Bs Afnr 2017 12 001

CHAPTER THREE
Polyphenols and Their

Interactions With Other Dietary
Compounds: Implications
for Human Health
Nevena Kardum, Maria Glibetic1
Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, University of
Belgrade, Belgrade, Serbia
1
Corresponding author: e-mail address: mglibetic@gmail.com
Contents
1. Introduction 104
2. Phenolic Compounds as Part of the Optimal Diet 105
3. Bioavailability of Phenolic Compounds: Determinant of Health-Promoting
Effects 108
3.1 Role of Microbiota in Metabolism of Polyphenols 109
4. Interactions of Polyphenols With Other Compounds in Food Matrix 110
4.1 Interactions of Polyphenols With Food Proteins 111
4.2 Interactions of Polyphenols With Food Lipids 112
4.3 Interactions of Polyphenols With Food Carbohydrates 114
5. Interactions of Polyphenols With Macronutrients: Effects on Metabolism and
Absorption 114
5.1 Polyphenols’ Impact on Metabolism of Proteins 114
5.2 Impact of Proteins on Polyphenols’ Bioavailability 115
5.3 Polyphenols’ Impact on Metabolism of Fats and Fatty Acids 117
5.4 Impact of Lipids on Absorption of Polyphenols 119
5.5 Polyphenols’ Impact on Metabolism of Carbohydrates 121
5.6 The Impact of Carbohydrates on Polyphenols’ Bioavailability 122
6. Interactions of Polyphenols With Other Dietary Compounds: Beneficial Effects on
Human Health 123
6.1 Impact of Poylphenols on Cardiovascular Health 125
6.2 Interactions of Poylphenols With Lipids and Proteins in Cell Membranes 126
7. Intestinal Microbiota and Its Role in Polyphenols–Macronutrient Interactions 130
7.1 Interactions Between Gut Microbiota and Macronutrients 131
7.2 Interactions Between Gut Microbiota and Polyphenols 133
8. Concluding Remarks 134
References 134
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Advances in Food and Nutrition Research, Volume 84 2018 Elsevier Inc. 103
ISSN 1043-4526 All rights reserved.
https://doi.org/10.1016/bs.afnr.2017.12.001
104 Nevena Kardum and Maria Glibetic
Abstract
Regular and optimal intake of polyphenols associates with numerous health-promoting
effects. Bioavailability and activity of polyphenols depend on foods’ structure and inter-
actions with other food constituents, especially proteins, lipids, and carbohydrates.
Polyphenols–proteins interactions can result in various biological effects, such as sense
of astringency. So far, polyphenols interactions with food lipids have not been of special
importance, except in case of plant oils. Polyphenols–carbohydrates interactions can
influence the organoleptic properties, while interactions with dietary fibers are partic-
ularly significant. Polyphenols can decrease the synthesis of fats and fatty acids in the
liver, or delay their absorption in intestines. Also, polyphenols can slow down digestion
of carbohydrates, through the inhibition of digestive enzymes or modulation of glucose
uptake.
Both animal and plant proteins have low impact on the bioavailability of polyphe-
nols, but some in vitro studies reported that milk proteins could enhance intestinal
absorption of polyphenols from tea. Dietary fats may alter the passage of polyphenols
through gastrointestinal tract and impact absorption of more hydrophobic polyphenols
in particular. While some studies reported that associations with carbohydrates could
decrease bioavailability of polyphenols, the others showed the opposite effects. Mac-
ronutrients can be used for encapsulation of polyphenols, which can increase their bio-
availability and ensure controlled and targeted release. Polyphenols’ interactions in the
body include their incorporation in cell membranes which causes changes in fatty acid
profile and impacts membrane-bound transporters and enzymes. Finally, gut micro-
biota plays essential role in metabolism of both polyphenols and macronutrients
and thus can have great impact on their interactions.
1. INTRODUCTION
It is well established that diet and lifestyle are crucial for maintaining
overall health and preventing diseases. In accordance, potential health effects
of polyphenols are frequent subject of research, and studies have showed that
continuous and optimal intake of polyphenols could lower the incidence of
cardiovascular disease (CVD), diabetes, as well as cancer, low-grade inflam-
mation, and cognitive disorders (Del Rio, Borges, & Crozier, 2010; Konic-
Ristic, Kroon, & Glibetic, 2015; Rodriguez-Mateos, Vauzour, et al., 2014;
Vauzour, Rodriguez-Mateo, Corona, Oruna-Concha, & Spencer, 2010).
Owing to their abundance in foods of plant origin and high antioxidant
activity, polyphenols are often considered as the most important dietary anti-
oxidants. Antioxidant capacity of polyphenols is based on their structure and
ability to capture electrons from free radicals and make them more stable
Polyphenols–Macronutrients Interactions and Human Health 105
(Rice-Evans, Miller, & Paganga, 1997). Besides their direct antioxidant

effects, polyphenols may act indirectly through the modulation of gene
expression and signaling pathways affecting the activity of cellular antioxi-
dant enzymes (Mitjavila & Moreno, 2012; Scalbert, Manach, Morand,
Remesy, & Jimenez, 2005).
In accordance with the increasing number of studies investigating health-
promoting effects of polyphenols, the interest of industry, as well as small-
and medium-sized enterprises for developing products rich in polyphenols is
rising. However, only few health claims referring to beneficial effects of
polyphenols on health and biomarkers of cardiovascular risk, have been
approved by EFSA (European Food Safety Authority). This is not surprising,
since studies often fail to show the causal relationship between polyphenols
intake and health benefits, and lack detail description of polyphenol source,
especially in case of whole food items. Also, some of the clinical trials are
having limitations, such as inappropriate design with lack or use of not suit-
able placebos or control foods (Kardum et al., 2017).
2. PHENOLIC COMPOUNDS AS PART OF THE

OPTIMAL DIET
In their recent review, Pinto and Santos (2017), searching through the
Phenol-Explorer database, selected 50 foods with the highest content of
polyphenols. When serving size was accounted, fruits were identified as
the food group richest in polyphenols. Among different fruits, berries, espe-
cially chokeberry and elderberry, were indicated as particularly high in poly-
phenols. Nevertheless, other fruits, such as apples and oranges are not less
important, since their consumption is generally more frequent and higher
than the consumption of berries. Beside fruits, other food groups rich in
polyphenols are: vegetables, cereal products, seeds and related products,
spices, and herbs. Another interesting finding of the mentioned review
was the diverse distribution of different phenolic classes and subclasses
among listed foods. Although some subclasses were identified as less abun-
dant than others, this may not imply their lower dietary relevance, since they
may be more frequently consumed.
More than 8000 compounds with phenolic structure—at least one
aromatic ring and one or more hydroxyl groups—have been identified.
Polyphenols can be generally classified as flavonoids, compounds with
C6–C3–C6 structure, and nonflavonoids. The flavonoids of dietary rele-

