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Effect of food matrix on the content and bioavailability of flavonoids

Senem Kamiloglu, Merve Tomas, Tugba Ozdal, Esra Capanoglu

PII: S0924-2244(20)30653-1
DOI: https://doi.org/10.1016/j.tifs.2020.10.030
Reference: TIFS 3007

To appear in: Trends in Food Science & Technology

Received Date: 30 April 2020

Revised Date: 4 September 2020
Accepted Date: 22 October 2020

Please cite this article as: Kamiloglu, S., Tomas, M., Ozdal, T., Capanoglu, E., Effect of food matrix on
the content and bioavailability of flavonoids, Trends in Food Science & Technology (2020), doi: https://
doi.org/10.1016/j.tifs.2020.10.030.

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 1 Effect of food matrix on the content and bioavailability of flavonoids

3 Senem Kamiloglu,1 Merve Tomas,2 Tugba Ozdal,3 Esra Capanoglu4,*

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5 Mevsim Gida Sanayi ve Soguk Depo Ticaret A.S. (MVSM Foods), Turankoy, Kestel,

6 16540, Bursa, Turkey

7 e-mail: senem@mvsm.com.tr; Tel: +90 224 3833601; Fax: +90 224 3833123
2
8 Department of Food Engineering, Faculty of Engineering and Natural Sciences, Istanbul

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9 Sabahattin Zaim University, 34303 Halkali, Istanbul, Turkey

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10 e-mail: mervetomas@gmail.com; Tel: +90 212 6929688; Fax: +90 212 6938229

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Department of Food Engineering, Faculty of Engineering, Istanbul Okan University, 34959
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12 Tuzla, Istanbul, Turkey
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13 e-mail: tugba.ozdal@okan.edu.tr; Tel: +90 216 6771630; Fax: +90 216 6771647
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14 Department of Food Engineering, Faculty of Chemical and Metallurgical Engineering,
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15 Istanbul Technical University, 34469 Maslak, Istanbul, Turkey

16 e-mail: capanogl@itu.edu.tr; Tel: +90 212 2857340; Fax: +90 212 2857333
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17

18 *Corresponding author.

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19 Highlights

20 • Co-ingestion of flavonoids with macro- and micro-constituents affects flavonoid

21 bioavailability.

22 • Proteins, dietary fiber and minerals may reduce the bioavailability of flavonoids.

23 • Reduced bioavailability might be due to the entrapment of flavonoids to the food

24 matrix.

25 • Digestible carbohydrates, lipids, and vitamins may favorably affect flavonoid

26 bioavailability.

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27 • Improved micellization might result in enhanced bioavailability of flavonoids.

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28 Abstract

29 Background

30 Dietary flavonoids have drawn great interest owing to their potential positive effects on

31 health, which considerably rely on their bioaccessibility, transport and further metabolism in

32 the body. One of the key parameters that influence the flavonoid bioavailability is the

33 interaction of these compounds with other nutrients present in the human diet.

34 Scope and Approach

35 This review highlights the current findings on the influence of co-ingestion of flavonoids

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36 with other macro- (carbohydrates, lipids and proteins) and micro-constituents (vitamins,

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37 minerals, and other micronutrients) in foods.

38 Key Findings and Conclusions

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39 Majority of both in vitro and in vivo studies in the literature suggest that proteins, dietary
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40 fiber, and minerals may induce disadvantageous impact on the bioavailability of flavonoids.
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41 On the other hand, lipids, digestible carbohydrates, vitamins, alkaloids, carotenoids and other

42 flavonoids are likely to improve flavonoid bioavailability. Nevertheless, interaction of

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43 flavonoids with food matrix components is a complicated parameter that needs to be explored
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44 further in order to ensure utmost positive health effects to humans.

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46 Keywords: absorption, bioaccessibility, macroconstituents, microconstituents, phenolics

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47 1. Introduction

48 Flavonoids are compounds of low molecular weight, consisting of 15 carbon atoms

49 organized in a configuration of C6−C3−C6. Fundamentally, the structure comprises of 2

50 aromatic rings, linked through a 3−carbon bridge, often in a heterocyclic ring form.

51 Alterations in this heterocyclic ring's substitution pattern generate six distinct subclasses, i.e.,

52 flavonols, flavanols, flavones, flavanones, isoflavones and anthocyanidins (Balasundram,

53 Sundram, & Samman, 2006) (Figure 1). Epidemiological studies reported that diets rich in

54 flavonoids provide numerous benefits associated with health-promoting effects by reducing

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55 the risk of development of chronic diseases such as cardiovascular diseases, diabetes type II

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56 and some types of cancers (Domínguez-Avila et al., 2017).

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Bioavailability is a significant feature when investigating the function of flavonoids in
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58 health of humans. The term “bioavailability” is described as the portion of the digested
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59 flavonoids that is uptaken and metabolized through regular pathways, whereas

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60 “bioaccessibility” means the proportion of flavonoids that is liberated from the food matrix

61 and is free for the uptake in the small intestine (Grundy et al., 2016; Barba et al., 2017). It is
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62 reported that 5-10% of the total intake of flavonoids, mostly those with monomeric and
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63 dimeric structures, can be absorbed in the small intestine, often after deconjugation reactions

64 such as deglycosylation. The remaining reach the colon where they are further metabolized to

65 compounds with different physiological significance by the enzymatic action of the gut

66 microbiota. In the human body, ingested flavonoids are subjected to phase I and phase II

67 transformations. Phase I transformations consist of oxidation, reduction and hydrolysis,

68 which occur less frequently. Phase II biotransformations taking place in the liver and the

69 intestine are formed more intensively. These phase II transformations comprise of

70 conjugation reactions where different metabolites are formed, i.e., methyl, glucuronic and

71 sulphate derivatives (Grootaert, Kamiloglu, Capanoglu, & Van Camp, 2015). Not only phase

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72 I and II metabolites, but also microbial derived products dominate in plasma, while the parent

73 molecules are generally absent or attain very low levels that cannot provide effective cellular

74 concentrations (Luca et al., 2020).

75 Both macronutrients, i.e., carbohydrates, lipids, proteins, and micronutrients, i.e.,

76 vitamins, minerals, are usually present in food materials together in a food matrix, and are

77 often ingested along with meal together with other foods (Singh & Gallier, 2014). It is worth

78 emphasizing that macro- and micro-constituents that surround flavonoids in the

79 gastrointestinal tract have a significant effect on their bioaccessibility and bioavailability

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80 (Singh & Gallier, 2014; Jakobek, 2015). Furthermore, the bioavailability of flavonoids can be

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81 modified due to interaction of molecules among all these components of food matrix

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(Palafox Carlos, Ayala Zavala, & González Aguilar, 2011). These molecular interactions
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83 can be either advantageous or disadvantageous for flavonoid related bioactivity (Tomas et al.,
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84 2018).
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85 Several studies discussed the impact of flavonoids on the macro- and micro-

86 constituents. However, at this stage information about the effect of macro- and micro-
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87 constituents on flavonoid bioaccessibility/bioavailability is limited. In this perspective, this

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88 review aims to discuss the current findings on the influence of food matrix on bioaccessibility

89 and bioavailability of flavonoids.

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91 2. Effect of macroconstituents on flavonoid bioavailability

92 2.1. Carbohydrates

93 Flavonoids and carbohydrates are dietary constituents of plant foods and are

94 associated with positive health benefits. Recently, researches on the influence of food matrix

95 on the flavonoid bioavailability are extending. Molecular interactions between the flavonoids

96 and carbohydrates can affect their absorption (González-Aguilar, Blancas-Benítez, &

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 97 Sáyago-Ayerdi, 2017). However, there is little information on the impact of the added

98 carbohydrates such as starch, sugar, and dietary fiber on the bioavailability/bioaccessibility of

99 flavonoids (Table 1 and Table 2).

100 Carbohydrates are generally categorized in two groups as digestible or non-digestible

101 in food systems. The first group might be further divided into sugars, glucose oligomers

102 (such as maltodextrins) and starch. However, the second group mostly consists of dietary

103 fibers, a large category of polysaccharides with a vast chemical and structural diversity

104 (Bordenave, Hamaker, & Ferruzzi, 2014). Sugar intake is an important factor that could

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105 regulate flavonoid bioavailability. An example of this has been shown by Neilson et al.

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106 (2009), who reported that the availability of sucrose in chocolate may favorably affect the

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bioavailability of flavan-3-ols. Additionally, in another study investigating chocolate matrix
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108 effect on the bioavailability of flavan-3-ols from cocoa using rats, it was shown that plasma
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109 concentrations of total flavan-3-ol were the highest in chocolate containing high-sucrose
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110 (AUC: 41314 nM h) when compared to reference dark chocolate (AUC: 36360 nM h) which

111 yielded intermediate concentrations (Neilson et al., 2010). Moreover, Schramm et al. (2003)
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112 examined the influence of sugar on the uptake of flavanols from cocoa ((+)-catechin and (-)-
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113 epicatechin), and showed that sugar-rich diet has led to significant increases in plasma Cmax

114 (416.4 ng/mL) and plasma AUC (1761.9 ng*h/mL) levels compared to cocoa alone in

115 humans. It was also observed that sugar-containing test meals significantly enhanced the

116 flavanol area under the curve values to 140% of the control values. Another in vivo study

117 (Matsumoto, Matsukawa, Chiji, & Hara, 2007) reported that a difructose anhydride III,

118 indigestible saccharide, promotes alpha glucosyl rutin absorption in portal cannulated rats. In

119 the presence of difructose anhydride III, the absorption of alpha glucosyl rutin was increased

120 by 1.5-3 times. These authors proposed that higher transport of alpha glucosyl rutin, a soluble

121 flavonoid glycoside, is due to the presence of difructose anhydride III, which inhibited the

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122 conversion of alpha glucosyl rutin to rutin, a scarcely absorbable flavonoid owing to its

123 incapability of being dissolved (Matsumoto et al., 2007). In another study, Peters, Green,

124 Janle, & Ferruzzi (2010) evaluated the impact of sucrose on bioavailability of (+)-catechin

125 from green tea both in vivo and in vitro. It has been shown that the plasma levels of

126 epigallocatechin and epigallocatechin gallate were significantly (p<0.05) increased in the

127 presence of sucrose and ascorbic acid (AUC 0–6 h = 3237.0 and 181.8 pmol h/L plasma,

128 respectively) in comparison with green tea alone (AUC 0–6 h = 1304.1 and 61.0 pmol h/L

129 plasma, respectively).Considering these results, the authors suggested that the promoting

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130 effect of sucrose might be associated with its pre-uptake action on (+)-catechin solubility in

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131 rodent gastrointestinal tract and in the intestinal model. Furthermore, they reported that green

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tea containing sucrose had viscosities nearly six times greater than formulations that do not
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133 contain sucrose. Catechin uptake by the intestine may be increased due to enhanced viscosity
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134 of green tea solutions, which affects the gastrointestinal transit time (Peters et al., 2010).
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135 Moreover, the same researchers reported that bioavailability of gallated catechins were less

136 than non-gallated ones in all formulations. It is known that in green tea, less soluble gallated
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137 catechins have a higher affinity to precipitate in comparison with more soluble non-gallated
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138 catechins (Peter et al., 2010). Few studies have examined the influence of type of sugar on

139 the flavanol bioavailability in cocoa (Rodriguez-Mateos et al. 2012). A study by Rodriguez-

140 Mateos et al. (2012) revealed that the absorption of total flavanols was higher upon

141 consumption of chocolate containing sucrose compared to subsequent consumption of its

142 maltitol counterpart. Consumption of the sucrose-containing test chocolate, furthermore,

143 resulted in a 19% higher total AUC and 17% higher Cmax for plasma unmethylated

144 epicatechin levels compared with its maltitol equivalent. Based on the results, the researchers

145 suggested that maltitol may act to restrict the absorption flavanols owing to its impact on the

146 osmolarity of the small intestinal substances. On the other hand, the possible effect of sugar

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147 content on resveratrol and quercetin bioavailability was studied by Meng, Maliakal, Lu, Lee,

148 & Yang (2004), who showed that the aglycones of resveratrol and quercetin in grape juice

149 were transported to a higher extent compared to their glycoside forms. In addition, Sengul,

150 Surek, & Nilufer-Erdil (2014) found that carbohydrates including glucose, lactose, starch,

151 and pectin turned out to influence the reduction of polyphenols from pomegranate and

152 resulted in two-fold reductions in the dialyzed fraction by using in vitro model. However,

153 inclusion of sucrose in beverages and foods could bring unfavorable effects on health due to

154 over-consumption of sucrose. World Health Organization (WHO) suggested that additional

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155 sugars should provide less than 10% of the total dietary energy (Malik et al. 2006). The

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156 consumption of low-calorie sweeteners such as xylitol instead of sucrose provided less

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energy and a synergic impact on enhancing catechin stability for the green tea beverage
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158 formulation (Shim et al. 2012; Chung et al. 2013). Shim et al. (2012) indicated that xylitol
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159 and vitamin C could enable gallated and non-gallated catechins in green tea to increase
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160 digestive stability (3 times higher) and intestinal absorption (11 times higher). One

161 explanation could be that vitamin C, as an antioxidant, may protect tea catechins from
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162 oxidation under alkaline conditions that occur in the intestinal stage of digestion. Similarly,
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163 Chung et al. (2013) showed that modulating green tea formulation with xylitol and vitamin C

164 may be a good action to enhance the catechin delivery and bioavailability in humans.

