. Journal of Neurochemistry, 103(4), 1355-1367.
• [171] Jang, S., Dilger, R.N., Johnson, R.W. (2010). Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. The Journal of Nutrition, 140(10), 1892-1898.
• [172] Xu, B., Li, X.X., He, G.R., Hu, J.J., Mu, X., Tian, S., Du, G.H. (2010). Luteolin promotes long-term potentiation and improves cognitive functions in chronic cerebral hypoperfused rats. European Journal of Pharmacology, 627(1-3), 99-105.
• [173] Darvesh, A.S., Mcclure, M., Sadana, P., Paxos, C., Geldenhuys, W.J., Lambert, J.D., Haqqi, T.M., Richardson, J.R. (2017). Neuroprotective properties of dietary polyphenols in Parkinson’s disease. Neuroprotective Effects of Phytochemicals in Neurological Disorders, 243-263.
• [174] Lee, J.S., Kim, H.W., Chung, D., Lee, H.G. (2009). Catechin-loaded calcium pectinate microparticles reinforced with liposome and hydroxypropylmethylcellulose: Optimization and in vivo antioxidant activity. Food Hydrocolloids, 23(8), 2226-2233.
• [175] Pan, M.H., Tung, Y.C., Yang, G., Li, S., Ho, C.T. (2016). Molecular mechanisms of the anti-obesity effect of bioactive compounds in tea and coffee. Food and Function, 7(11), 4481-4491.
• [176] Sun, H., Chen, Y., Cheng, M., Zhang, X., Zheng, X., Zhang, Z. (2018). The modulatory effect of polyphenols from green tea, oolong tea and black tea on human intestinal microbiota in vitro. Journal of Food Science and Technology, 55(1), 399-407.
• [177] Sun, L., Ma, L., Ma, Y., Zhang, F., Zhao, C., Nie, Y. (2018). Insights into the role of gut microbiota in obesity: Pathogenesis, mechanisms, and therapeutic perspectives. Protein and Cell, 9(5), 397-403.
• [178] Kanaya, S., Goto, K., Hara, H. (1995). The physiological effects of tea catechins on human volunteers. Proc Inter Symp Tea Sci, 314-317.
• [179] Tengilimoglu, M.M., Büyüktuncer, Z. (2011). Çay ve sağlıkla ilişkisi. Beslenme ve Diyet Dergisi, 39(1-2),100 59-65.
• [180] Weinreb, O., Mandel, S., Amit, T., Youdim, M.B.H. (2004). Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. Journal of Nutritional Biochemistry, 15(9), 506-516.
• [181] Forester, S.C., Waterhouse, A.L. (2009). Metabolites are key to understanding health. The Journal of Nutrition, 138, 1824-1831.
• [182] Huang, W.Y., Davidge, S.T., Wu, J. (2013). Bioactive natural constituents from food sources-potential use in hypertension prevention and treatment. Critical Reviews in Food Science and Nutrition, 53(6), 615-630.
• [183] Barroso, E., Sánchez-Patán, F., Martín-Alvarez, P.J., Bartolomé, B., Moreno-Arribas, M.V., Peláez, C., Requena, T., van de Wiele, T., Martínez-Cuesta, M.C. (2013). Lactobacillus plantarum IFPL935 favors the initial metabolism of red wine polyphenols when added to a colonic microbiota. Journal of Agricultural and Food Chemistry, 61(42), 10163-10172.
• [184] Cueva, C., Sánchez-Patán, F., Monagas, M., Walton, G.E., Gibson, G.R., Martín-Álvarez, P.J., Bartolomé, B., Moreno-Arribas, M.V. (2013). In vitro fermentation of grape seed flavan-3-ol fractions by human faecal microbiota: Changes in microbial groups and phenolic metabolites. FEMS Microbiology Ecology, 83(3), 792-805.
• [185] Sánchez-Patán, F., Cueva, C., Monagas, M., Walton, G.E., Gibson, G.R., Quintanilla-López, J.E., Lebrón-Aguilar, R., Martín-Álvarez, P.J., Moreno-Arribas, M.V., Bartolomé, B. (2012). In vitro fermentation of a red wine extract by human gut microbiota: Changes in microbial groups and formation of phenolic metabolites. Journal of Agricultural and Food Chemistry, 60(9), 2136-2147.
• [186] Moreno-Indias, I., Sánchez-Alcoholado, L., Pérez-Martínez, P., Andrés-Lacueva, C., Cardona, F., Tinahones, F., Queipo-Ortuño, M.I. (2016). Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients. Food and Function, 7(4), 1775-1787.
• [187] Queipo-Ortuno, M.I., Boto-Ordonez, M., Murri, M., Gomez-Zumaquero, J.M., Clemente-Postigo, M., Estruch, R., Cardona Diaz, F., Andrés-Lacueva, C., Tinahones, F.J. (2012). Influence of red wine polyphenols and ethanol on the gut microbiota. The American Journal of Clinical Nutrition, 95(2), 1323-1334.
• [188] Hooper, L., Kroon, P.A., Rimm, E.B., Cohn, J.S., Harvey, I., Le Cornu, K.A. , Ryder, J.J., Hall, W.L., Cassidy, A. (2018). Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. The American Journal of Clinical Nutrition, 88(1), 38-50.
• [189] Wollgast, J., Anklam, E. (2000). Review on polyphenols in Theobroma cacao: Changes in composition during the manufacture of chocolate and methodology for identification and quantification. Food Research International, 33(6), 423-447.
• [190] Wang, J.F., Schramm, D.D., Holt, R.R., Ensunsa, J.L., Fraga, C.G., Schmitz, H.H., Keen, C.L. (2000). A dose-response effect from chocolate consumption on plasma epicatechin and oxidative damage. The Journal of Nutrition, 130(8), 2115-2119.
• [191] Baba, S., Osakabe, N., Natsume, M., Yasuda, A., Takizawa, T., Nakamura, T., Terao, J. (2000). Cocoa powder enhances the level of antioxidative activity in rat plasma. British Journal of Nutrition, 84(5), 673-680.
• [192] Nanetti, L., Raffaelli, F., Tranquilli, A.L., Fiorini, R., Mazzanti, L., Vignini, A. (2012). Effect of consumption of dark chocolate on oxidative stress in lipoproteins and platelets in women and in men. Appetite, 58(1), 400-405.
• [193] Ahmad, A., Biersack, B., Li, Y., Kong, D., Bao, Bin., Schobert, Rainer., Padhye, S.B., Sarkar, F.H. (2013). Deregulation of PI3K/Akt/mTOR signaling pathways by isoflavones and its implication in cancer treatment, Anti-Cancer Agents in Medicinal Chemistry, 13(7), 1014-1024.
• [194] Walsh, K.R., Zhang, Y.C., Vodovotz, Y., Schwartz, S.J., Failla, M.L. (2003). Stability and bioaccessibility of isoflavones from soy bread during in vitro digestion. Journal of Agricultural and Food Chemistry, 51(16), 4603-4609.
• [195] Dündar, Y. (2001). Fitokimyasallar ve sağlıklı yaşam. Kocatepe Tıp Dergisi, 2, 131-138.
• [196] Özcan, T., Delikanlı, B., Akın, Z. (2015). Soya biyoaktif bileşenleri ve sağlık üzerine etkisi. Türk Tarım - Gıda Bilim ve Teknoloji Dergisi, 3(6), 350-355.