vance are flavonols, flavones, isoflavones, flavan-3-ols, flavanones, and
anthocyanidins. Flavonols are widely distributed in plants, highly present
in onion, while quercetin is the most ubiquitous and studied representative
(Crozier, McDonald, Lean, & Black, 1997). Unlikely, flavones are not
so widespread; apigenin and luteolin are representatives abundant in
parsley and celery (Del Rio et al., 2010). Isoflavones are almost exclusively
present in legumes, with significant amounts of genistein and diadzein in
soybean. Owing to the structural similarities to estrogens, isoflavones are
known for their phytoestrogen activity, together with the nonflavonoid
compounds—lignans, present in cereals (Coward, Smith, Kirk, & Barnes,
1998). Flavan-3-ols are the widest group of flavonoids, which consist of
simple monomers—epicatechin and catechin, as well as oligomeric and
polymeric proanthocyanidins, known as condensed tannins. Green tea is
the richest source of monomeric flavan-3-ols, while proanthocyanidins are
widely distributed in plants, especially procyanidins, consisted of (epi)cate-
chin as monomer subunit (Del Rio et al., 2010). Flavanones, such as
naringenin and hesperetin, are highly abundant in citrus fruits (Del Rio
et al., 2010). The most frequent aglycone of anthocyanidins are cyanidin,
peonidin, delphinidin, pelargonidin, petunidin, and malvidin, which form
conjugates with sugar molecules and organic acids, making anthocyanins—
compounds that give color to fruits and flowers ranging from red to blue
and purple (Ozeki, Matsuba, Abe, Umemoto, & Sasaki, 2011). Anthocy-
anins are present in considerable amounts in berries and red wine. Among
nonflavonoids, highly important in diet are phenolic acids: gallic, ellagic,
chlorogenic, neochlorogenic, and hydroxycinnamic, present mostly in
fruits: raspberries, strawberries, and pomegranate; nuts and coffee bever-
ages (Landete, 2011). Stilbenes also make nonflavonoid group of poly-
phenols, with resveratrol as the most important and mostly studied
representative, occurring in red grapes and wines (Crozier, Borges, &
Ryan, 2010).
Although epidemiological studies and clinical trials assessed the intake of
polyphenols, many of them had limitations, such as small study population,
use of different methods for dietary assessment and different databases for the
calculation of intake (Pinto & Santos, 2017). Thus, the heterogeneity in
polyphenols intake, observed among different countries, may reflect, not
just different dietary habits, but also some of the mentioned limitations.
Despite studies are not giving the most precise data on intake, they are still
pointing out notable differences in polyphenols’ consumption between
different parts of the world. According to literature data, polyphenols’ intake

in European countries like Spain, France, and Poland do not differ very
much, with values ranging from 820 to 1741 mg per day (Grosso,
Stepaniak, Topor-Madry, Szafraniec, & Pajak, 2014; Perez-Jimenez et al.,
2011; Tresserra-Rimbau et al., 2013; Vogiatzoglou et al., 2015; Zamora-
Ros et al., 2016). However, the intake in Brazil was estimated as much
lower, less than 500 mg per day, most likely due to the low intake of fruits
and vegetables (Miranda, Steluti, Fisberg, & Marchioni, 2016). As Pinto and
Santos (2017) reported in their literature survey, the lowest values for con-
sumption of polyphenols were found in Fiji Islands (less than 300 mg per
day), which may be caused by low intake of fruits and vegetables, but also
by limitations in reporting. The other authors stressed out the importance of
estimating polyphenols’ intake in elderly, considering both the scarce liter-
ature data and polyphenols’ association with lower risks of substantial cog-
nitive decline (Taguchi et al., 2015). As they established, the average
polyphenol intake among elderly Japanese was almost 1500 mg/day, with
the majority provided by beverages, such as coffee and green tea. They also
found no correlation between polyphenols’ intake and the intake of micro-
nutrients, implying that polyphenols may act beneficially regardless the
nutritional intake. The authors estimating polyphenols’ consumption in
Polish adult population found the intake similar to those in other countries
(roughly 1 g of polyphenols per day) with no difference in consumption for
both genders and various age groups. However, the authors stressed out that
pattern of consumption vary for genders, as well as different age groups
(Zujko, Witkowska, Waskiewicz, & Sygnowska, 2012).
Some authors strongly believe that estimation of polyphenols’ intake on
global level with comparisons among different countries is not feasible with
the available data (Pinto & Santos, 2017). As a possible solution, they suggest
a strategy that would include: collection of data on food intake by multiple
24-h recalls (Gurinovic et al., 2015), distributed through the year; uniform
protocols for extraction and determination of polyphenols, with the creation
of national databases that further should be merged into worldwide database.
Another important issue, when estimating polyphenols’ intake and its reflec-
tion on human health, is their bioavailability. Ideally, biomarkers, measured
in urine and blood, should be used to raise right conclusions on polyphenols
impact on health-related outcomes. What is important, the mostly con-
sumed polyphenols are not necessarily the most active ones in the body,
since they may be poorly digested and absorbed in small intestine, exten-
sively metabolized, or rapidly excreted (Pinto & Santos, 2017).
3. BIOAVAILABILITY OF PHENOLIC COMPOUNDS:

DETERMINANT OF HEALTH-PROMOTING EFFECTS
Polyphenols are generally bioactive compounds of low bioavailability
and intense metabolism. Since their health effects should be attributed to
compounds present in circulation upon ingestion, absorption, distribution,
metabolism, and elimination of phenolic subclasses is increasingly investi-
gated. These investigations showed clear difference in metabolic fate of dif-
ferent subclasses, indicating isoflavones, flavanones, catechins, quercetin
glycosides, and gallic acid as the most effectively, and the proanthocyanidins,
anthocyanins, and catechin gallate as the most poorly absorbed compounds
(Manach, Williamson, Morand, Scalbert, & Remesy, 2005). The most
recent findings have shown that anthocyanins have better bioavailability
than it was previously thought. Research on isotopic 13C-labeled anthocy-
anin cyanidin-3-glucoside, its intake and recovery in body fluids (serum,
urine, and feces) showed notable number of metabolites, such as breakdown
products and their conjugates, with presence in circulation up to 48 h upon
ingestion (Czank et al., 2013; De Ferrars et al., 2014). The majority of pre-
sent compounds were metabolites with lower mass than the parent antho-
cyanin; cyanidin-3-glucoside made only 2% of detected compounds. The
use of radio-labeled polyphenols provides more accurate and comprehensive
assessment of their absorption, metabolism, and excretion. However, not
many data on this particular topic are available so far (Ottaviani et al., 2016).
Some studies indicated that polyphenols dosage can be factor that deter-
mines their bioavailability, implying that higher doses can sometimes have
different effects comparing to the lower ones. For instance, chlorogenic acid
present in coffee beverages has decreased bioavailability when it is ingested
in higher amounts (Stalmach, Williamson, & Crozier, 2014). In order to act
on target tissue and cells, phenolic compounds must be transported through
bloodstream. Thus, in order to completely understand their functions in the
body, we first must identify their metabolites, as well as the concentrations
that occur in circulation. Further testing of identified metabolites in relevant,
physiological concentration, would give more insights into mechanisms of
action and provide stronger evidence of their health benefits (Kroon
et al., 2004).
Generally, absorption of most phenolic compounds is largely carried out
in small intestine. Usually, absorption starts with the cleavage of sugar mol-
ecule and diffusion of phenolic aglycone to enterocytes. Prior to entering
circulation, polyphenols may undergo the phase II of metabolism, which

results in formation of conjugates, i.e., glucuronic, sulfate, and/or methyl
derivatives. From circulation, metabolites can be returned to the intestinal
lumen, or distributed to the liver, where second phase of metabolism can
be continued. Liver metabolites can also be returned to intestines in process
called enterohepatic recirculation. If the compound is resistant to the activity
of hydrolytic enzymes in small intestine, it would pass intact to the colon.
Even compounds partly transformed in upper parts of gastrointestinal tract,
may be further degraded in colon (Del Rio et al., 2010), by the action of
bacterial microbiota.
3.1 Role of Microbiota in Metabolism of Polyphenols