165 Moreover, sugars can also affect pigment stability. Several studies have pointed out that

166 sugar causes reduction in water activity (aw), and slight variations in the sugar concentration

167 and aw enhance the stability of pigments (Gil-Izquierdo, Zafrilla, & Tomás-Barberán, 2002;

168 Toydemir et al. 2013). Gil-Izquierdo et al. (2002) reported that diffusion of phenolics may be

169 affected during in vitro digestion due to high sugar content in samples like jams.

170 Dietary fiber is another component that could impact flavonoid bioavailability.

171 Dietary fibers can be classified as either soluble or insoluble in water. The former group

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172 comprises pectin, β-glucans, galactomannans, fructans, oligosaccharides, some

173 hemicelluloses, gums, and mucilages, whereas the latter group comprises hemicellulose,

174 cellulose, and lignin (González-Aguilar et al., 2017). Free phenolic compounds are rapidly

175 absorbed during gastrointestinal digestion, whereas flavonoids associated with a dietary fiber

176 are less absorbed (Palafox Carlos et al., 2011). In a human study, the wheat fiber-rich diet

177 reduced the presence of isoflavonoid genistein in the plasma by 55% probably due to the

178 bulking effect of wheat fiber and hydrophobic binding to this compound (Tew, Xu, Wang,

179 Murphy, & Hendrich, 1996). In another in vivo study Tamura, Iwami, Hirayama, & Itoh

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180 (2009) investigated the influence of a high fiber diet including rice bran hemicellulose on the

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181 cecal and plasma isoflavonoids in mice. These authors reported that as shown by plasma

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concentrations, the availability of daidzein decreased slightly but significantly as a result of
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183 addition of 5% hemicellulose to a diet already including 5% cellulose (Tamura et al., 2009).
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184 A similar trend was also demonstrated in another study by Tomas et al. (2018) who showed
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185 that tomato sauces containing both 5% and 10% inulin significantly reduced the total

186 phenolic content (up to 31%), total flavonoid content (up to 36%), and total antioxidant
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187 capacity (up to 48-58%) during in vitro gastrointestinal digestion. Viuda-Martos et al. (2018)
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188 also found that anthocyanins in the maqui combined with the fibers displayed lower

189 concentrations (p<0.05) compared to the corresponding undigested samples which could be

190 due to the binding interactions with fiber. Liu, Ying, Sanguansri, Cai, & Le (2018), for

191 instance, showed that (+)-catechin was adsorbed onto the hydrophilic cellulose surface by

192 intermolecular forces. Moreover, Padayachee et al. (2012) found that cellulose and pectin

193 were able to bind anthocyanins.

194 Interaction may also be dependent on the structure of flavonoids. The possible effect

195 of the structure of flavonoid on the β-glucan binding activity was examined by Wang, Liu,

196 Chen, & Zhao (2013). They reported that the binding was facilitated in the presence of three

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197 or fewer hydroxyl groups, whereas four or more hydroxyl groups reduced the binding action.

198 What is more, capacity of adsorption among isomers of flavonoid increased in the order of (i)

199 flavonol, (ii) flavone, (iii) flavanone and (iv) isoflavone. In the view of current literature on

200 dietary fiber, it can be suggested that dietary fiber directly interacts with flavonoids, thus

201 affecting their bioavailability. Due to the interactions between flavonoids and dietary fiber,

202 hydrogen bonds (between the oxygen atoms of the glycosidic linkages of polysaccharides and

203 hydroxyl group of flavonoids), and covalent bonds (such as ester bonds between

204 polysaccharides and flavonoids) can be formed, and hydrophobic interactions may appear.

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205 Moreover, dietary fibers can act as entrapping agents thus restricting flavonoid

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206 bioaccessibility. It is quite clear that polyphenols bound to dietary fibers are not bioavailable

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in the upper intestinal tract, so they are transferred to the large intestine where they could be
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208 produced by fermentation processes of the bacterial flora and help gut health (Palafox
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209 Carlos et al., 2011; Saura-Calixto, 2011; Jakobek, 2015). On the other hand, some studies
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210 showed that interactions between dietary fiber and polyphenols enabled protective effects to

211 be transported to colon during in vitro digestion. For instance, Calvache, Cueto, Farroni, de
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212 Escalada Pla, & Gerschenson (2016) showed that considerable amounts of polyphenols (for
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213 each 100 g, 0.112 g and 0.209 g soluble fraction; 0.049 g and 0.155 g insoluble fraction)

214 remain associated with indigestible fractions (soluble and insoluble) and transferred to the

215 large intestine. More recently, Tomas et al. (2020) investigated the influence of soluble

216 dietary fiber (pectin and inulin, 5 or 10% (w/w)) addition to blackberry puree on their

217 phenolic profile and antioxidant activity during simulated gastrointestinal digestion and

218 colonic fermentation process. The presence of soluble fiber supported the generation of low

219 molecular weight compounds including 4-vinylphenol, tyrosol and benzoic acid, along with

220 some other phenolic acids (i.e., gallic and ferulic acids). Bermúdez-Oria et al. (2019)

221 investigated the influence of simulated gastric and small intestinal digestion on

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222 hydroxytyrosol/3,4-dihydroxyphenylglycol bound to dietary fiber material in strawberries.

223 They reported that both soluble and insoluble fraction of fiber showed a high retention of

224 hydroxytyrosol and 3,4-dihydroxyphenylglycol, which may be protected against transport

225 during gastrointestinal transit to arrive to the large intestine. In addition, hydroxytyrosol/3,4-

226 dihydroxyphenylglycol soluble and insoluble dietary fiber complexes showed antioxidant

227 activity. Another study conducted by Koh, Xu, and Wicker (2020) reported that during the in

228 vitro gastrointestinal digestion, chelator soluble blueberry pectin prevented the degradation of

229 cyanidin-3-glucoside, malvidin-3-glucoside, and blueberry extract. Moreover, Chitindingu,

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230 Benhura, and Muchuweti (2015) observed that the cereal grains having higher fiber content

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231 indicated higher in vitro bioaccessibility in the colon (≈62%) than in the small intestine

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(≈28%). On the other hand, after evaluating the effects of pectin on plasma quercetin and the
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233 gut microbiota of mice fed with rutin, Tamura, Nakagawa, Tsushida, Hirayama, & Itoh
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234 (2007) reported that isorhamnetin and quercetin concentrations in the plasma were elevated
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235 significantly in the diet containing pectin and rutin than in the diet containing cellulose and

236 rutin diet. Furthermore, soluble fibers such as pectin increases the time to transit
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237 gastrointestinal tract, which improves the absorption of polyphenols (Tamura et al., 2007).
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238 On the other hand, in another study, the presence of dietary fiber in papaya, mango and

239 pineapple did not represent a major restriction on the polyphenol bioaccessibility during

240 simulated digestion (Velderrain-Rodriguez et al., 2016). More recently, Trakooncharoenvit et

241 al. (2019) investigated the effects of co-administration of pectin, soybean fiber, and guar gum

242 (water-soluble dietary fibers) with quercetin glucosides containing quercetin-3-O-glucoside

243 and its glucose adducts using in vivo model. A test diet including 0.7% quercetin glucoside

244 mixture with or without 5% of each dietary fiber was administered to Wistar/ST rats for 8

245 weeks and the changes in plasma, urine, and feces concentrations of quercetin derivatives

246 were monitored. The authors reported that dietary fibers soluble in water, particularly

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247 soybean fiber, increased the bioavailability of quercetin glycoside after long-term feeding of

248 rats. It can be also concluded that the size of the dietary fiber may influence bioaccessibility.

249 For instance, rice bran insoluble dietary fiber that is ground into superfine powder enhanced

250 phenolic bioaccessibility (252.25 mg GAE/100 g) compared to the its coarse counterpart

251 (127.03 mg GAE/100 g) (Zhao et al., 2018). Kruger et al. (2020) investigated the effect of

252 pectin and sucrose on the bioaccessibility of naringenin using an in vitro gastrointestinal

253 digestion model combined with Caco-2 cells. Addition of 2% pectin to 700 μM naringenin

254 reduced the bioaccessibility of naringenin by 65%, whereas Caco-2 cellular absorption of

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255 bioaccessible naringenin was increased from 47% to 95% in the presence of pectin.

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256 Furthermore, inclusion of 5% sucrose to 700 μM naringenin containing 2% pectin reduced

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the inhibitory effect of pectin and increased naringenin bioaccessibility from 8% to 15%. In
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258 this case, Caco-2 cellular absorption of bioaccessible naringenin was reported to be 100%
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259 (Kruger et al., 2020).

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261 2.2. Lipids

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262 Most of the studies reporting the interaction between dietary lipids and flavonoids
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263 have been carried out with quercetin using in vivo models (Table 2). This is probably due to

264 the low bioavailability of quercetin, which resulted in intentions to enhance the absorption of

265 this lipophilic compound by co-administering it with various dietary lipids. In one of the

266 earliest studies on this topic (Azuma, Ippoushi, Ito, Higashio, & Terao, 2002), the impact of

267 lipids and emulsifiers on the bioavailability of quercetin was examined in rats. Intake of 150

268 μmol/kg of quercetin with lipids including lecithin (10%) and soybean oil (20%) or

269 emulsifiers such as polyglycerol fatty acid ester, sucrose fatty acid ester, and sodium

270 taurocholate (3% each) showed no statistically significant effect on the bioavailability of

271 quercetin. On the other hand, the transport of quercetin was increased significantly when it is

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272 co-administered with lipids and emulsifiers (Azuma et al., 2002). The same researchers

273 (Azuma, Ippoushi, Ito, Horie, & Terao, 2003) also investigated the influence of co-digestion

274 of quercetin glucoside rich onion (equivalent of 3.9 mg quercetin aglycone) with various lipid

275 sources such as fish oil, soybean oil, beef tallow and lecithin. Concentration of quercetin

276 metabolites in rat plasma was enhanced significantly with the diet containing 4.6% soybean.

277 Similarly, diets containing 9.5% beef tallow and fish oil also increased the concentration of

278 plasma metabolites of quercetin to a similar degree to that with soybean oil, while 9.5%

279 lecithin was the most potent amongst all the tested lipids. Furthermore, emulsifiers also

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280 demonstrated an improved impact on the concentration of quercetin metabolites (Azuma et

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281 al., 2003). Afterwards, the influence of dietary fat (lard) on the absorption of quercetin was

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investigated in pigs by another research group (Lesser, Cermak, & Wolffram, 2004).
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283 Quercetin (30 μmol/kg body weight) aglycone or quercetin-3-O-glucoside was administered
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284 in control meals with different fat contents (3, 17, or 32 g fat/100 g diet). The results showed
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285 that for both the aglycone and the glycoside forms, the quercetin bioavailability was greater

286 in the diet containing 17% fat in comparison with the diet containing 3% fat (p<0.05). On the
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287 other hand, when the compounds were ingested with 32% fat diet, no further impact was
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288 observed on the bioavailability of flavonols (Lesser et al., 2004). These researchers also

289 examined the effect of fatty acid pattern of fats on the quercetin bioavailability, which was

290 increased by 38% (p<0.05) and 12% (p > 0.05) after ingestion of medium- and long-chain

291 triacylglycerols (15 g fat/100 g diet), respectively, in comparison with the control diet

292 (Lesser, Cermak, & Wolffram, 2006). In an in vivo study (Guo et al., 2013), 1095 mg of

293 quercetin was ingested together with a fat-free (<0.5 g), low-fat (4.0 g), or high-fat (15.4 g)

294 diet by overweight men and post-menopausal women. Compared to fat-free diet, high-fat diet

295 enhanced plasma concentration of quercetin by 45% (p<0.05). During the high-fat diet,

296 methylated metabolites of quercetin, i.e., tamarixetin and isorhamnetin, were also enhanced

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297 up to 43%. It has been suggested by the authors that dietary lipids may increase the quercetin

298 micellarization in the upper gastrointestinal tract, which promoted its solubility and transport

299 (Guo et al., 2013). More recently, Riva et al. (2019) investigated the oral absorption of

300 Quercetin Phytosome®, a novel lecithin-based dietary formulation of quercetin, in a

301 randomized crossover pharmacokinetic study of healthy volunteers. They found that the new

302 food-grade lecithin-based formulation of quercetin coped with the low bioavailability hurdle

303 of quercetin. They also showed that this formulation enabled high quercetin plasma levels —

304 up to 20-fold more than usually achieved following a dosage of quercetin to fulfil the health

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305 benefits.