Intestinal microbiota of human adults contains approximately 1014 bacterial
cells—10 times more than the total number of cells in human body, while
metabolic capacity of microbiota can be up to 100 times higher than the
metabolic rate of liver. Thus, gut microbiota can be of great importance
for metabolism of various chemical compounds within foods, and for many
of them microbial transformation is crucial for exerting their effects in the
body. The acknowledgment of the importance of interactions between
food, microbiota, and host opens new field of research aiming to establish
novel therapeutic approaches (Holmes et al., 2012). Altered bacterial micro-
biota in the body has been associated with metabolic disorders, such as obe-
sity, diabetes, or nonalcoholic fatty liver disease (Zhu, Wang, & Li, 2010).
It has been estimated that bioavailability and effects of polyphenols in the
body largely depend on activity of gut microbiota. Namely, human micro-
biota is involved in the metabolism of polyphenols, based on reaction of
dehydroxylation, decarboxylation, demethylation, hydrogenation, and oxi-
dation (Possemiers, Bolca, Verstraete, & Heyerick, 2011). Consequently,
the lower mass molecules are created; mainly aromatic phenolic acids that
could be further absorbed and thus exert their effects on human health.
In addition, these molecules can be further metabolized in liver, before they
are being exerted in urine. Since metabolites formed by gut microbiota are
often the only one that are absorbed and thus the only one that act benefi-
cially on human health, altered microbiota or absence of some bacterial
types/species can lead to lack of desired effects of polyphenols (Duda-
Chodak, Tarko, Satora, & Sroka, 2015).
Composition of gut microbiota depends on various factors, and it
involves different types of bacterial cells. Some of the key features
influencing the gut microbiota are age, gender, ethnicity, and use of drugs
(mostly antibiotics). Besides the mentioned factors, diversity of gut micro-
biota highly depends on diet. The alterations in gut microbiota are noted
when common diet is replaced with diet rich in proteins or fats, as well
as when intake of some compounds, such as probiotics or prebiotics, is
increased (O’Connor, Chouinard-Castonguay, Gagnon, & Rudkowska,
2017; Sen et al., 2017). Accordingly, each individual has unique profile
of microbial species, which could be even compared to a fingerprint. Thus,
the amount and type of phenolic metabolites formed by gut microbiota can
vary among different individuals, and contribute to interindividual variabil-
ity of polyphenols’ effects on human health. In addition, a lack of particular
bacterial species could lead to lack of polyphenol effects even though it
has been ingested. As some authors pointed out, some polyphenols and
products of their microbial metabolism may have negative effects on host
(Galati & O’Brien, 2004; Nunes, Almeida, & Laranjinha, 2008). Quercetin
and rutin, for example, are transformed by intestinal microbiota to 3,4-
dihydrophenylacetic acid, which is also a metabolite of the dopamine.
Although this metabolite has antiinflammatory, cardioprotective, neuro-
protective, and anticancer activity, it has been shown that it can, in the pres-
ence of nitric oxide, partake in neurodegeneration associated with Parkinson
disease (Nunes, Barbosa, Almeida, & Laranjinha, 2011).
Besides polyphenols activity against pathogens, they could also affect
composition of beneficial gut microbiota. Thus, it has been indicated that
some polyphenols can stimulate the growth of nonpathogenic gut bacterial
species, and at the same time inhibit the growth of pathogenic ones (Lee,
Jenner, Low, & Lee, 2006). This mostly refers to tea polyphenols, but other
plant bioactives, such as citrus and red wine’ polyphenols can act similarly. It
has been demonstrated that daily consumption of red wine can modulate gut
microbiota and increase the number of various beneficial species from dif-
ferent bacterial groups (Queipo-Ortuño et al., 2012).
4. INTERACTIONS OF POLYPHENOLS WITH OTHER

COMPOUNDS IN FOOD MATRIX
Polyphenols are important biologically active compounds which
activity largely depends on the structure of plant foods and interactions with
other food constituents, mainly lipids, proteins, and carbohydrates. These
interactions can affect polyphenols accessibility, and while some food matri-
ces can enhance availability of polyphenols, others can impair it.
4.1 Interactions of Polyphenols With Food Proteins

Polyphenols interact with proteins mostly through reversible noncovalent
hydrophobic interactions, which can be further stabilized by hydrogen bind-
ing. Furthermore, irreversible covalent interactions between polyphenols
and proteins have been also suggested, especially in case of enzymes
(Rohn, Rawel, & Kroll, 2002). In addition, covalent interactions have been
shown between protein functional groups and quinones formed by flavo-
noid oxidation. Flavonoids can be oxidized in foods in presence of high
pH, heat, or reactive oxygen species or in any process which allows release
of degradation enzymes (Bittner, 2006). The interactions between polyphe-
nols and proteins can be specific or nonspecific. The specific ones are mostly
occurring in case of enzymes and proteins with defined tertiary structure
(such as milk immunoglobulin). Protein–polyphenol interactions depend
on the structure and molecular weight of polyphenols—bigger molecules
bind more strongly. Flexibility of polyphenols is also determining
factor—less flexible polyphenols bind stronger to some proteins and weaker
to others, while more flexible polyphenols bind equally to various proteins
(Frazier et al., 2010).
Proteins–polyphenols interactions can result in various biological effects.
One of them is astringency, as a consequence of interactions between sali-
vary proline-rich proteins and polyphenols. Astringency is a sensation
described as dryness, tightening, and shrinking perceived in the oral cavity.
This sensation is well known to red wine consumers and deeply associated
with quality of red wine. It has been estimated that salivary proteins more
preferable interact with polyphenols than with other proteins. Among poly-
phenols, tannins, present in wine, are recognized as the ones that mostly
interact with salivary proteins. However, an interaction was also reported
between the anthocyanin (malvidin-3-glucoside) from red wine with sali-
vary acidic proline-rich protein (Ferrer-Gallego et al., 2015). Astringency
and overall sensorial characteristics of foods may be modulated by pre-
existing complexes of polyphenols and proteins in foods and beverages.
For example, tea astringency can be reduced by the addition of milk
( J€
obstl, Howse, Fairclough, & Williamson, 2006; Yan, Hu, & Yao,
2009). Flavan-3-ols from tea that are bound to milk proteins—casein and
whey proteins—are less available for interactions with salivary proteins,
resulting in lower astringency.
Besides interactions with salivary proteins, polyphenols can also exert
health-promoting effects in oral cavity. Polyphenols are actually present
in the highest concentration in oral cavity, and it is believed that they
may prevent dental caries formation. This effect is based on polyphenols’

antibacterial activity, but it can be also mediated by inhibition of enzymes
glucosyltransferase B and C, responsible for the production of insoluble
polysaccharides, that can form a plaque and contribute to adherence of oral
bacteria to the dental surface (Thimothe, Bonsi, Padilla-Zakour, & Koo,
2007). Importantly, interactions with polyphenols may affect the structure
and quality of proteins. Since nutritive value of proteins depends on their
amino acid composition, polyphenols interacting with amino acids, could
cause changes in proteins structure and affect their functionality. Further-
more, polyphenols can bind to proteins in a way to block essential amino
acids and thus decrease their availability (Rawel, Czajka, Rohn, & Kroll,
2002). Physicochemical properties of foods and beverages can also be chan-
ged due to the interactions between polyphenols and proteins. For instance,
flavonoids–proteins interactions have been associated with haze formation
in plant-based beverages, such as apple juice, wine, and beer.
Proteins interactions with polyphenols could have valuable applications.
Namely, it is believed that protein–polyphenol interactions may stabilize or
even enhance antioxidant capacity of polyphenols. Polyphenols are prone to
oxidation in conditions such as elevated pH or temperature, which can
occur during heating or processing of foods and beverages. Trapping poly-
phenols and preventing them from autooxidative reactions could be
achieved by use of proteins as carriers of polyphenols. Accordingly,
Wegrzyn et al. (2008) showed that flavonoids stability over storage time
could be increased by interactions with milk proteins. They suggested that
polyphenol-milk models of beverages could be used for delivering fruit phe-
nolic compounds. Also, both stability and antioxidant activity could be pre-
served during beverage storage and processing.
4.2 Interactions of Polyphenols With Food Lipids