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306 Martínez-Huélamo et al. (2015) reported that the bioavailability of polyphenols from

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tomatoes was affected by the addition of refined olive oil during processing. The results
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308 showed that the concentrations of 5-caffeoylquinic acid and naringenin were greater in
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309 refined olive oil supplemented tomato sauce than oil-free tomato sauce, whereas adding an
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310 oil matrix to the sauce did not cause significant differences. On the other hand, another study

311 conducted by the same research group showed that the bioavailability of quercetin and
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312 naringenin glucuronide was higher in tomato sauce enriched with refined olive oil than in
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313 tomato or tomato without refined olive oil (Martínez-Huélamo et al., 2016). In their research

314 Suarez et al. (2011) examined the influence of the enhancement of virgin olive oil with their

315 own polyphenols on their bioavailability in human subjects. They observed that enriched

316 virgin olive oil enhanced the plasma concentration of the phenolic metabolites, especially

317 vanillin sulphate and hydroxytyrosol sulphate.

318 In addition to the studies reporting the effect of dietary lipids on the quercetin

319 bioavailability, some other in vivo experiments were carried out with complex fruit matrices

320 (Tulipani et al., 2012; Zhang et al., 2012; Molinar-Toribio et al., 2017; Molinar-Toribio et al.,

321 2018). Accordingly, Tulipani et al. (2012) performed a randomized controlled cross-over trial

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322 to examine the influence of supplementation of virgin or refined olive oil on the

323 bioavailability of tomato polyphenols. After the ingestion of 100 g of tomato sauce enriched

324 with 5% oil, the changes in concentration of the major flavonoid metabolite, naringenin

325 glucuronide, was found to be statistically not significant due to large interindividual response

326 variability (Tulipani et al., 2012). Similarly, Zhang et al. (2012) reported that consumption of

327 milk fat with jujube juice (1:1, v/v) did not affect the bioavailability of phenolics in jujube

328 juice. In another study (Molinar-Toribio et al., 2017), the effect of marine originated omega-3

329 polyunsaturated fatty acids on the digestive fate of proanthocyanidins from grapes was

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330 examined. Proanthocyanidin metabolites in rats administered with a diet including omega-3

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331 polyunsaturated fatty acids (16.6 g/kg feed) and grape seed extract (0.8 g/kg feed) did not

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significantly differ from those fed only with grape seed extract (Molinar-Toribio et al., 2017).
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333 On the other hand, in a more recent study carried out by the same research group (Molinar-
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334 Toribio et al., 2018), accumulation of total microbial-derived proanthocyanidin metabolites

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335 were lower in urine and feces of rats administered with high-fat, high-sucrose diet and grape

336 proanthocyanidins than the group fed only with grape seed extract (30 mg/kg body weight).
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337 In addition, conjugated epicatechin metabolites were increased in the high-fat high-sucrose
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338 diet group, possibly owing to up-regulation of hepatic enzymes (Molinar-Toribio et al.,

339 2018).

340 In vitro studies on the interaction of dietary lipids with flavonoids are quite limited

341 (Table 1) and most of the work belongs to recent years (Ortega, Reguant, Romero, Macia, &

342 Motilva, 2009; Simmons, Chitchumroonchokchai, Vodovotz, & Failla, 2012; Oksuz, 2013;

343 Ribnicky et al., 2014; Sengul et al., 2014). Ortega et al. (2009) evaluated the bioaccessibility

344 of cocoa polyphenols, including phenolic acids, procyanidins and flavones, in the presence of

345 cocoa liquor (≈50% fat) or cocoa powder (≈15% fat). The results of the in vitro

346 gastrointestinal digestion model revealed that higher fat content in the cocoa liquor had a

15
347 protecting effect, possibly due to the improved micellarization that promoted the polyphenol

348 stability in the course of digestion (Ortega et al., 2009). Similarly, Ortega et al. (2011)

349 revealed that the lipid fraction that is rich in polyunsaturated fatty acids displayed a

350 protecting effect on the recovery of the polyphenols in the course of duodenal digestion. This

351 effect could be explained with the interactions between PUFA (under digestion) and phenolic

352 compounds which enhanced the compounds’ recovery and stability during digestion (Ortega

353 et al., 2011). Rubió et al. (2014) carried out studies investigating the effect of the co-

354 existence of bioactive compounds from thyme and olive oil on bioaccessibility using a

of
355 simulated digestion model. They reported that the bioaccessibility of hydroxytyrosol

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356 increased in the presence of both thyme and olive oil extract due to thyme bioactives ability

357
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to preserve olive polyphenols from degradation in the gastrointestinal tract prior to transport,
re
358 therefore making them bioaccessible to a greater extend.
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359 Another study investigating the bioaccessibility and transport of isoflavones in

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360 pretzels prepared with or without lipids from canola oil, shortening, ground almond, or

361 ground hazelnut oils (2.9 or 6.0%), concluded that the amount or lipid source does not
ur

362 influence the bioaccessibility as well as the uptake and metabolism of isoflavones as
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363 investigated by intestinal Caco-2 cells (Simmons et al., 2012). Similarly, gastrointestinal

364 digestion of anthocyanins in pomegranate (Sengul et al., 2014) and sour cherry (Oksuz, 2013)

365 with sunflower oil, did not induce a significant change on the bioaccessibility of

366 anthocyanins. On the other hand, another study (Ribnicky et al., 2014) in which TNO

367 intestinal model (TIM-1) was used to compare the bioaccessibility and transport of blueberry

368 anthocyanins with or without a high-fat meal reported that malvidin-3-arabinoside and

369 delphinidin-3-(6“-acetoyl)-glucoside were two times more bioaccessible under fasted

370 conditions, whereas delphinidin-3-glucoside, delphinidin-3-arabinoside, delphinidin-3-

371 galactoside and petunidin-3-arabinoside were two times more bioaccessible in fed state. As a

16
372 result, the authors suggested that lipid-rich matrices selectively influence the bioaccessibility

373 of anthocyanins (Ribnicky et al., 2014). More recently, Mendes et al. (2019) revealed that the

374 bioaccessibility of total procyanidin ranged between 125.9 and 151.3% for guaraná with

375 vegetable oil and 73.0% for guaraná. The higher bioaccessibility of procyanidins in the

376 presence of oil might be related to the development of vesicular and micellar structures.

377

378 2.3. Proteins

379 Studies on the relationship between proteins and flavonoids in foods have shown that

of
380 proteins can attach to polyphenols, leading to the generation of complexes, which can be

ro
381 either soluble or insoluble (Papadopoulou & Frazier, 2004), thus affecting the bioavailability

382
-p
of these compounds by the association between proteins and polyphenols (He, Yuan, Zeng,
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383 Tao, & Chen, 2015). Ozdal et al. (2013) have reviewed the influences of protein–phenolic
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384 interactions under diverse contexts on the structure and functionality of proteins and phenolic
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385 compounds. However, the results on the bioavailability studies are inconsistent.

386 The results of the studies present in the current literature have indicated conflicting
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387 findings about the effect of proteins on the bioavailability of cocoa and tea polyphenols. The
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388 differences in the antioxidant activity results of protein-phenolic complexes might be

389 attributed to the phenol-protein thiols binding, types of proteins and phenolic compounds,

390 i.e., isolated compounds, a complex extract and/or food matrix, and protein: phenolic

391 compound proportion. On the other hand, thiol-based compounds may also serve as

392 antioxidants, and phenol-protein thiols bindings affect the activity of the complex. For

393 instance, Sęczyk, Świeca, Kapusta, & Gawlik-Dziki (2019) reported that the abundance of

394 free thiol groups (in white bean proteins) was decreased up to 37% after phenolic treatment.

395 Serafini et al. (2003) observed that the concentration of (-)-epicatechin in the

396 bloodstream was reduced as a result of the milk protein and chocolate flavonoid interactions.

17
397 On the other hand, Schroeter, Holt, Orozco, Schmitz, & Keen (2003) contradictorily reported

398 that after ingestion of a water-based or milk-containing cocoa drink or under isolipidemic and

399 isocaloric conditions, there was no substantial change in the (-)-epicatechin concentration in

400 the plasma. Moreover, Schramm et al. (2003) also published similar findings to Schroeter et

401 al. (2003), reporting that milk had no effect on flavonol transport from cocoa. Similar studies

402 on tea also showed that introducing milk to black or green tea has no statistically significant

403 impact on catechin, quercetin or kaempferol bioavailability in humans (Van het Hof, Kivits,

404 Weststrate, & Tijburg, 1998; Hollman, Van Het Hof, Tijburg, & Katan, 2001). Roura et al.

of
405 (2007) have also reported that milk proteins do not impair the bioavailability of cocoa

ro
406 polyphenols. These findings were also confirmed by Kyle, Morrice, McNeill, & Duthie

407
-p
(2007) and Keogh, McInerney, & Clifton (2007), who showed that addition of milk to black
re
408 tea or cocoa did not affect the plasma concentrations of flavonoids. On the other hand,
lP

409 slightly accelerated absorption of catechin and epicatechin from cocoa was observed in the
na

410 presence of milk (Keogh et al., 2007). In the study of Larkin Price, & Astheimer (2007), it

411 was reported that the bioavailability of soy isoflavones, i.e., daidzein and genistein, did not
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412 change significantly with probiotic yoghurt intake. Similarly, the production of metabolites,
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413 i.e., equol, was not also increased with the intake of probiotic yoghurt.

414 In some other studies, changes in the bioavailability of anthocyanins due to their

415 interactions with proteins in different food matrices were investigated. Mullen, Edwards,

416 Serafini, & Crozier (2008) studied the bioavailability of pelargonidin-3-O-glucoside in

417 strawberry ingested with or without cream through an in vivo method sampling from plasma

418 and urine. They have concluded that there was no statistically significant differences between

419 strawberry with cream and strawberry alone digestions (Mullen et al., 2008). On the other

420 hand, Serafini et al. (2009) investigated the bioavailability and the in vivo plasma antioxidant

421 capacity of polyphenols following blueberries (Vaccinium corymbosum L.) consumption with

18
422 and without milk. They have conducted a crossover design study with 11 healthy human

423 volunteers consuming 200 g of blueberries with 200 ml of water or 200 ml of whole milk.

424 Samples were taken at 1, 2 and 5 h after consumption. The results of this study revealed that

425 intake of blueberries enhanced the reducing and chain-breaking potential levels in plasma

426 (+6.1%, p<0.001; +11.1%, p<0.05). In case milk and blueberries were digested together, the

427 plasma antioxidant capacity did not increase. The administration of blueberries together with

428 milk, impaired the in vivo antioxidant activity of blueberries (Serafini et al., 2009).

429 Nizamova, Ziyatdinova, & Budnikov (2011) suggested a novel method for measuring the

of
430 polyphenol bioavailability using a coulometric titrant electrogenerated bromine. They have

ro
431 observed that when milk was incorporated in tea in increasing amounts, the total antioxidant

432
-p
capacity of tea decrease in the range from 7% to 85% gradually. They proposed that the
re
433 observed results were independent from the brand of the black tea, and the degree of
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434 reduction in the total antioxidant capacity of tea remained constant. They concluded that milk
na

435 proteins bind tea polyphenols in the form of complexes due to intermolecular interactions and

436 thus reduce their bioavailability (Nizamova et al., 2011).

ur

437 Świeca, Gawlik-Dziki, Dziki, Baraniak, & Czyż (2013) also observed that bread
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438 proteins decreased the bioavailability and total antioxidant capacity of onion skin

439 polyphenols which includes significantly high flavonoid content, in particular quercetin

440 aglycone, in fortified bread. Sivam, Sun-Waterhouse, Perera, & Waterhouse (2013) proposed

441 that decreased recovery of polyphenols from enriched breads was impaired by the

442 stabilization of polyphenols during bread making and their extractability from the bread

443 matrix system; polyphenols could have developed polyphenol-polysaccharide or polyphenol-

444 protein complexes by hydrophobic interactions and/or hydrogen bonding. On the other side,

445 at each phase of bread preparation, Han & Koh (2011) observed a reduction in the phenolic

19
446 content and corresponding antioxidant activity, which appears to suggest a key function in

447 protein-phenolic interactions.

448 Rodríguez-Roque, Rojas-Graü, Elez-Martínez, & Martín-Belloso (2014a) studied the

449 effect of drink formulations on the digestibility and bioaccessibility of polyphenols and

450 antioxidant capacity in milk, blended fruit juice and their mixture using an in vitro model.

451 Throughout the gastric digestion of milk and blended fruit juice with milk, the production of

452 certain phenolic compounds was increased (around 5 to 75 %), but not in blended fruit juice.

453 Flavonoids and hydrophilic compounds with antioxidant activity were more bioaccessible in

of
454 blended fruit juice (up to 3.4 times) in comparison with milk and blended fruit juice with

ro
455 milk. Reversely, the bioaccessibility of compounds possessing lipophilic antioxidant activity

456
-p
was enhanced in case milk was incorporated to blended fruit juice (up to 1.9 times). As a
re
457 conclusion, the results of this study suggested that the incorporation of milk enhanced the
lP

458 bioaccessibility of lipophilic compounds, however not that of hydrophilic compounds

na

459 (Rodríguez-Roque et al., 2014a). Rodríguez-Roque, Rojas-Graü, Elez-Martínez, & Martín-

460 Belloso (2014b) also studied the influence of a simulated gastrointestinal digestion on the
ur

461 concentration of polyphenols and antioxidant capacity of a beverage containing soymilk and
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462 a blended fruit juice. The effect of the food matrix on these compounds' bioaccessibility was

463 also examined. Hydrophilic components from blended fruit juice with soymilk displayed

464 greater bioaccessibility (12–26.5%) than lipophilics (6.5–13.8%). Quercetin and genistein

465 were the most bioaccessible compounds whereas cis-violaxanthin and neoxanthin were the

466 lowest. Compared to blended fruit juice and soymilk, some compounds were found to be less

467 bioaccessible in blended fruit juice with soymilk (6.5-14%). Conversely, in blended fruit

468 juice with soymilk, phenolic acids and isoflavone aglycones demonstrated their optimum

469 bioaccessibility. This study revealed that both the food matrix and in vitro gastrointestinal

20
470 digestion had a major effect on these compounds' bioaccessibility (Rodríguez-Roque et al.,

471 2014b).

472 Sengul et al. (2014) also investigated impact of individual food components and food

473 matrix on the bioaccessibility of pomegranate antioxidants by simulating gastrointestinal

474 digestion. They have reported that proteins caused losses in post gastric and non-dialyzable

475 fractions. Besides, proteins did not significantly affect total antioxidant capacity in dialyzable

476 fraction, but showed an inhibitory effect after post gastric digestion. After gastric digestion,

477 proteins such as meat protein, soy protein, gluten and casein decreased the total antioxidant

of
478 capacity (Sengul et al., 2014).

ro
479 Additionally, Oksuz, Tacer-Caba, Nilufer-Erdil, & Boyacioglu (2019) recently

480
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studied the effect of dairy model systems including skim milk, non-fat-yoghurt, probiotic
re
481 yoghurt or cream on the bioaccessibility of sour cherry phytochemicals by a simulated
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482 gastrointestinal digestion method. They have reported that bioaccessibility of rutin was
na

483 decreased significantly when combined with protein-based food matrices including milk,

484 soymilk, probiotic yoghurt and yoghurt, as well as cyanidin-3-O-glucoside. They found that
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485 dairy food matrix components had lowering impact on the measured bioaccessibility of
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486 individual sour cherry phenolics (Oksuz et al., 2019). In contrast, milk and yoghurt as food

487 matrices had reducing impact on the bioavailability of anthocyanins. This observation may be

488 due to the interaction and great affinity between anthocyanins and milk proteins (Trigueros,

489 Wojdyło, & Sendra, 2014).

490 Stability of phenolic compounds is another important factor influencing their

491 bioavailability, therefore the oxidation of these compounds should be prevented (Domínguez-

492 Avila et al., 2017; Oliveira & Pintado, 2015). The bioaccessibility of polyphenols may be

493 prevented from degradation reactions by being consumed together with other food

494 components and may have increased absorption and bioaccessibility (Oliveira & Pintado,

21
495 2015). Lamothe, Azimy, Bazinet, Couillard, & Britten (2014) suggested another fascinating

496 approach to shield the polyphenols from degradation, the protein complexation that may

497 often serve as carriers of phenolic compounds and defend them from oxidative degradation

498 through digestion. However, it is important to remember that the polyphenols must be

499 bioaccessible for absorption, for example, after going through gastric digestion it must be

500 extracted from the food matrix (Oliveira & Pintado, 2015). Recently, de Morais et al. (2020)

501 evaluated the effect of protein-phenolic complexation on the antioxidant activity, digestibility

502 and stability of the complexed compounds following simulated digestion. They studied the

of
503 interaction of whey protein isolate with (-)-epigallocatechin gallate. They worked at pH 3.5

ro
504 and 7.0 to simulate conditions before and after simulated digestion. Protein structural

505
-p
modifications in complex structure were observed when whey protein isolate was applied to
re
506 (-)-epigallocatechin gallate. According to the individual compounds in general, complexation
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507 likely reduced the antioxidant potential due to hydrophobic contact and H-bonding between
na

508 the compounds. However, when interacting with the protein, (-)-epigallocatechin gallate was

509 protected against degradation during the in vitro digestion when complexed with whey
ur

510 protein isolate and became more soluble and stable, as they were shielded from the simulated
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511 gastrointestinal system conditions (de Morais et al., 2020).

512

513 3. Effect of microconstituents on flavonoid bioavailability

514 3.1. Vitamins

515 Only few studies investigated the effect of vitamins on bioavailability of flavonoids

516 (Table 3 and Table 4). In particular, the effect of vitamin C (ascorbic acid) on green tea

517 catechins has been well documented. One of the first studies on this subject (Chen, Zhu,

518 Wong, Zhang, & Chung, 1998) examined the interaction between these molecules using an in

519 vitro set-up simulating intestinal conditions. The results of this study demonstrated that the

22
520 addition of 0.2 mg/mL ascorbic acid to 0.5 mg/mL green tea catechins significantly improved

521 the stability of these flavonoids, particularly (-)-epigallocatechin and (-)-epigallocatechin

522 gallate, up to 20 h. The observed effect was dose-dependent as the addition of 0.005 mg/mL

523 ascorbic acid did not exert any protection whereas the inclusion of 0.05 mg/mL ascorbic acid

524 only slightly enhanced the stability of green tea catechins (Chen et al., 1998). In the study of

525 Green, Murphy, Schulz, Watkins, & Ferruzzi (2007), green tea water extracts formulated in

526 beverages providing 4.5, 3.5, 18 and 23 mg per 100 mL (-)-epicatechin, (-)-epicatechin

527 gallate, (-)-epigallocatechin and (-)-epigallocatechin gallate, respectively, were subjected to

of
528 simulated gastrointestinal digestion together with ascorbic acid. Stability of green tea

ro
529 catechins was poor with less than 20% total catechins remaining post-digestion. On the other

530
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hand, inclusion of 30 mg ascorbic acid in 250 mL of tea beverage significantly (p<0.05)
re
531 enhanced the recovery of (-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin and (-)-
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532 epigallocatechin gallate, to 74, 45, 54 and 82%, respectively. Same effects were also
na

533 observed in tea beverages that contain citrus fruit juices rich in vitamin C (Green et al.,

534 2007). In another study (Chung et al., 2013), intestinal transport of green tea catechins
ur

535 formulated with vitamin C was examined using the human intestinal Caco-2 cell model. It
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536 was shown that addition of vitamin C (4, 10, 20 ppm) increased the transport rate of non-

537 gallated catechins, i.e., (-)-epicatechin and (-)-epigallocatechin. For (-)-epicatechin, 10 ppm

538 of vitamin C showed 8 times higher intestinal transport compared to (-)-epicatechin only

539 formulation (Chung et al., 2013). In some studies, more representative models combining in

540 vitro gastrointestinal digestion and Caco-2 cells were developed to investigate the same

541 interaction (Peters et al., 2010; Shim et al., 2012; Son, Chung, Ko, & Shim, 2016). Using one

542 of these models, Shim et al. (2012) determined the effect of vitamin C on digestive stability

543 and intestinal uptake of green tea catechins. Combination of 10 mg vitamin C with 50 mg

544 green tea extract enhanced the digestive stability of (-)-epicatechin gallate, (-)-

23
545 epigallocatechin and (-)-epigallocatechin gallate up to 11 times, whereas no significant effect

546 was observed for (-)-epicatechin. Moreover, accumulation of catechins to the human

547 intestinal Caco-2 cells was also significantly increased by the addition of vitamin C (Shim et

548 al., 2012). In another study carried out by the same research group (Son et al., 2016), green

549 tea formulated with 20 ppm vitamin C and 49.5 ppm xylitol were coated with hydroxypropyl

550 methyl cellulose phthalate or encapsulated into γ-cyclodextrin. In vitro gastrointestinal

551 digestion model coupled to Caco-2 cells showed that coating with hydroxypropyl methyl

552 cellulose phthalate and encapsulation into γ-cyclodextrin could increase the absorption of

of
553 green tea catechins up to 11.97% and 14.36%, respectively (Son et al., 2016). Similarly, in

ro
554 the study of Peters et al. (2010), formulation of 50 mg green tea with 10 mg ascorbic acid

555
-p
improved overall catechin digestive recovery and absorption (p<0.05). This was also shown
re
556 in vivo in the same study (Peters et al., 2010), where up to 3 times incresed rate of absorption
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557 of catechins was reported with intake of 50 mg green tea containing 10 mg ascorbic acid and
na

558 1240 mg sucrose in a Sprague Dawley rat model. In another in vivo study on the same topic

559 (Gawande, Kale, & Kotwal, 2008), a cross-over human study was conducted with five
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560 volunteers, who were given a single oral dose (1000 mg) of green tea extract and a nutrient
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561 mixture containing 730 mg ascorbic acid. Supplementation of green tea extract with nutrient

562 mixture containing ascorbic acid resulted in an increased bioavailability of (-)-

563 epigallocatechin gallate by 14% (Gawande et al., 2008). Another research on sixteen high-fat

564 diet fed pigs (Fang et al., 2019) revealed that ingestion of a single dose of green tea extract

565 (190 mg/kg/day) with lemon juice (0.75 mL/kg/day) rich in ascorbic acid increased the levels

566 of (-)-epigallocatechin and (-)-epigallocatechin gallate in plasma by 1.64-fold. Vitamin C

567 may have a stronger antioxidant effect on catechins, which are susceptible to degradation in

568 an alkaline solution of the upper intestinal tract. This may explain the enhanced absorption of

569 green tea catechins in the presence of vitamin C (Shim et al., 2012). In addition, it was

24
570 reported that vitamin C could modify gene expression of efflux transporters, consequently

571 blocking the efflux of catechins by apical intestinal membranes (Peters et al., 2010).

572 Aside from the interaction between vitamin C and green tea catechins, the effect of

573 vitamin C and vitamin E (α-tocopherol) on the bioaccessibility of anthocyanins from

574 pomegranate (Sengul et al., 2014) and sour cherry (Oksuz, 2013) were studied using an in

575 vitro gastrointestinal digestion model. Addition of 5 g of ascorbic acid to 5 g pomegranate or

576 sour cherry had no significant effect on the total anthocyanin content in the stomach, whereas

577 it showed a promoting effect on the total anthocyanin content of serum and colon available

of
578 fractions after intestinal digestion. Similarly, co-digestion of 5 g vitamin E and 5 g

ro
579 anthocyanin-rich fruit resulted in an enhanced bioaccessibility of total anthocyanins at all

580
-p
stages of in vitro gastrointestinal digestion. However, these spectrophotometric analyses
re
581 results were not compatible with the outcomes of HPLC-PDA analysis of individual
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582 anthocyanins (Oksuz, 2013; Sengul et al., 2014). In another study (Ferri et al., 2015), inflence
na

583 of co-ingestion of alpha-tocopherol with (-)-epigallocatechin gallate, quercetin and rutin was

584 examined using an in vivo Sprague Dawley rat model. Eighteen rats were fed with a standard
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585 diet, or a diet including 1.5% alpha-tocopherol, or a diet with a mixture of (-)-
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586 epigallocatechin gallate, quercetin and rutin (1% each); or with a mixture of 1.5% alpha-

587 tocopherol and the three flavonoids (1% each). The concentrations of flavonoids in plasma

588 and brain showed that alpha-tocopherol was able to support the transport of quercetin and

589 rutin, whereas (-)-epigallocatechin gallate transport was not affected. The researchers

590 reported that the increased absorption of quercetin, rutin and their metabolites could be

591 related to the action of P-glycoprotein and/or impairment of the

592 phosphorylation/dephosphorylation pathway controlling the in/out flux of polyphenol

593 metabolites through the blood-brain barrier. On the other hand, (-)-epigallocatechin gallate

594 tended to form complexes with proteins and hence did not show the same behavior (Ferri et

25
595 al., 2015). In addition to the above, a recent study (Katz, Nagar, Okun, & Shpigelman, 2020)

596 investigating the storage stability of strawberry polyphenols in the presence of ascorbic acid

597 (0.022% w/v) reported that the stability of phenolic acids and anthocyanins were decreased in

598 the presence of ascorbic acid, whereas the stability of flavonols were increased by its

599 presence.