Unlike the polyphenols–proteins interactions that have been extensively
studied, interactions with other food macronutrients, lipids, and carbohy-
drates, are not so well known. So far, investigations of polyphenols–lipids
interaction have not been of special importance, except in case of plant
oils—primarily the one made from olives.
Olive oil is one of the best sources of oleic fatty acid and total monoun-
saturated fatty acids (MUFA). It is believed that oleic acid can decrease oxi-
dation of lipoproteins and beneficially influence blood pressure and blood
glucose level. However, health effects of olive oil, largely consumed in
Mediterranean diet, are more often being attributed to the present phenolic
compounds, and not only to the MUFA. Significant amounts of various
polyphenol compounds were identified in olive pomade and its mill waste
waters which are generated when oil is being processed. As some authors
suggested, only small amounts of polyphenols are present in olive oil itself.
Thus, efforts have been made in order to recover valuable polyphenols from
olive oil extraction wastes. Aiming to transform plant oils into foods with
promising health effects, researchers have examined addition of flavonoids
from olive tree leaves to different oils. As a result, oils enriched in polyphe-
nols with better resistance to oxidation have been created (Bordenave,
Hamaker, & Ferruzzi, 2014).
Besides phenolic compounds from olive tree, it is believed that other
polyphenols could serve as potential natural antioxidants used for stabiliza-
tion of plant oils toward oxidation. So, the use of these enriched oils in diet
still requires further investigation. Nevertheless, the use of polyphenols for
creating functional foods could result in decreased oxidation of lipids and
unsaturated fatty acids in foods and consequently reduced intake of
prooxidants. On the other side, it was shown that lipids from foods could
enhance acute absorption of some flavonoids, such as quercetin (Guo
et al., 2013). The fact that some polyphenols can be absorbed together with
lipids, using the same metabolic pathways, leads to conclusion that it may be
feasible to incorporate polyphenols in lipoprotein particles, such as HDL
(high-density lipoprotein) and LDL (low-density lipoprotein), but in adi-
pose tissue as well (McAnlis, McEneny, Pearce, & Young, 1999). Taking
into account all mentioned facts, it is evident that polyphenols–lipids inter-
actions and consequent effects in the body should be further investigated.
There is an increased interest in using of some polyphenols, such as green
tea catechins, as food additives that could provide better shelf-life of food
products and decrease susceptibility to oxidative damage. Studies have
investigated the incorporation of tea phenolic compounds into dairy prod-
ucts, such as low-fat and high-fat cheeses. Thus, it has been reported that free
tea catechins can change pH and microstructure of cheeses making them less
homogenous. Other authors reported negative effects on organoleptic prop-
erties and hardness of Cheddar cheese (Giroux et al., 2013). However, this
disruption of cheese microstructure has not been found for encapsulated cat-
echins. Recent study by Rashidinejad, Birch, Hindmarsh, and Everett
(2017) indicated that different tea polyphenols could affect differently milk
fat globules, and emphasized the need for further investigations using not just
catechin, but also epicatechin, epigallocatechin, and others.
4.3 Interactions of Polyphenols With Food Carbohydrates

In vitro investigations revealed that polyphenols can interact with carbohy-
drates in plant cell wall, like cellulose, pectin, and dietary fibers, as a result of
weak hydrogen and hydrophobic binding. These interactions were shown
for different phenolic subclasses, such as anthocyanins, phenolic acids, and
procyanidins. The phenolic structure can influence the degree of interac-
tions with polysaccharides; improved interactions were observed in case
of hydroxylation of flavonoids and galloylation of catechins, while methyl-
ation or methoxylation of phenolic acids had opposite effect (Wang, Liu,
Chen, & Zhao, 2013).
Studies have demonstrated that gelatinization and retrogradation of
starch can be influenced by some flavonoids. Thus, gelatinization is enhanced
by the quercetin and green tea flavan-3-ols, while starch retrogradation is
slowed down or inhibited (Wu, Lin, Chen, & Xiao, 2011). Owing to the
hydrogen binding to amylose chains, flavonoids could act as plasticizers in
starch. Interactions with nonstarch polysaccharides, particularly dietary fibers
are of great interest. Large portions of polyphenols in food matrices are bound
to dietary fibers and not easily extracted. Their role as polyphenols’ carriers is
one of the physiological functions of dietary fibers, contributing to the overall
health effects of fiber-rich diets (Saura-Calixto, 2011).
Polyphenols–carbohydrates interactions can influence organoleptic prop-
erties. Namely, polysaccharides present in wine may interact with complexes
of tannins and salivary proteins, and change perception of wine astringency.
More specific, wine astringency could be decreased by acidic polysaccharides,
while neutral ones have no or limited effect. Carbohydrates–polyphenols
interactions can be applied in microencapsulation of polyphenols. Polyphe-
nols from green tea can be encapsulated by maltodextrin being more effective
in prevention of CVD than nonencapsulated one ( Jung, Seong, Kim,
Myong, & Chang, 2013).
5. INTERACTIONS OF POLYPHENOLS WITH

MACRONUTRIENTS: EFFECTS ON METABOLISM
AND ABSORPTION
5.1 Polyphenols’ Impact on Metabolism of Proteins
The results of the in vivo experiment with rats showed that the digestion of
whey proteins can be jeopardized by the reactions with some phenolic com-
pounds, specifically with chlorogenic acid (Petzke, Schuppe, Rohn,
Rawel, & Kroll, 2005). In this study, derivatization with chlorogenic acid
was investigated in order to determine whether it affects protein digestibility
and nutritional quality of β-lactoglobulin. As a result, nitrogen digestibility
was lower in case of high derivatization with chlorogenic acid, compared to
low derivatization or no derivatization at all. Since there was no deficiency
in all amino acids, the authors concluded that only at high levels this deriv-
atization with chlorogenic acid could threaten good nutritional quality of
whey proteins.
The derivatization with chlorogenic acid and quercetin was also tested
for soy proteins (Rawel et al., 2002). As main outcomes, nitrogen level
in diets, urine and feces were assessed along with the distribution of amino
acids. This derivatization resulted in an increased excretion of nitrogen in
feces and urine. The estimation of amino acid distribution revealed marked
influence on lysine and tryptophan as well as the sulfur-containing amino
acids: cysteine, methionine, reflected as a decreased content of these amino
acids, depending on the level of derivatization.
5.2 Impact of Proteins on Polyphenols’ Bioavailability