600

601 3.2. Minerals

602 Several flavonoids have been shown to decrease the bioavailability of minerals,

of
603 particularly iron (Hu et al., 2006; Lesjak et al., 2014) and zinc (Kim, Pai, & Han, 2011). This

ro
604 effect was explained by the formation of unavailable forms of mineral–polyphenol chelates in

605
-p
the lumen during digestion (Koutelidakis & Kapsokefalou, 2012). On the other hand, the
re
606 studies on the effect of minerals on flavonoid bioavailability are quite rare (Table 3 and Table
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607 4). In most of these studies, the total phenolic content was determined via the Folin–
na

608 Ciocalteu colorimetric assay, assuming that the individual phenolic compounds act in a

609 similar way. Iron is the most studied mineral probably due to frequently addressed lumenal
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610 interactions of phenolic compounds with iron. Argyri, Komaitis, & Kapsokefalou (2006)
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611 applied an in vitro gastrointestinal digestion model to investigate the changes in the total

612 phenolic content and antioxidant capacity of red wine during digestion in the lumen with

613 other dietary components including iron. The results of this study revealed that consumption

614 of 50 mL wine with 0.25 mM or 1 mM iron significantly (p<0.05) decreased the total

615 phenolic content and antioxidant activity of red wine (Argyri et al., 2006). The same research

616 group (Argyri, Proestos, Komaitis, & Kapsokefalou, 2005) also determined the alterations in

617 the phenolic profile of red wine when consumed together with iron. In agreement with their

618 previous work (Argyri et al., 2006), the authors reported that iron reduced the concentration

619 of individual phenolic compounds before and after simulated gastrointestinal digestion

26
620 (Argyri et al., 2005). In the following years, similar research investigating the interaction

621 between green tea polyphenols and iron was conducted both in vitro (Alexandropoulou,

622 Komaitis, & Kapsokefalou, 2006) and in vivo (Kapsokefalou, Zhu, & Miller, 2006). In vitro

623 gastrointestinal digestion of 20 mL green tea with 0.25 mM or 1 mM iron reduced the total

624 phenolic content and antioxidant capacity, which was statistically significant (p<0.05) when

625 iron was added at 1 mM (Alexandropoulou et al., 2006). The same effect was also observed

626 in vivo, where significant reductions in polyphenol content and antioxidant capacity of

627 plasma occurred with intake of green tea (0.04 g/mL) containing iron (0.1 mg/mL) in a

of
628 Sprague Dawley rat model (Kapsokefalou et al., 2006). In another in vivo study (Karabela,

ro
629 Koutelidakis, Proestos, Komaitis, & Kapsokefalou, 2012), ten female volunteers received

630
-p
white tea infusion (containing 6 g white tea) or a mixture of white tea infusion and iron
re
631 lactate (6 g white tea and 30 mg iron lactate) in a randomized cross over design. White tea
lP

632 increased the phenolic content and antioxidant capacity of plasma in a time dependent
na

633 manner (p<0.0001), however in the presence of iron the increase was lower (p=0.0057).

634 Consequently, the authors suggested that iron may modify the content of tea polyphenols in
ur

635 human plasma (Karabela et al., 2012). In another study reporting the interaction between
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636 phenolics and iron (Cilla, González-Sarrías, Tomás-Barberán, Espín, & Barberá, 2009), an in

637 vitro gastrointestinal digestion model was used to evaluate the bioavailability of polyphenols

638 in fruit beverages when ingested with iron. Addition of iron (3 mg/100 ml of fruit beverage)

639 to fruit beverages prepared with juice concentrates of grape, orange and apricot decreased the

640 phenolic content by 13% and 60% before and after digestion, respectively (Cilla et al., 2009).

641 Later, this group (Cilla, Lagarda, Barberá, & Romero, 2010) also determined the phenolic

642 profile of fruit beverages fortified with zinc (1.6 mg/100 mL of fruit beverage) using the

643 same in vitro gastrointestinal digestion model. In all zinc-fortified samples, digestion

644 decreased the phenolics up to 32% with respect to the original fruit beverages (Cilla et al.,

27
645 2010). According to the results of the studies mentioned above, it can be concluded that

646 formation of poorly absorbed iron-polyphenol or zinc-polyphenol chelates may inhibit the

647 absorption of polyphenols and consequently may affect their biological properties.

648 In addition to iron and zinc, the effect of sodium chloride (salt) on the bioaccessibility

649 of anthocyanins from pomegranate (Sengul et al., 2014) and sour cherry (Oksuz, 2013) were

650 also reported. Unlike the effect of iron and zinc on phenolics, in vitro gastrointestinal

651 digestion of pomegranate and sour cherry with salt increased the recovery of total

652 anthocyanins. On the other hand, as in the studies mentioned above for iron and zinc, the total

of
653 phenolic content of pomegranate and sour cherry significantly decreased after gastric and

ro
654 intestinal digestion (Oksuz, 2013; Sengul et al., 2014).

655
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re
656 3.3. Other micronutrients
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657 There are multiple flavonoids present in the human diet, which are usually ingested
na

658 together. Considering that, several co-administration studies investigating the interaction

659 between different flavonoids have been carried out in order to understand the bioavailability,
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660 metabolic fates and health benefits of these compounds (Table 3 and Table 4). One of the
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661 earliest studies on this topic (Silberberg, Morand, Manach, Scalbert, & Remesy, 2005) was

662 performed on rats adapted to diets containing 0.25% quercetin, or 0.25% (+)-catechin, or

663 0.25% quercetin and 0.25% (+)-catechin. When quercetin and (+)-catechin were administered

664 together, their concentration in plasma reduced significantly (35 and 28%, respectively),

665 whereas the urinary and hepatic concentrations were only decreased in case of quercetin

666 (36%). However, the metabolite formation, i.e., glucurono- and sulfo- conjugates, was not

667 affected when quercetin and (+)-catechin were co-ingested (Silberberg et al., 2005). In

668 another study (Moon & Morris, 2007), the effect of quercetin and (-)-epigallocatechin-3-

669 gallate on the bioavailability of biochanin A was studied on rats fed intravenously (5 mg/kg)

28
670 or orally (50 mg/kg). The results showed that co-ingestion of quercetin and (-)-

671 epigallocatechin-3-gallate significantly enhanced the plasma concentration of biochanin A

672 after both intravenous and oral supplementation (Moon & Morris, 2007). In an in vitro Caco-

673 2 cell study (Brand, Padilla, van Bladeren, Williamson, & Rietjens, 2010), the modulation of

674 the metabolism and absorption of hesperetin was investigated by investigating the impact of

675 co-ingestion of several flavonoids (rutionosides, flavonols, flavones, isoflavones, flavanols

676 and chalcones). Co-exposure of 10 μM hesperetin with 10 μM of the tested flavonoids

677 resulted in decreased efflux of hesperetin metabolites to the apical side, whereas the transport

of
678 to the basal side, simulating the blood or plasma of the intestinal barrier, was increased. In

ro
679 case of quercetin, basal transport of hesperetin was doubled, in spite of the 27% decrease in

680
-p
formation of phase II metabolites, i.e., hesperetin 7-O-glucuronide and hesperetin 7-O-sulfate
re
681 (Brand et al., 2010). Later, a similar study (Sanchez-Bridge et al., 2015) was conducted on
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682 Caco-2 cells to investigate the modulation of (-)-epicatechin metabolism by co-ingestion with
na

683 other flavonoids at varying concentrations (1, 5, 10 and 50 μM). Administration of (-)-

684 epicatechin with certain flavonoids, like genistein or nevadensin, promoted the transport of (-
ur

685 )-epicatechin metabolite, i.e., 3’-O-methyl-epicatechin, towards the basal side while reducing
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686 the apical efflux. On the other hand, the appearance of this (-)-epicatechin conjugate was

687 inhibited both in the apical and basal sides when quercetin and luteolin are co-incubated

688 (Sanchez-Bridge et al., 2015). In the study of Orrego-Lagarón, Martínez-Huélamo, Quifer-

689 Rada, Lamuela-Raventos, & Escribano-Ferrer (2016), co-administration of quercetin and

690 naringenin, the common compounds present in tomatoes as well as other fruits and

691 vegetables, was studied using an intestinal perfusion model in mice. When 3.5 μg/mL

692 naringenin and 2.36 μg/mL quercetin were fed together, the values of permeability

693 coefficients were reduced by 50%, while the phase II metabolite concentrations were

694 enhanced (Orrego-Lagarón et al., 2016). Another study conducted both with male rats and

29
695 Caco-2 cells indicated that concurrent administration of (+)-catechin (140 mg/kg) and

696 puerarin (200 mg/kg) significantly enhanced the absolute bioavailability of puerarin while

697 reducing its own absolute oral bioavailability (Su et al., 2016). Recently, instead of pure

698 compounds, complex food matrices were used to study interactions between flavonoids.

699 Accordingly, Dudonné et al. (2016) studied the effect of co-ingestion of blueberry extract

700 with grape extract using an in vivo mice model. Targeted metabolomic profiling in plasma

701 and feces of mice administered with a blueberry extract (31.1 mg/kg), a grape extract (266.4

702 mg/kg) or their combination resulted in 3–5 fold enhanced concentrations of blueberry

of
703 phenolic metabolites in plasma in the presence of a co-administered grape extract, which

ro
704 resulted in an equivalent decrease in their presence in feces (Dudonné et al., 2016). Similarly,

705
-p
another recent study (Choi et al., 2017) reported the impact of flavonol-rich food (onion peel
re
706 and Dendropanax morbifera) on the bioavailability of green tea catechins using both in vitro
lP

707 (gastrointestinal digestion/Caco-2 cells) and in vivo (Sprague Dawley rats) models. Increased
na

708 cellular uptakes of epicatechins (up to 188%) were observed as a result of ingestion with

709 onion peel and Dendropanax morbifera. In addition, the plasma concentration of total
ur

710 epicatechins in rats supplemented with green tea with 5% onion peel, was reported to be
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711 almost twice of that obtained with green tea alone. The mechanism behind this behavior is

712 possibly the action of flavonols as boosters of digestive stability and also influencers of the

713 epicatechin biotransformations (Choi et al., 2017). Absorption of green tea catechins was also

714 studied in the presence of quercetin and fisetin using an in vitro Caco-2 cell and an in vivo rat

715 models (Chung et al., 2018). The intestinal transport of green tea catechins by Caco-2 cells

716 was increased up to 244% by the addition of 5% mixture of quercetin and fisetin.

717 Furthermore, the plasma concentrations were also increased in rats administered with (-)-

718 epigallocatechin gallate with 10% quercetin or 10% fisetin than in those administered with (-

719 )-epigallocatechin gallate only (Chung et al., 2018). Another recent study (Choi, Rha,

30
720 Balusamy, Kim, & Shim, 2019) investigating the impact of flavonol aglycones in green tea

721 extract on the bioaccessibility and cellular uptake of epicatechins using a combined in vitro

722 gastrointestinal digestion and Caco-2 cell model indicated that the bioaccessibility of

723 epicatechins from green tea extract enhanced with the inclusion of 10% flavonol aglycone

724 rich fraction. Moreover, intestinal cellular transport of epicatechins also enhanced by

725 332.46%, 273.92%, 150.22% and 131.21% for (-)-epigallocatechin gallate, (-)-epicatechin

726 gallate, (-)-epicatechin and (-)-epigallocatechin, respectively (Choi et al., 2019). Similarly, in

727 an ex vivo study performed on everted goat intestine (Pandit, Joshi, Dalal, & Patole, 2019),

of
728 the permeability of green tea catechins increased from 20.57% to 53.15% when administered

ro
729 together with curcumin at a ratio of 220:50. A study investigating the effects of combination

730
-p
of cereal 3-deoxyflavonoids (apigenin, naringenin) with pulse flavonols (quercetin)
re
731 (Ravisankar et al., 2019) reported that the absorption of quercetin through Caco-2 cells was
lP

732 enhanced more than 3-fold when administered together with apigenin (at 1:1 ratio), whereas
na

733 apigenin absorption was only increased by 50%. The mechanism of the observed effect was

734 explained as the synergistic inhibition of phase II enzyme and membrane transporter
ur

735 functions (Ravisankar et al., 2019). In summary, although there are some exemptions; the
Jo

736 majority of studies suggest that flavonoids may have higher bioavailability when they are

737 digested with other flavonoids than when taken alone.

738 Besides the interaction of flavonoids with each other, the influence of alkaloids

739 (Lambert, Hong, Kim, Mishin, & Yang, 2004; Nakagawa et al., 2009; Junsaeng et al., 2019)

740 and carotenoids (Zuniga & Erdman, 2011; Phan, Bucknall, & Arcot, 2019) on the

741 bioavailability of flavonoids was also reported. For example, simultaneous administration of

742 163.8 μmol/kg (-)-epigallocatechin gallate and 70.2 μmol/kg piperine, an alkaloid derived

743 from black pepper, to male CF-1 mice enhanced the plasma concentration by 1.3-fold in

744 comparison with mice treated with (-)-epigallocatechin gallate only. Piperine enhanced (-)-

31
745 epigallocatechin gallate bioavailability through inhibition of glucuronidation and

746 gastrointestinal transit (Lambert et al., 2004). Piperine also enhanced the bioavailability of

747 oxyresveratrol by almost 2–fold in male Wistar rats administered with 10 mg/kg

748 oxyresveratrol and 1 mg/kg piperine intravenously or 100 mg/kg oxyresveratrol and 10

749 mg/kg piperine orally (Junsaeng et al., 2019). Similarly, caffeine was co-administered with (-

750 )-epigallocatechin-3-gallate to human volunteers considering the levels found in commercial

751 tea drinks. Plasma concentration after ingestion of a beverage containing 95 mg (-)-

752 epigallocatechin-3-gallate and 40 mg caffeine was significantly higher compared to the

of
753 beverage containing 95 mg of (-)-epigallocatechin-3-gallate alone. On the other hand, after

ro
754 ingestion of a beverage with 95 mg (-)-epigallocatechin-3-gallate and 180 mg caffeine, the

755
-p
plasma concentration of (-)-epigallocatechin-3-gallate tended to be somewhat higher,
re
756 however not significantly, compared with the beverage with (-)-epigallocatechin-3-gallate
lP

757 alone (Nakagawa et al., 2009). As regards to carotenoids, the results of a study, in which
na

758 Male Copenhagen rats were fed with diets containing 10% tomato powder, 2% soy germ,

759 neither, or a combination, suggested interactions between soy germ and tomato powder that
ur

760 increase the uptake of isoflavones but decrease the bioavailability of carotenoids (Zuniga &
Jo

761 Erdman, 2011). A recent study investigated the effects of co-ingestion of red cabbage with

762 carotenoid-rich vegetables including carrots, spinach and cherry tomatoes on the

763 bioaccessibility of anthocyanins and carotenoids using an in vitro gastrointestinal digestion

764 model (Phan et al., 2019). The authors reported that the bioaccessibility of total anthocyanins

765 was increased by 10–15% (p<0.05) when red cabbage was co-ingested with the carotenoid-

766 rich vegetables, except for carrot. On the other hand, the co-ingestion decreased the

767 bioaccessibility of total carotenoids by 21–33% and 42–56%, for carrot and cherry tomato,

768 respectively (p<0.05) (Phan et al., 2019).

769

32
770 4. Conclusions

771 Bioavailability of flavonoids depends on a variety of factors, one of which is the food

772 matrix. In vivo and in vitro studies have shown that in general, the presence of proteins,

773 dietary fiber and minerals may induce disadvantageous impact on the bioavailability of

774 flavonoids. On the other hand, lipids, digestible carbohydrates, vitamins, alkaloids,

775 carotenoids and other flavonoids are likely to improve flavonoid bioavailability. An overview

776 of the general effects of macro- and micro-nutrients on the bioavailability of flavonoids is

777 illustrated in Figure 2. Although the exact mechanisms behind these observations remain to

of
778 be unclear, it has been proposed that reduced bioavailability might be due to the entrapment

ro
779 of flavonoids to the food matrix; whereas improved micellization and activation of

780
-p
transporters involved in flavonoid uptake might result in enhanced bioavailability of
re
781 flavonoids. Nevertheless, the studies carried out on this subject are limited and also some
lP

782 outcomes are contradictory. Moreover, in most of the studies, only a single food component
na

783 or isolated pure flavonoids are used. Although there are some co-digestion studies where

784 more than one matrix component and flavonoid-rich foods are involved (McDougall,
ur

785 Dobson, Smith, Blake, & Stewart, 2005; Cebeci & Şahin-Yeşilçubuk, 2014; Kamiloglu,
Jo

786 Pasli, Ozcelik, & Capanoglu, 2014), further research is necessary to understand the fate of

787 flavonoids in the presence of multiple matrices. In addition, risk of deficiencies of other

788 important nutrients (e.g. minerals) with elevated flavonoid intake is another issue that needs

789 to be considered. Eventually, understanding the mechanism of interaction between dietary

790 flavonoids and food matrix will help to develop food products with higher beneficial health

791 effects to the consumers.

792

793 References

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985 promotes absorption of the soluble flavonoid αG-rutin in rats. Journal of Agricultural

986 and Food Chemistry, 55(10), 4202-4208.

987 McDougall, G. J., Dobson, P., Smith, P., Blake, A., & Stewart, D. (2005). Assessing potential

988 bioavailability of raspberry anthocyanins using an in vitro digestion system. Journal

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990 Mendes, T. M. N., Murayama, Y., Yamaguchi, N., Sampaio, G. R., Fontes, L. C. B., da Silva

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1199 Agricultural and Food Chemistry, 59(10), 5335-5341.

na
ur
Jo

50
1200 Figure captions

1201 Figure 1. Classification and examples of dietary flavonoids

1202 Figure 2. Overview of the general effects of macro- and micro-nutrients on the

1203 bioavailability of flavonoids

of
ro
-p
re
lP
na
ur
Jo

51
 Flavonoids

f
oo
Flavonols Flavones Flavanones Flavanols Isoflavones Anthocyanidins

pr
e-
Pr
al
rn
Quercetin Apigenin Naringenin Catechin Genistein Cyanidin

u
Jo

Kaempferol Luteolin Hesperetin Epicatechin Daidzein Delphinidin

Figure 1

52
 Bioavailability

Digestible carbohydrates

Macronutrients

f
oo
Dietary fiber

pr
e-
Lipids

Pr
al
Proteins

rn
+ Jo
u
Flavonoids
Micronutrients

Vitamins

Alkoloids

Carotenoids
2+
Fe
Minerals
Figure 2

53
Table 1. In vitro studies on the effect of macroconstituents on bioavailability of flavonoids
Nutrient Flavonoid Model Key outcomes Effect Reference
Carbohydrates
Sucrose Green tea Gastrointestinal • Inclusion of green tea with sucrose improved overall catechin digestive recovery Peters et al.
catechins digestion significantly (p<0.05), enhancing total catechins in digesta from 19.1 μmol/reaction to 23.2 2010
combined with μmol/reaction.
Caco-2 cells • Formulation of green tea with ascorbic acid and sucrose had significantly higher catechin
retention (up to 437%) than other formulations (p<0.05).
Sucrose Green tea Gastrointestinal • Digestive stability of total catechins in green tea containing xylitol and citric acid or vitamin Shim et al. 2012
Glucose extracts digestion C enhanced by 1.7-2.5 and 3 times, respectively.

f
Xylitol combined with • Intestinal absorption of total catechins significantly enhanced in green tea with xylitol and

oo
Caco-2 cells citric acid or vitamin C, 6 and 11 times respectively, compared to green tea alone.
Xylitol Green tea Caco-2 cells • A 10 ppm of vitamin C, 20 ppm of vitamin C with 49.5 ppm of xylitol, 20 ppm of vitamin C Chung et al.

pr
catechins with 49.5 ppm of xylitol, and 20 ppm of vitamin C with 49.5 ppm of xylitol formulation for 2013
EC, ECG, EGC, and EGCG, respectively, exerted 8, 2, 2.4 times, and 1.9 times increased

e-
intestinal absorption than catechins only formulations.

Pr
Glucose Pomegranate Gastrointestinal • The starch, glucose, lactose and pectin affected the phenolic loss and showed two fold Sengul et al.
Lactose arils digestion reduction in serum fraction. 2014
Pectin phenolics

al
Starch
•

rn
Dietary fiber Mango, Gastrointestinal The existence of dietary fiber in papaya, mango and pineapple did not cause a major - Velderrain-
Papaya and digestion restriction on the bioaccessibility of polyphenols Rodriguez et al.
Pineapple
phenolics u 2016
Jo
Chitosan Maqui berry Gastrointestinal • The combination of maqui berry with the various fibers enhanced the bioaccessibility index Viuda-Martos et
Xanthan gum powder digestion of the phenolics and flavonoids in all cases. al. 2018
Guar gum anthocyanins
Inulin
β-glucan
Sodium
carboxymethyl
cellulose
Pectin
Cellulose
(Continues)

54
Table 1. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Carbohydrates
Inulin Tomato sauce Gastrointestinal • Tomato sauce containing both 5% and 10% inulin significantly reduced the total phenolic Tomas et al.
flavonoids digestion content (up to 31%), total flavonoid content (up to 36%), and total antioxidant capacity (up 2018
to 48-58%).
Strawberry HT Gastrointestinal • Hydroxytyrosol (HT) /3,4-dihydroxyphenylglycol (DHPG) and strawberry dietary fiber Bermúdez-Oria
fiber DHPG digestion complex showed antioxidant activity. et al. 2019
• Reduced polysaccharide size increased the antioxidant capacity of the complex.
Pectin Blackberry Gastrointestinal • 10% soluble dietary fiber changed the polyphenol bioaccessibility. Tomas et al.

f
Inulin phenolics digestion • Supplementation of soluble dietary fibers promoted the formation of phenolic metabolites. 2020

oo
Blueberry Malvidin-3- Gastrointestinal • Chelator soluble blueberry pectin protected malvidin-3-glucoside, cyanidin-3-glucoside, Koh et al. 2020
pectin glucoside, digestion and blueberry extract against degradation.

pr
cyanidin-3- • Water soluble blueberry pectin protected cyanidin-3-glucoside only.
glucoside, •

e-
Delphinidin-3-glucoside completely disappeared after gastrointestinal digestion.
delphinidin-3-
glucoside

Pr
Pectin, Naringenin Gastrointestinal • Addition of 2% pectin to 700 μM naringenin reduced the bioaccessibility of naringenin by Kruger et al.,
Sucrose digestion 65%. Caco-2 cellular absorption of bioaccessible naringenin was increased from 47% to 2020

al
combined with 95% in the presence of pectin.
Caco-2 cells •

rn
Addition of 5% sucrose to 700 μM naringenin containing 2% pectin reduced the inhibitory
effect of pectin and increased naringenin bioaccessibility from 8% to 15%. In this case,

u
Caco-2 cellular absorption of bioaccessible naringenin was 100%.
Jo
Lipids
Cocoa liquor Cocoa Gastrointestinal • Higher fat content in the cocoa liquor had a preservative effect that promoted the stability Ortega et al.
fat, Cocoa procyanidins digestion of polyphenols during digestion 2009
powder fat and flavones
Hazelnut oil Carob flour Gastrointestinal • The concentrations of all the phenolic groups were enhanced significantly in the presence Ortega et al.
phenols digestion of the hazelnut oil fraction for both sample mixtures. 2011
• Lipid fraction that is rich in PUFA demonstrated a protective effect on the stability of the
phenolics in the course of duodenal digestion.
Almond oil, Isoflavones Gastrointestinal • The concentration or lipid source dis not influence the bioaccessibility and absorption and − Simmons et al.
Canola oil, digestion metabolism of isoflavones. 2012
Hazelnut oil, combined with
Shortening Caco-2 cells
(Continues)

55
Table 1. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Lipids
Sunflower oil Pomegranate Gastrointestinal • Addition of the sunflower oil did not affect a significant change on the bioaccessibility of − Oksuz 2013;
anthocyanins, digestion anthocyanins Sengul et al.,
Sour cherry 2014
anthocyanins
High-fat diet Blueberry TIM-11 • Lipid-rich matrices selectively influence the bioaccessibility anthocyanins. Ribnicky et al.
anthocyanins gastrointestinal • Delphinidin-3-(6“-acetoyl)-glucoside and malvidin-3-arabinoside were two times more as 2014
model bioaccessible under fasted conditions, whereas delphinidin-3-glucoside, delphinidin-3-

f
arabinoside, delphinidin-3-galactoside and petunidin-3-arabinoside were two times more as

oo
bioaccessible in fed state.
Olive oil Olive oil and Gastrointestinal • The bioaccessibilty of hydroxytyrosol increased in presence of thyme. Rubió et al.,

pr
thyme digestion • Bioavailability of eriodictyol and naringenin increased when olive and thyme are co- 2014
phenolics combined with ingested.

e-
Caco-2 cells
•

Pr
Vegetable oil Guaraná Gastrointestinal Oil improved the bioaccessibility of total procyanidins. Mendes et al.
procyanidins digestion 2019
Proteins

al
Casein and Tea Titration method • The proteins bind rutin and quercetin (from 14 to 90%) at a high rate and thus reduce the Nizamova et al.,

rn
bovine serum polyphenols polyphenol bioavailability. 2011
albumin • The total AOC of tea drops from 7 to 85%, in proportion to the increase in the amount of

• u
milk in the mixture.
Jo
Milk proteins bind tea polyphenols into complexes because of intermolecular interactions
and thus reduce their bioavailability.
Bread proteins Onion skin Gastrointestinal • Bread proteins decreased the onion skin bioavailability Świeca et al.,
digestion 2013
Milk proteins Blended fruit Gastrointestinal • Compared to BFJ with milk, flavonoids and hydrophilic compounds with antioxidant Rodríguez-
juice (BFJ) digestion activity were up to 3.4 times more bioaccessible in BFJ alone. Roque et al.
phenolics • When milk was added to BFJ, the bioaccessibility of compounds with lipophilic antioxidant (2014a)
activity was increased up to 1.9 times.
• The bioaccessibility of lipophilic constituents enhanced with the corporation of milk,
however not that of hydrophilics.
(Continues)

56
Table 1. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Proteins
Soymilk Blended fruit Gastrointestinal • BFJ – SMB hydrophilic components showed greater bioaccessibility (12–26.5%) than those Rodríguez-
proteins juice (BFJ) digestion lipophilics (6.5–13.8%). Roque et al.
phenolics • Quercetin and genistein were the most bioaccessible compounds whereas cis- (2014b)
violaxanthin+neoxanthin was the lowest.
• Compared to BFJ and SM, in BFJ-SMB the bioaccessibility of some compounds were
decreased (6.5-14%).
• BFJ – SMB, phenolic acids and aglycone isoflavones demonstrated their optimum
bioaccessibility.

f
•

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Simulated gastrointestinal digestion and food matrix had a major effect on the
bioaccessibility of the phenolics.