Recent study by Draijer et al. (2016) investigated the effects of proteins from
dairy and soy, in form of beverage, on the polyphenols absorption, their
presence in blood and also the urinary excretion of metabolites. More pre-
cisely, they measured the amounts of phenolic compounds in blood and
urine following the consumption of wine and grape polyphenols, which
were mixed into a diary, soy, or a fruit-flavored drink free of proteins. As
a comparing formulation, the authors investigated the gelatin capsules con-
taining these polyphenols, taken with water. Obtained results indicated
minor impact of the added proteins from both animal (dairy) and plant
(soy) sources on the bioavailability of polyphenols and their metabolites.
All tested formats raised plasma and urine levels of identified polyphenols
in a similar manner, with no significant differences between them. The ear-
lier studies showed similar lack of effect of proteins on the bioavailability of
catechins from cocoa or black and green tea (Schramm et al., 2003). How-
ever, Xie, Kosinska, Xu, and Andlauer (2013) reported that milk proteins
could actually enhance intestinal transport and absorption of catechins from
tea. They used Caco-2 cells in vitro model and found that content of cate-
chins had increased in digested green tea with added milk (at 10%). Still, the
authors of the recent review (Rashidinejad, Birch, Sun-Waterhouse, &
Everett, 2017) pointed out negative effects of milk on antioxidant potential
of tea, based on associations of milk proteins, mainly casein, and tea polyphe-
nols. The authors also indicated that effects may vary for different concentra-
tions of milk proteins and tea polyphenols. Also, they suggested that opposite
conclusions from different studies are caused by the use of different milks,
teas, and assays for measurement of antioxidant activity.
Research conducted by Ribnicky et al. (2014) investigated effects of soy
proteins on bioavailability of polyphenols from extract of Artemisia sp. in ani-
mal model. The authors reported beneficial effects on bioavailability of pre-
sent polyphenols, resulting from formation of complexes with soy proteins.
Beneficial effects on polyphenols’ absorption could be achieved by the use of
proteins as their carriers in gastrointestinal tract.
5.2.1 Proteins as Carriers of Polyphenols

Nanotechnology is fast developing, while nanoparticles are greatly appreci-
ated as potential tools for targeted delivery of drugs and bioactive com-
pounds to the tissues and cells. Protein carriers have several benefits
against other materials, such as: biodegradability, low cost, availability,
and stability in biological fluids, which enables controlled release of carried
molecules (Sahoo, Sahoo, Biswas, Guha, & Kuotsu, 2015). Albumin and
gelatin are most commonly applied proteins for design of nanoparticles,
since they are highly abundant.
Besides drugs, polyphenols could also be entrapped in protein-based
nanoparticles, and this could enhance their beneficial activity, such as antip-
roliferative one, but also protect them against oxidative degradation
(Shpigelman, Israeli, & Livney, 2010; Von Staszewski et al., 2012). Study
that had investigated complexes of epigallocatechin gallate (EGCG) and
casein showed that casein, especially the glycosylated one could protect this
phenolic compound from degradation in alkaline environment, like small
intestine. It also demonstrated that these nanocomplexes could ensure slow
and sustained release of EGCG in intestinal fluid. Glycosylated casein
exerted better effect than casein alone, since glycosylation of proteins
inhibits their precipitation that could occur as a result of binding to polyphe-
nols (Xue, Tan, Zhang, Feng, & Xia, 2014).
Collagen is a unique connective tissue protein, with many applications
and its stabilization is thus of crucial importance. Studies have shown that
polyphenols, specifically catechin, can stabilize type I collagen. Madhan,
Subramanian, Rao, Nair, and Ramasami (2005) showed that thermal stabil-
ity of collagen could be increased by 10°C after treatment with catechin, as a
result of hydrogen bonding and hydrophobic interactions. Additionally,
collagen fibers treated by catechin were stable even after application of des-
tabilizers such as urea. Importantly, the native structure of collagen remained
the same, after treatment with catechin.
5.3 Polyphenols’ Impact on Metabolism of Fats and Fatty Acids

Polyphenols can affect lipid status through the impact on enzymes involved
in metabolism of fats, as well as fatty acids. For instance, they can influence
synthesis of lipids in the liver, including triglycerides and fatty acids. This
effect has been shown for resveratrol, highly abundant in grape and red wine,
in in vitro study that used hepatic cells isolated from rats’ liver. After incu-
bation of hepatocytes with resveratrol, inhibitory effect on fatty acids’ and
triglycerides’ synthesis was noted, as well as decreased activity of enzyme
acetyl–coenzyme A carboxylase (Gnoni & Paglialonga, 2009). This enzyme
was identified as the crucial one in synthesis of fatty acids, with palmitic acid
as primary product. On the other side, incubation with resveratrol did not
influence synthesis of cholesterol in hepatocytes, or the activities of enzymes
involved. Although the mentioned study investigated acute effects of resver-
atrol, literature data have indicated that resveratrol could have chronic effects
on triglycerides’ synthesis as well. Some authors linked these chronic effects
to the impact of resveratrol on expression of genes responsible for lipid syn-
thesis in liver (Shang et al., 2008). Decreased intracellular synthesis of triglyc-
erides in liver could lead to lower production of lipoproteins of very low
density (VLDL), and consequently the level of triglycerides in blood.
Anthocyanins, present in berry fruits, have also exerted beneficial effects
on lipid status. Thus, consumption of 100 mL of chokeberry juice for
4 weeks decreased triglycerides’ level in blood (Kardum et al., 2015). Like-
wise, addition of anthocyanin-rich extract (obtained from Lonicera caerulea)
to high-fat diet of rats caused significantly lower increase in triglycerides and
cholesterol levels, comparing to high-fat diet only. As an underlying mech-
anism the authors suggested lowered or delayed absorption of lipids in intes-
tines, caused by inhibition of enzyme pancreatic lipase, involved in lipids
degradation (Takahashi et al., 2014). A study that investigated effects of
12-week consumption of grape extract, rich in anthocyanins, resveratrol
and other phenolic compounds, revealed beneficial effects on lipid status
in female guinea pigs. In treated animals, significantly lower level of triglyc-
erides and VLDL lipoproteins was detected as compared to the control
group of animals (Zern, West, & Fernandez, 2003). Although level of
LDL was not lower in treated group, changes in its structure were observed,
as well as decreased accumulation in aorta, indicating the antiatherosclerotic

potential of grape extract. These changes in LDL particles structure could be
caused by decreased activity of liver enzyme acyl–coenzyme A cholesterol
acyltransferase, involved in formation and metabolism of these lipoproteins.
Another study, with healthy human volunteers, showed that 3-month
consumption of extract rich in saponins, glycosides, and phenolic com-
pounds, decreased levels of triglycerides and total cholesterol. The authors
attributed this effect to present flavonoids, pointing out their ability to
decrease activity of lecithin–cholesterol acyltransferase that mediates con-
version of HDL to LDL and VLDL and their consequent removal from
blood into hepatocytes (Katare et al., 2014).
5.3.1 Impact of Polyphenols on Fats’ Emulsification and Absorption