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UHT skim Pomegranate Gastrointestinal • Proteins influenced losses in post gastric and non-dialyzable fractions. Sengul et al.,
milk, Minced polyphenols digestion • Proteins did not significantly influence total antioxidant capacity in dialyzable fractions, 2014

e-
lean meat, however were inhibitory after gastric digestion.
Bread, Skim • After the simulated digestion in the stomach, protein sources such as meat protein, soy

Pr
plain yoghurt, protein, gluten and casein decreased the total antioxidant capacity.
Probiotic
yoghurt, Soy

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milk, Cream,

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Soybean
Skim milk, Sour cherry Gastrointestinal • The bioavailability of rutin was decreased significantly when combined with protein-based Oksuz et al.,
Non-fat- phenolics digestion
u
food matrices including milk, soymilk, probiotic yoghurt and yoghurt, as well as cyanidin-3- 2019
Jo
yoghurt, O-glucoside.
Probiotic • Dairy food matrix components analyzed had lowering effects on the bioavailability of
yoghurt or polyphenols from sour cherry.
Cream
Whey protein CA, EGCG Gastrointestinal • EGCG was not degraded during the in vitro digestion when complexed with WPI and Morais et al.,
isolate (WPI) digestion became more soluble and stable, as they were shielded from the simulated gastrointestinal 2020
system conditions.
BFJ: blended fruit juice, EGCG: (-)-epigallocatechin gallate, WPI: whey protein isolate.

57
Table 2. Animal and clinical studies on the effect of macroconstituents on bioavailability of flavonoids
Nutrient Flavonoid Model Key outcomes Effect Reference
Carbohydrates
Control diet Soybean Crossover • The diet rich in fiber caused 55% and 46% lower concentrations of genistein and daidzein in Tew et al. 1996
(15 g dietary isoflavones study with 7 plasma, at 24 h after administration of soy (p<0.05)
fiber) (0.9 mg volunteers
Wheat fiber isoflavones/kg
supplemented body)
diet (40 g
dietary fiber)
Sugar 1.53 mg (+)- Crossover • The co-ingestion of sugar with cocoa rich in flavanols led to a significant increase in Schramm et al.

f
oo
catechin and (-)- study with 6 maximal plasma concentration (Cmax, 18-44%) and area under the plasma pharmacokinetic 2003
epicatechin from volunteers curve (AUC, 22-40%) of catechin and epicatechin and speeded up their renal elimination
cocoa/kg body

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weight (115

e-
mg/75 mg)
Difructose αG-rutin Wistar ST rats • In the presence difructose anhydride III, the absorption of alpha glucosyl rutin was increased Matsumoto et

Pr
anhydride III 1.5-3 times. al. 2007
Pectin Rutin Crj mice • The plasma concentrations of quercetin and isorhamnetin were increased significantly in the Tamura et al.

al
Cellulose diet containing pectin and rutin (9.16) in comparison with the diet containing cellulose and 2007
rutin (1.52).

rn
Hemicellulose Daidzein Crj mice • The addition of 5% hemicellulose to a diet already including 5% cellulose reduced the Tamura et al.
availability of daidzein. 2009
• u
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Sucrose Chocolate Crossover The presence of a high-sucrose containing chocolate might positively affect the flavan-3-ol Neilson et al.
flavan-3-ols study with 6 bioavailability. Pharmacokinetic analysis revealed Cmax:34 nM, Tmax:1.8 h, AUC:128 nM 2009
volunteers h
Chocolate Sprague- • The plasma concentrations of total flavan-3-ols (AUC: 41314 nM h, Cmax: 8110 nM: Tmax: Neilson et al.
flavan-3-ols Dawley Rats 3.5 h) were highest with the high-sucrose chocolate whereas a reference dark chocolate 2010a
resulted in moderate recovery (AUC: 36360 nM h, Cmax: 5916 nM: Tmax: 5.5 h).
Green tea Sprague • The plasma levels of epigallocatechin and epigallocatechin gallate were significantly Peters et al.
catechins Dawley rats (p<0.05) enhanced in the presence of sucrose and ascorbic acid (AUC 0–6 h = 3237.0 and 2010
181.8 pmol h/L plasma respectively) in comparison with green tea alone (AUC 0–6 h =
1304.1 and 61.0 pmol h/L plasma respectively).
(Continues)

58
Table 2. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Carbohydrates
Maltitol High-flavanol Crossover study • The total flavanol absorption was lower in maltitol-containing test chocolate in Rodriguez-Mateos
chocolate with 15 comparison to a sucrose-containing equivalent. et al. 2012
containing volunteers
maltitol or
sucrose,
Low-flavanol
chocolate with
sucrose

f
oo
Pectin, Quercetin Wistar/ST rats • Water-soluble dietary fibers, in particular soybean fiber, increased the bioavailability of Trakooncharoenvit
Soybean fiber, glucoside quercetin glycoside after long-term feeding of rats. et al. 2019
Guar gum

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Lipids

e-
Lecitin and Quercetin Wistar rats • Co-ingestion of lecithin and soybean oil or emulsifiers with quercetin had statistically no Azuma et al. 2002
emulsifier significant impact quercetin absorption, whereas a significantly increased the absorption

Pr
of quercetin was observed when lipids and emulsifiers are combined.
Beef tallow, Quercetin Wistar rats • Bioavailability of quercetin glucosides from onion was enhanced after co-digestion with Azuma et al. 2003

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Fish oil glucosides in lipids and emulsifiers.
onion

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Lard Quercetin, Q3G Cross-bred • Bioavailability of quercetin was greater from the glucosides in comparison with the Lesser, Cermak,
growing aglycones for each diet. and Wolffram
castrated pigs • u
Quercetin bioavailability was greater in diet containing 17% fat in comparison with the 2004; Lesser,
Jo
diet containing 3% fat. Cermak, and
Wolffram 2006
• Co-administration of MCT and LCT diets increased the quercetin by 38% and 12%,
respectively.
Virgin olive Olive oil Crossover study • The concentration of hydroxytyrosol sulphate and vanillin sulphate were higher in plasma Suarez et al. 2011
oil phenolics with 13 from the enriched virgin olive oil than after ingestion virgin olive oil (p<0.05).
volunteers
Milk fat Jujube juice Wistar rats • Consumption of milk fat with jujube juice (1:1, v/v) did not affect the bioavailability of − Zhang et al. 2012
phenolics phenolics in jujube juice.
(Continues)

59
Table 2. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Lipids
Olive oil Tomato phenolics Crossover • Naringenin glucuronide, was found to be statistically not significant due to large − Tulipani et al.
study with 5 interindividual response variability 2012
volunteers
Butter Quercetin Crossover • Quercetin bioavailability was improved in the presence of dietary fat. Guo et al. 2013
study with 4 • The methylated metabolites of quercetin, i.e., isorhamnetin and tamarixetin, were also
volunteers enhanced up to 43% during high-fat diet.
Refined olive Tomato phenolics Crossover • Oil enhanced the bioavailability of lipophilic compounds but with no significant − Martínez-

f
oil study with 8 differences. Huélamo et al.

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volunteers • The concentration of 5-caffeoylquinic acid and naringenin were higher in enriched refined 2015
olive oil sauce than oil free sauce.

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Refined olive Tomato phenolics Crossover • The bioavailability of quercetin and naringenin glucuronide was increased in tomato sauce Martínez
oil study with 40 Huélamo et al.

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enriched with refined olive oil than in tomato or tomato without refined olive oil.
volunteers 2016

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Omega-3 Grape Wistar-Kyoto • Omega-3 PUFAs affects the proanthocyanidin metabolism. − Molinar-
PUFAs1 proanthocyanidins rats • Omega-3 PUFAs did not significantly affect proanthocyanidin metabolites from those fed Toribio et al.
only with grape seed extract metabolism given at high doses. 2017

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Sunflower Quercetin Crossover • The application of the novel dietary lecithin-based formulation of quercetin overcame the Riva et al. 2019

rn
lecithin study with 12 low bioavailability hurdle of quercetin.
volunteers • The formulation caused significant developments in both solubility and transport of
uquercetin
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Proteins
Milk proteins Tea catechins Crossover study • Bioavailability of tea catechins does not reduce with the presence of milk. - Van het Hof et
with 12 al.,1998
volunteers
Tea flavonols Comparative • The presence of milk did not influence the transport of tea flavonols. - Hollman et al.,
(quercetin, study with 18 2001
kaempferol) volunteers
Black tea Study with 9 • Addition of milk to black tea did not affect the plasma concentrations of catechins, - Kyle et al., 2007
polyphenols volunteers quercetin and kaempferol.
(Continues)

60
Table 2. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Proteins
Milk proteins Chocolate Crossover • Presence of milk, both in the course of digestion and in the manufacturing process, reduced Serafini et al.,
flavonoids study with 12 the absorption of EC into bloodstream. 2003
(EC) volunteers
Cocoa Crossover • The presence of milk did not influence the absorption and bioactivity of monomeric cocoa - Schroeter et al.,
flavonoids study with 12 flavanols. 2003
(EC) volunteers
Crossover • No significant impact on flavonol absorption was observed after administration of flavanol- - Schramm et al.,
study with 6 rich cocoa with milk. 2003

f
volunteers

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Crossover • The presence of milk did not influence the bioavailability of polyphenols. - Roura et al.,
study with 21 2007

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volunteers
Crossover • Presence of milk did not influence the average concentration of catechin and EC, while it - Keogh et al.,

e-
study with 24 slightly accelerated absorption of these compounds. 2007
volunteers

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Blueberry Crossover • The in vivo antioxidant characteristics of blueberries were not influenced by the presence of - Serafini et al.,
anthocyanins study with 11 milk. 2009
volunteers

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Probiotic Soy Crossover • The bioavailability of soy isoflavones, i.e., daidzein and genistein, did not change significantly - Larkin et al.,

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yoghurt isoflavones study with 31 with probiotic yoghurt intake. 2007
volunteers • Equol production was not increased with probiotic yoghurt intake.
Cream Strawberry Crossover • u - Mullen et al.,
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There was statistically no significant difference between strawberries consumed with or
anthocyanin study with 8 without cream. 2008
(P3G) volunteers
AUC: area under the plasma pharmacokinetic curve, Cmax: maximal plasma concentrations, EC: (-)-epicatechin, ECG: (-)-epicatechin gallate, EGC: (-)-epigallocatechin, EGCG: (-)-
epigallocatechin gallate, MCT: medium-chain triacylglycerols, P3G: pelargonidin-3-O-glucoside, PUFA: polyunsaturated fatty acids, Q3G: quercetin-3-O-glucoside, TIM-1: The
TNO intestinal model, Tmax: time at which the maximum plasma concentration.
: increased bioaccessibility/bioavailability of flavonoids; : decreased bioaccessibility/bioavailability of flavonoids; - : no change in bioaccessibility/bioavailability of flavonoids

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Table 3. In vitro studies on the effect of microconstituents on bioavailability of flavonoids
Nutrient Flavonoid Model Key outcomes Effect Reference
Vitamins
Vitamin C Green tea Intestinal • Addition of 0.2 mg/mL AA to 0.5 mg/mL green tea catechins significantly improved the Chen et al.,
(AA) catechins digestion stability of EGC and EGCG (Complete destruction in the absence of AA, whereas only 25 and 1998
(EC, ECG, 15% destruction in the presence of AA, respectively).
EGC, EGCG) • The observed protective effect was dose dependent as 0.005 mg/mL AA did not show any
effect while 0.05 mg/mL AA only slightly promoted the recovery of green tea catechins.
Gastrointestinal • Addition of 30 mg AA to 250 mL tea enhanced the recovery of EC, ECG, EGC and EGCG Green et al.,
digestion from <20% to 74, 45, 54 and 82%, respectively. 2007

f
• Addition of AA rich citrus fruit juices (grapefruit, lemon, lime, and orange) to tea (prepared

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by displacing water at 10, 20, and 50%) resulted in increased recovery of EC (86–95%), ECG
(30–55%), EGC (81–98%), and EGCG (56–76%).

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Gastrointestinal • Addition of 10 mg AA to 50 mg green tea increased total catechin recovery from 19.1 to 20.0 Peters et al.,

e-
digestion μmol/reaction. Catechin retention by Caco-2 cells also increased (from 5.5-8.3 to 8.2-44.1 2010
combined with pmol/mg).

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Caco-2 cells • Addition of 10 mg AA and 1240 mg sucrose to 50 mg green tea increased digestive stability
of EGC (up to 13.3 ± 0.1 μmol/reaction). Catechin retention by Caco-2 cells also increased
(from 5.5-8.3 to 12.4-66.7 pmol/mg).

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Gastrointestinal • Addition of 10 mg vitamin C to 50 mL mg green tea extract increased the digestive stability of Shim et al.,

rn
digestion ECG, EGC and EGCG up to 11-times, while no effect was observed for EC. Accumulation of 2012
combined with catechins to Caco-2 cells also increased significantly.
Caco-2 cells •
u
Addition of 10 mg vitamin C and 200, 500 or 1000 mg xylitol to 50 mL mg green tea extract
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increased the digestive recovery of total catechins by 3 times. Similarly, intestinal uptake of
total catechins was also enhanced by 11-times.
Caco-2 cells • Addition of 10 ppm of vitamin C to catechin mixture showed 8 times higher intestinal Chung et al.,
transport for EC. 2013
• Addition of 10 ppm of vitamin C and 49.5 ppm of xylitol to catechin mixture showed 2, 2.4,
and 1.9-times increased intestinal absorption for ECG, EGC and EGCG, respectively.
Gastrointestinal • Encapsulation of green tea catechins mixed with 20 ppm vitamin C and 49.5 ppm xylitol into Son et al., 2016
digestion hydroxypropyl methyl cellulose phthalate and γ-cyclodextrin increased the absorption of green
combined with tea catechins up to 11.97% and 14.36%, respectively.
Caco-2 cells
(Continues)

62
Table 3. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Vitamins
Vitamin C Sour cherry Gastrointestinal • Addition of 5 g of AA to 5 g sour cherry powder had no significant impact on the total Oksuz, 2013
(AA), anthocyanins digestion anthocyanin content after gastric digestion, whereas after intestinal digestion promoting
Vitamin E effects were observed both for the serum and colon available fractions.
(α-tocopherol) • Addition of 5 g of Vitamin E to 5 g sour cherry powder increased the bioaccessibility of total
anthocyanins at all stages of gastrointestinal digestion.
Pomegranate Gastrointestinal • Addition of 5 g of AA to 1 g pomegranate powder had no significant impact on the total Sengul et al.,
anthocyanins digestion anthocyanin content after gastric digestion, whereas after intestinal digestion promoting 2014

f
effects were observed both for the serum and colon available fractions.

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• Addition of 5 g of Vitamin E to 1 g pomegranate powder increased the bioaccessibility of
total anthocyanins at all stages of gastrointestinal digestion.

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Minerals
•

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Iron Red wine Gastrointestinal Addition of 0.25 mM or 1 mM of iron to 50 mL red wine reduced the total phenolic content Argyri et al.,
phenolics digestion and antioxidant capacity. 2005; Argyri et

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• Similarly, addition of 0.25 mM or 1 mM of iron to 50 mL red wine also reduced the al., 2006
concentration of individual polyphenols.
•

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Green tea Gastrointestinal Addition of 0.25 mM or 1 mM of iron to 20 mL green tea reduced the total phenolic content Alexandropoulou
phenolics digestion and antioxidant activity. et al., 2006

rn
Iron, Fruit (grape- Gastrointestinal • Addition of 3 mg of iron to 100 mL fruit beverages prepared with concentrates of grape, Cilla et al., 2009;
Zinc orange-
apricot)
digestion
combined with
u
orange and apricot decreased the phenolic content by 13 and 60% before and after digestion,
respectively.
Cilla et al., 2010
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phenolics Caco-2 cells • Addition of 1.6 mg of zinc to 100 mL fruit beverages prepared with concentrates of grape,
orange and apricot decreased the phenolic content by 32%.
Sodium chloride Sour cherry Gastrointestinal • Addition of 5 g of sodium chloride to 5 g sour cherry powder increased the recovery of total Oksuz, 2013
anthocyanins digestion anthocyanins, whereas the total phenolic content decreased significantly.
Pomegranate Gastrointestinal • Addition of 5 g of sodium chloride to 5 g pomegranate powder increased the recovery of Sengul et al.,
anthocyanins digestion total anthocyanins, whereas the total phenolic content decreased significantly. 2014
(Continues)

63
Table 3. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Other micronutrients (flavonoids, alkaloids, carotenoids)
Apigenin Quercetin Caco-2 cells • Co-incubation of apigenin with quercetin (1:1) increased the absorption of quercetin more Ravisankar et
than 3-fold, whereas apigenin absorption was also increased by 50%. al., 2019
(+)-Catechin Puerarin Caco-2 cells • Co-incubation of (+)-catechin (300 and 600 μmol/L) significantly enhanced the cell uptake Su et al., 2016
and transport of puerarin.
Flavonol Green tea Gastrointestinal • Co-incubation of 100 mg green tea with 10 mg of flavonol aglycones increased the Choi et al., 2019
aglycones catechins digestion bioaccessibility of epicatechins from green tea extract as well as the intestinal cellular uptake
from green tea (EC, ECG, combined with of EGCG, ECG, EC and EGC by 332.46, 273.92, 150.22 and 131.21%, respectively.

f
extract EGC, EGCG) Caco-2 cells

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Genistein, EC Caco-2 cells • Co-incubation of EC with genistein or nevadensin at concentrations of 1, 5, 10 and 50 μM, G,N: Sanchez-Bridge
Luteolin, promoted the transport of EC metabolite, i.e., 3’-O-methyl-epicatechin, towards the basal Q,L: et al., 2014

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Nevadensin, side while reducing the apical efflux.
Quercetin • Co-incubation of EC with quercetin and luteolin at concentrations of 1, 5, 10 and 50 μM

e-
inhibited the appearance of 3’-O-methyl-epicatechin both in the apical and basal
compartments.

Pr
Onion peel, Green tea Gastrointestinal • Digestion of 0.5 g green tea catechins with onion peel and 5, 10 and 20 g Dendropanax Choi et al. 2017
Dendropanax catechins digestion morbifera increased the cellular uptakes of epicatechins up to 188%.

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morbifera (EC, ECG, combined with
phenolics EGC, EGCG) Caco-2 cells

rn
Puerarin (+)-Catechin Caco-2 cells • Co-incubation of puerarin (300 and 600 μmol/L) significantly reduced the cellular Su et al., 2016

• u
absorption of (+)-catechin.
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Quercetin Hesperetin Caco-2 cells Co-incubation of 10 μM hesperetin with 10 μM of quercetin doubled the basal transport of Brand et al.,
hesperetin, although phase II metabolite formation, i.e., hesperetin 7-O-sulfate and 2010
hesperetin 7-O-glucuronide, reduced by 27%.
Quercetin, Green tea Caco-2 cells • Co-incubation of green tea with fisetin and quercetin increased the intestinal absorption of Chung et al.,
Fisetin catechins catechins from 1.3- to 1.6-fold and 1.4- to 1.7-fold, respectively. 2018
(EC, ECG, • Co-incubation of green tea with 5% mixture of fisetin and quercetin increased the intestinal
EGC, EGCG) transport of EGC, EGCG, and ECG by 235, 244 and 242%, respectively.
Carrot, Red cabbage Gastrointestinal • Co-administration of 5 g red cabbage with 5 g vegetables rich in carotenoids increased the Phan et al., 2019
spinach and anthocyanins digestion total anthocyanin bioaccessibility by 10–15%, except for carrot; whereas the total carotenoid
cherry tomato bioaccessibility was decreased by 21–33% and 42–56% for carrots and cherry tomato,
carotenoids respectively.
AA: ascorbic acid, EC: (-)-epicatechin, ECG: (-)-epicatechin gallate, EGC: (-)-epigallocatechin, EGCG: (-)-epigallocatechin gallate, G: genistein, L: luteolin, N: nevadensin, Q:
quercetin

64
: increased bioaccessibility/bioavailability of flavonoids; : decreased bioaccessibility/bioavailability of flavonoids

f
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pr
e-
Pr
al
u rn
Jo

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Table 4. Animal and clinical studies on the effect of microconstituents on bioavailability of flavonoids
Nutrient Flavonoid Model Key outcomes Effect Reference
Vitamins
Vitamin C Green tea Cross-over • Consumption of 1000 mg of green tea with 730 mg of AA increased the bioavailability of Gewande et al.,
(AA) catechins study with 5 EGC by 14%. 2008
(EC, ECG, volunteers
EGC, EGCG)
Sprague • Intake of 50 mg green tea containing 10 mg AA and 1240 mg sucrose resulted in 3-times Peters et al.,
Dawley rats higher rate of absorption of catechins. 2010
High-fat diet • Intake of 190 mg/kg green tea with 0.75 mL/kg of AA rich lemon juice enhanced the Fang et al., 2019
fed pigs concentration of EGC and EGCG in plasma by 1.64-fold.

f
oo
Vitamin E EGCG, Sprague • The concentrations of flavonoids in plasma and brain of rats fed with 1.5% α-tocopherol Q: Ferri et al., 2015
(α-tocopherol) quercetin, rutin Dawley rats and EGCG, quercetin (Q), rutin (1% each) showed that α-tocopherol improved the EGCG:

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transport of quercetin and rutin, whereas EGCG transport was not affected. -
Minerals

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Iron Green tea Sprague • Intake of 0.04 g/mL green tea with 0.1 mg/mL iron reduced the plasma polyphenol content Kapsokefalou et
phenolics Dawley rats al., 2006

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and antioxidant activity.
White tea Cross-over • Consumption of white tea infusion containing 6 g white tea with 30 mg iron lactate Karabela et al.,
phenolics study with 10 reduced the total phenolic content and antioxidant activity of plasma. 2012

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volunteers
Other micronutrients (flavonoids, alkaloids, carotenoids)

rn
(+)-Catechin Quercetin Wistar rats • Co-ingestion of quercetin and (+)-catechin (0.25% each in a diet), decreased their plasma Silberberg et al.,

u
concentration by 35 and 28%, respectively; whereas the hepatic and urinary concentrations 2005
Jo
were just decreased for quercetin (36%).
• Co-ingestion of (+)-catechin and quercetin (0.25% each in a diet) had no impact on the
metabolite formation (i.e., glucurono- and sulfo- conjugates).
Puerarin Sprague • Co-administration of 140 mg/kg (+)-catechin and 200 mg/kg puerarin increased the Su et al., 2016
Dawley rats bioavailability of puerarin.
Curcumin Green tea Everted goat • Co-administration of green tea extract with curcumin (220:50) increased the permeability Pandit et al.,
catechins intestine of catechins from 20.57% to 53.15%. 2019
(EC, ECG,
EGC, EGCG)
Grape Blueberry Mice • Co-administration of 31.1 mg/kg blueberry extract and 266.4 mg/kg grape extract revealed Dudonné et al.,
phenolics phenolics 3–5 fold increased accumulation of blueberry phenolic metabolites in plasma and 2016
decreased their presence in feces to the same extent.
(Continues)

66
Table 4. Continues
Nutrient Flavonoid Model Key outcomes Effect Reference
Other micronutrients (flavonoids, alkaloids, carotenoids)
Naringenin Quercetin Intestinal • Co-administration of 3.5 μg/mL naringenin and 2.36 μg/mL quercetin decreased the Orrego-Lagarón
perfusion in permeability coefficient values by 50%, while the accumulation of phase II metabolites et al., 2016
mice were increased.
Onion peel Green tea Sprague • Co-administration with green tea with 5% onion peel increased the plasma concentration Choi et al. 2017
phenolics catechins Dawley rats of total epicatechins by 2-fold.
(EC, ECG, EGC,
EGCG)
Puerarin (+)-Catechin Sprague • Co-administration of 140 mg/kg (+)-catechin and 200 mg/kg puerarin decreased the Su et al., 2016

f
oo
Dawley rats bioavailability of (+)-catechin.
Quercetin, Biochanin A Sprague– • Co-ingestion of EGCG and quercetin significantly enhanced the plasma concentration of Moon & Morris,

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EGCG Dawley rats biochanin A after both intravenous (5 mg/kg) and oral supplementation (50 mg/kg). 2007
Quercetin, EGCG Sprague– • Co-ingestion of green tea with 10% quercetin or 10% fisetin increased the plasma Chung et al.,

e-
Fisetin Dawley rats concentrations from AUC: 111.3 ng.h/mL to 365.5 and 825.3 ng.h/mL, respectively. 2018

Pr
Caffeine EGCG Cross-over • Co-ingestion of 95 mg EGCG with 40 mg caffeine increased the plasma concentration Nakagawa et al.,
study with 4 significantly. 2009
volunteers • Co-ingestion of 95 mg EGCG with 180 mg caffeine also increased the plasma

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concentration, however the change was not significant.

rn
Piperine EGCG Mice • Co-administration of 163.8 μmol/kg EGCG and 70.2 μmol/kg piperine enhanced the Lambert et al.,
EGCG concentration in plasma by 1.3-fold. 2004
Oxyresveratrol Wistar rats • u Co-administration of 10 mg/kg oxyresveratrol and 1 mg/kg piperine intravenously or Junsaeng et al.,
Jo
100 mg/kg oxyresveratrol and 10 mg/kg piperine orally, increased the bioavailability of 2019
oxyresveratrol by approximately 2–fold.
Tomato Soy germ Copenhagen • Co-administration of 2% soy germ powder with 10% tomato powder enhanced the Zuniga &
carotenoids isoflavones rats absorption of isoflavones, however reduced the bioavailability of carotenoids. Erdman, 2011
AA: ascorbic acid, EC: (-)-epicatechin, ECG: (-)-epicatechin gallate, EGC: (-)-epigallocatechin, EGCG: (-)-epigallocatechin gallate, Q: quercetin
: increased bioaccessibility/bioavailability of flavonoids; : decreased bioaccessibility/bioavailability of flavonoids; - : no change in bioaccessibility/bioavailability of flavonoids

67
CRediT author statement

Senem Kamiloglu: Formal analysis, Investigation, Writing - Original Draft, Writing -

Review & Editing, Visualization
Merve Tomas: Formal analysis, Investigation, Writing - Original Draft, Writing - Review &
Editing, Visualization
Tugba Ozdal: Formal analysis, Investigation, Writing - Original Draft, Writing - Review &
Editing, Visualization
Esra Capanoglu: Conceptualization, Methodology, Formal analysis, Writing - Review &
Editing, Visualization, Supervision, Project administration

of
ro
-p
re
lP
na
ur
Jo

68