Emulsification of fats is necessary for their degradation and absorption, while
the size and area of lipid droplets affect activity of enzymes involved in lipid
digestion. By affecting emulsification process it is possible to decrease activ-
ity of lipolytic enzymes and thus decrease fats’ absorption, which could be
useful in control of obesity and related diseases. An investigation on the
effects of polyphenols on fats’ emulsification has shown that polyphenols
from green and black tea can increase size of lipid droplets and decrease
the specific area of contact with enzymes (Shishikura, Khokhar, &
Murray, 2006). The underlying mechanism includes interaction of polyphe-
nols with phosphatidyl-choline, used in experimental model. These inter-
actions are feasible since phophatidyl-choline contains hydrophilic, polar
heads oriented toward the exterior of lipid droplets, and polyphenols them-
selves have many hydrophilic groups. Thus, polyphenols and lipid droplets
can form complexes, to which additional phenolic molecules can link and
create aggregates. Polyphenols can increase the size of lipid droplets through
their incorporation in lipid layer as well, which can change physicochemical
properties of droplets.
On the other side, it has been indicated that interactions of polyphenols
and lipids have small impact of polyphenols’ absorption. Study investigating
different foods rich in lipids, proteins, or carbohydrates concluded that lipids
from dairy sources such as butter and milk have limited effect on absorption
of cacao flavanols (Schramm et al., 2003). On the contrary, one research
showed that bioavailability of chlorogenic acid from coffee can be decreased
by joint intake of coffee and milk. Furthermore, it has been suggested that
milk can decrease the absorption of polyphenols only when they are present
at low concentrations, but its impact is limited in the presence of higher
amounts of polyphenols (Del Rio et al., 2010). The capture of polyphenols

in lipid particles has been proposed as a possible way of increasing their sta-
bility and preventing them from unwanted degradation in the gastrointes-
tinal tract. Thus, investigations of polyphenols–lipids interactions are
often directed toward the formation of liposomes, as models of controlled
release and action of polyphenols in the body.
5.4 Impact of Lipids on Absorption of Polyphenols

Not many studies have investigated the impact of dietary lipids on polyphe-
nols’ absorption. This is not surprising, since polyphenols are water soluble
molecules transported via portal vein, and lipids have limited impact on
absorption of more hydrophilic polyphenols. However, this may not be
the case for more hydrophobic compounds, such as curcumin and xan-
thones, or even some flavonoid aglycones. Some authors suggested that die-
tary fats may alter the passage of polyphenols through gastrointestinal tract
and the kinetics of their absorption. Mullen, Edwards, Serafini, and
Crozier (2008) reported a delayed but not altered bioavailability of antho-
cyanins from strawberries when they were consumed with cream. Absorp-
tion of proanthocyandinis, but not of phenolic acids and flavones, was much
higher from lipid-rich cocoa liquor (45% of fat) than from the cocoa powder
with 15% of fat, in in vitro model (Ortega, Reguant, Romero, Macià, &
Motilva, 2009). This could be explained by stabilization of less polar poly-
phenols by food lipids, through the micelle formation. Even for more polar
polyphenols—tyrosol and hydroxytyrosol absorption from olive oil was bet-
ter than from the aqueous solution, as shown in rat model (Tuck, Freeman,
Hayball, Stretch, & Stupans, 2001). Furthermore, the authors pointed out
that protection by other antioxidants from olive oil could promote the
observed effect.
Omega-3 fatty acids are dietary ingredients of great importance for cardio-
vascular and overall health. Recent study investigated long-term effects of
omega-3 fatty acids of marine origin on the metabolism of grape
proanthocyanidins (Molinar-Toribio et al., 2017). The study was conducted
in rats, supplemented with docosahexaenoic (DHA) and eicosapentaenpoic
(EPA) acids, grape seed extract rich in proanthocyanidins or both. The authors
reported significant increase in many metabolites of proanthocyanidins in
urine and feces in animals that were supplemented with omega-3 fatty acids
comparing with animals on standard diet with small amounts of polyphenols.
There was no difference when comparison was made with animals
supplemented with grape seed extract only. Thus, the authors concluded that
omega-3 fatty acids can enhance metabolism of polyphenols when they are
present in small amounts in food matrix, but their effect is not relevant when
polyphenols are present in high amounts.
5.4.1 Liposomes as Carriers of Polyphenols

Liposomes are colloid particles consisting of one or more lipid bilayers
surrounding the hydrophilic core (Mozafari, Johnson, Hatziantoniou, &
Demetzos, 2008). This structure enables incorporation of different com-
pounds, while water soluble compounds are transported in hydrophilic core,
and nonsoluble compounds are placed in lipid membranes. Lipid bilayers
contain various phospholipids made of hydrophilic heads and fatty acids with
different degree of unsaturation, forming hydrophobic chains. One of the
most common components of liposomes is lecithin that can be isolated from
various plant sources and can contain different fatty acids. For example, lec-
ithin from rapeseed is rich in essential fatty acids: linoleic (LA) and alpha-
linoleic (ALA) (Coonrod, Brick, Byrne, DeBonte, & Chen, 2008). In water
solutions, phospholipids, including lecithin, form liposomes as particles of
different sizes ranging from nanometers to micrometers. It is estimated that
liposomes larger than 25 μM can negatively affect the compound they trans-
fer and be tasteless.
In order to increase the bioavailability of polyphenols and ensure health
benefits, their incorporation in liposomes has been suggested. Besides post-
poning polyphenols’ degradation in the gastrointestinal tract, it is believed
that liposomes can also affect flavor of some polyphenols, decrease their sen-
sitivity to pH, temperature and light; and mask their interactions with other
macronutrients from foods (Gibis, Thellmann, Thongkaew, & Weiss, 2014;
Jakobek, 2015). However, there are some limitations in use of liposomes,
such as leakage of incorporated compounds and their unwanted release.
Processing of foods with mechanical pressure can damage liposomal mem-
branes and lead to loss of transferred compounds even though it is possible
to increase the stability of liposomes with the use of nontoxic, biodegradable
polymer polysaccharides, like chitosan. A recent study has investigated the
incorporation of grape extracts, rich in flavan-3-ols, procyanidins, and non-
flavanoid compounds, in differently designed liposomes (Gibis, Ruedt, &
Weiss, 2016). The authors noted that release of polyphenols from liposomes
is increased in case of their coating with chitosan, and suggested the use
of this coated liposomes in designing and manufacturing foods. Another
study investigated the incorporation of apigenin, polyphenol from flavones
subclass in liposomes by ultrasound sonication, as a method for obtaining

small particles with great stability (Paini et al., 2015). Without use of organic
solvents, the authors obtained liposomes with high degree of apigenin
encapsulation that could be used for preparation of functional foods, such
as beverages enriched in apigenin.
5.5 Polyphenols’ Impact on Metabolism of Carbohydrates

Effects of polyphenols on carbohydrates’ metabolism and homeostasis of
glucose have been well documented in animal and in vitro studies, but in
some clinical trials as well. The degradation and digestion of carbohydrates
starts in oral cavity, and continues in pancreas and small intestine. Amylases
and α-glucosidases are key enzymes involved in these processes. Since dis-
turbances in metabolism of carbohydrates may lead to health concerns, such
as obesity, diabetes, or even dental caries, such enzymes are often targets of
drugs aiming to treat these diseases. Besides drugs, polyphenols as well can
inhibit the activity of enzymes involved in metabolism of carbohydrates. In
addition, the structure of flavonoids can be detrimental for their action
against these enzymes. Thus, the hydroxylation of carbon atoms at some
positions in ring remarkably increases the inhibiting activity, while glycosyl-
ation of hydroxyl groups weakens it.
Br€aunlich et al. (2013) indicated that phenolic compounds from choke-
berry could act as potent α-glucosidase inhibitors and consequently decrease
blood glucose and protect from diabetes. Accordingly, long-term consump-
tion of chokeberry juice decreased fasting blood glucose in men with mild
hypercholesterolemia, while in patient with noninsulin-dependent diabetes
it also decreased the levels of glycated hemoglobin—HbA1C (Simeonov
et al., 2002; Skoczynska et al., 2007). It is important to note that phenolic
compounds can act as inhibitor of α-glucosidase even if they are poorly
absorbed, since this is a membrane-bound enzyme, placed in the intestinal
epithelium.
In case of proanthocyanidins, literature data are not consisting. While
one group of authors (Bahadoran, Mirmiran, & Azizi, 2013) indicated that
more complex proanthocyanidins inhibited amylase and glucosidase more
than less polymerized tannins, the other suggested that the effect of polymer-
ization degree could depend on type of enzyme (Lee, Cho, Tanaka, &
Yokozawa, 2007). The last authors found that polymers exerted stronger
inhibitory effect against α-amylase, compared to oligomers. On the contrary,
oligomers showed a stronger activity against α-glucosidase. Yamashita,
Okabe, Natsume, and Ashida (2012) observed that procyanidins with high
polymerization degree (4) had stronger effect on inhibition of α-glucosi-
dase, than less polymerized ones. They also found that antihyperglycemic
effect of procyanidins with small degree of polymerization (3) could
be based on their stimulation of glucose uptake by glucose transporter 4 in
skeletal muscle. Another study showed that hypoglycemic effects of tannins
from grape seed could originate not only from the inhibition of digestive
enzymes, but also from the inhibition of glycation process (Adisakwattana
et al., 2010). This latter effect could lead to delayed digestion of absorbable
monosaccharaides.
Altogether, polyphenols can inhibit and slow down digestion of carbo-
hydrates, through the inhibition of digestive enzymes, but also by modula-
tion of glucose uptake after ingesting carbohydrate-rich meals. Thus, these
natural antioxidants, could serve as potential antidiabetic agents.
5.6 The Impact of Carbohydrates on Polyphenols’

Bioavailability
While some studies reported that bioavailability of polyphenols could be
decreased due to the associations with carbohydrates, other studies showed
that carbohydrates from human diet could increase the polyphenols’ uptake.
An animal study conducted by Adam et al. (2002) showed that cereal
matrix (whole and white flours) limited the bioavailability of ferulic acid,
as a result of associations between fiber fraction and crosslinking to
arabinoxylans and lignins. Other studies confirmed this, by showing that fer-
ulic acid could be more available when bran structure is interrupted,
enabling the release of this and other phenolic acids (Pekkinen et al., 2014).
A study on human volunteers showed that carbohydrates (bread) con-
sumption increased the uptake of flavanols. The authors (Schramm et al.,
2003) explained this with effect of carbohydrates on the gastrointestinal
physiology and possible impact on the activity of carbohydrate–flavanol
transporter that is yet to be identified. In vitro study by Serra et al. (2010)
reported that uptake of monomer proanthocyanidins was enhanced by
carbohydrate-rich food, while the absorption of dimers or trimers was
repressed.
Even if polyphenols cannot be easily released from carbohydrate associ-
ations in upper part of gastrointestinal tract, they may exert their beneficial
effects in large intestine. More and more studies are suggesting positive
effects of polyphenol–carbohydrate complexes in the colon. There, poly-
phenols could be released by the action of enzymes and microorganisms
naturally colonizing intestines. Transport of polyphenols to the colon could

result in: their release from associated carbohydrate molecule; their metab-
olism by colon microbiota; or beneficial effects of polyphenol–carbohydrate
complexes on the microbiota growth ( Jakobek, 2015). If polyphenols are
released in colon, they can also act beneficially there, and create good anti-
oxidant environment. Interactions of polyphenols with dietary fibers are of
great importance. Dietary fibers may have role of polyphenols’ carriers to the
colon, where both dietary fibers and polyphenols can enhance growth of
beneficial bacteria and suppress growth of pathogenic ones.
5.6.1 Encapsulation of Polyphenols by Carbohydrates

Carbohydrates can be used to make particles that can encapsulate polyphe-
nols and thus ensure their controlled and targeted release upon the ingestion.
Green tea polyphenols entrapped with use of maltodextrin-coated micro-
capsules showed more promising effects on preventing CVD, than the non-
capsulated extract ( Jung et al., 2013). Other examples include encapsulation
of quercetin with: guar-based matrix, for improved release; pectin–
hydroxypropylmethyl cellulose for specific delivery to large intestine; or
pectin for better bioavailability (Bordenave et al., 2014; Singhal, Jain,
Singhal, Elias, & Showkat, 2011).
Besides applications in food industry, carbohydrate–polyphenols micro-
spheres can be used for other purposes as well. Acosta et al. (2015) investi-
gated encapsulation of olive leaf extract—rich in polyphenols—in chitosan
microparticles by spray drying and potential use of developed system in cos-
metic industry. The authors performed stability and release studies before
and after the incorporation into moisturizer base. According to the obtained
results, they concluded that this encapsulation was effective because it had
provided an adequate release of active ingredients. Additionally, the antiox-
idant capacity was maintained, suggesting that these formulations could be
applied in dermatology and cosmetics.
6. INTERACTIONS OF POLYPHENOLS WITH OTHER

DIETARY COMPOUNDS: BENEFICIAL EFFECTS ON
HUMAN HEALTH
Mediterranean diet is commonly mentioned as a healthy dietary pat-
tern, but it is also an example of joint health effects of polyphenols and lipids.
This diet is characterized by high intake of virgin olive oil, nuts, fruits, veg-
etables, and cereals; a moderate intake of poultry, fish, and wine; and low
intake of processed and red meats, sweets, and dairy products. The major
compounds of olive oil are MUFA, while minor compounds include some
important phenolic compounds, such as hydroxytyrosol. The daily intake of
polyphenols from virgin olive oil depends on multiple agronomic and tech-
nological factors and there is quite a large variety of these oils in the market.
Healthy effects of olive oil have been recognized and approved by EFSA.
The established health claim stated that polyphenols from olive oils contrib-
ute to the protection of blood lipids from oxidative stress. In addition, this
claim can be used only if consumer’s intake is 20 g of olive oil that contains at
least 5 mg of hydroxytyrosol and its derivatives (Reboredo-Rodrı́guez et al.,
2017). Beside this, numerous studies have confirmed an association between
this diet and lower incidence of metabolic syndrome, CVD, and cancer
(Covas, Konstantinidou, & Fitó, 2009; Martı́nez-González et al., 2012).
Conjugation of polyphenols and omega-3 fatty acids, i.e., lipophilization
of phenolic compounds, has been investigated in order to, among others,
increase their therapeutic potential. Besides the synthetic derivation, several
natural sources of lipophenols have been identified, such as vegetables from
marine origin, which represent the richest source of these derivates—
especially algae. Additionally, omega-3 lipophenols were found in plants,
mainly in leaves and stems. Some of the therapeutic applications of these
lipophenolic structures could be addressed toward increased anticancer,
antiinflammatory, and antibacterial activities. Omega-3 fatty acids could
increase anticancer potential of polyphenols, since epidemiological studies
have shown that diet rich in these fatty acids lowers cancer incidence
(Crauste, Rosell, Durand, & Vercauteren, 2016). The derivate of flavonoid
rutin and ALA showed potential to decrease vascular endothelial growth fac-
tor production in lymphoblastic cell lines, known as regulator of tumor-
induced neoangiogenesis (Mellou, Loutrari, Stamatis, Roussos, & Kolisis,
2006). It also overcame the problems of solubility comparing to native com-
pounds. The mixture of EGCG and esters of DHA showed ability to reduce
azoxymethane-induced carcinogenesis in mice. This activity was higher
compared to activity of EGCG alone, which may be explained by an
increased lipophilicity that could alter in vivo metabolism, as authors
suggested (Zhong, Chiou, Pan, Ho, & Shahidi, 2012). Beneficial effects
of polyphenols against chronic inflammation may be explained by the inhi-
bition of NF-κB activation, involved in expression of proinflammatory
mediators. Since omega-3 fatty acids and their metabolites: eicosanoids,
resolvins, or protectins are potent antiinflammatory agents, studies have
investigated the effects of their mixtures with polyphenols on
proinflammatory mediators’ synthesis. For instance, mixture of EGCG and

docosapentaeonoic (DPA) esters inhibited production of nitric oxide and
prostaglandin E2 to greater extent than DPA alone did (Zhong, Chiou,
Pan, & Shahidi, 2012). Furthermore, larger inhibitory effect on the
TNF-α production was shown for mixture of polyphenol juglone and
omega-3 fatty acids, comparing to the juglone alone (Maruo et al., 2011).
In spite of promising effects of omega-3 lipophenolic derivates, the rising
concern is the fact that biological activity has been mostly investigated in
in vitro conditions, and to a smaller extent on mice or rats, while clinical
testing on humans is largely lacking (Crauste et al., 2016). For that reason,
additional studies are required to provide better understanding of in vivo
mechanisms of those conjugates’ effects.
6.1 Impact of Poylphenols on Cardiovascular Health

Preventive measures of CVD are being highly implemented worldwide,
including intake of medicinal/functional foods. Many dietary interventions
have investigated the impact of polyphenol-rich foods and products on
risk factors and markers of CVD. Hypertension is an important risk factor
of cardiovascular morbidity and mortality, and many polyphenols have
been evaluated for their effects on blood pressure. For instance, one
metaanalysis showed beneficial effects of grape seed extract (rich in resver-
atrol) on decreasing systolic blood pressure (SBP) and heart rate, with no
impact on diastolic blood pressure (DBP) (Feringa, Laskey, Dickson, &
Coleman, 2011). More recently, metaanalysis showed no significant impact
of resveratrol on both SBP and DBP, based on data from 10 randomized
clinical trials (Sahebkar et al., 2015). Green and black tea manifested
reducing effect on SBP and DBP in short-term and long-term intervention
studies, while results for pure quercetin were quite contradictory (Hartley
et al., 2013). In their review paper, Rodriguez-Mateos, Heiss, Borges,
and Crozier (2014) indicated that there is no sufficient evidence to support
the influence of berries and berries-derived products on blood pressure
level. On the contrary, significant reduction in ambulatory measured mean
24 h and awake SBP and DBP was detected in subjects with high normal
blood pressure or hypertension grade I, after regular consumption of
polyphenol-rich chokeberry juice for 4 weeks (Kardum et al., 2015).
Endothelial dysfunction is another well-established marker of CVD and
vascular aging, and several methods have been used for its evaluation, such as
flow-mediated dilatation (FMD). As a result of metaanalysis including
42 clinical trials, Hooper et al. (2012) indicated that both acute and chronic
consumption of cocoa flavan-3-ols could significantly improve FMD. Dys-
lipidemia is an important CVD risk factor, referred to elevated levels of tri-
glycerides, total and LDL cholesterol, and decreased HDL cholesterol. Based
on some metaanalyses, short-term consumption of cocoa-based products
can lead to decrease in total and LDL cholesterol, as well as to increase in
HDL cholesterol, with no effect on triglycerides (Hooper et al., 2012;
Shrime et al., 2011). However, data on cocoa effects on lipid status are quite
ambiguous, as well as results of interventions related to tea-preparations
effects. So, while metaanalyses reported decrease in total and LDL choles-
terol for green tea and its catechins, no effect was shown in case of black
tea (Khalesi et al., 2014; Zhao, Asimi, Wu, Zheng, & Li, 2015).
Prevention or delay in diabetes onset is especially important, since
chronic hyperglycemia is correlated with CVD, while its association with
other risk factors leads to metabolic syndrome. Two studies, although not
placebo-controlled, found significant decrease in fasting blood glucose, after
acute and short-term intake of polyphenol-rich pomegranate juice, accom-
panied with decrease in insulin resistance and improvement in β-cell func-
tion (Banihani et al., 2014; Parsaeyan, Mozaffari-Khosravi, & Mozayan,
2012). Recent clinical trial with prehypertensive participants showed that
4-week long intake of pure ( )-epicatechin improved insulin resistance,
but expressed no effect on fasting plasma glucose (Dower et al., 2015).
Although results on effects of cocoa-derived polyphenols on glycaemia
are inconclusive, improvements in insulin resistance were reported in
numerous publications. Products enriched in olive-based polyphenols
showed beneficial effects on HbA1c and fasting insulin in diabetic subjects
(Wainstein et al., 2012), as well as on insulin sensitivity and function of
β-cells in middle-aged overweight men (de Bock et al., 2013). Furthermore,
metaanalysis showed significant impact of tea on fasting insulin in interven-
tions longer than 8 weeks, with no effect on fasting glucose (Li et al., 2015).
Another metaanalysis indicated that supplementation with soy isoflavone
may be beneficial for controlling both glucose and insulin, but proper RCTs
are required as a confirmation (Zhang et al., 2013).
6.2 Interactions of Poylphenols With Lipids and Proteins

in Cell Membranes
Membranes are dynamic structures made of lipids and proteins as main com-
pounds and carbohydrates that can be attached to them. Lipids in cell mem-
branes, more precisely phospholipids, serve as functional and structural
compound. Phospholipids are polar, ionic molecules composed of 1,2-

diacylglycerol and a phosphodiester bridge that links the glycerol backbone
to some base usually a nitrogenous one, such as choline, serine, or
etanolamine. Owing to their specific structure, phospholipids in membranes
make bilayers with hydrophobic parts (made of fatty acid chains) oriented
one to another, and hydrophilic parts oriented toward outside, i.e., one layer
toward extracellular and the other one toward intracellular space. Besides
phospholipids, other lipids, such as cholesterol and glycolipids are present
in membranes, as well as proteins (ion channels or pumps) which can be cru-
cial for passage of different molecules into or out of cells. It has been well
established that fatty acid composition of phospholipids determine physico-
chemical properties of membrane, influencing not just function of lipids but
also of present proteins, i.e., ion pumps, receptors, and transporters. Thus,
the decrease in amount of polyunsaturated fatty acids (PUFA) may increase
the membrane microviscosity and modify the fluidity of phospholipids.
Also, this can contribute to the deregulated function of integral proteins
of cell membranes.
Studies have shown that polyphenols can interact with phospholipid
bilayer of cell membranes, and thus alter their physicochemical characteris-
tics. Incubation of plant extracts with erythrocytes, as model of bio-
logical membranes, revealed protective effects on membrane oxidation,
potentially through two mechanisms: indirect one—by scavenging of free
radicals in extracellular environment; and direct one, that is of special
importance—by incorporation of polyphenols in membrane (Cyboran,
Oszmia nski, & Kleszczynska, 2012). Polyphenols showed ability to incorpo-
rate in hydrophilic part of exterior phospholipid layer of cell membranes,
and protect membrane lipids, namely unsaturated fatty acids from oxidation
(Bonarska-Kujawa, Pruchnik, Oszmia nski, Sarapuk, & Kleszczynska, 2011).
Different plant extracts rich in polyphenols demonstrated this activity, while
the effect depended on the concentration and specific structure of present
phenolic compounds. For instance, the apple extract caused the biggest
alterations in membrane structure, compared with the strawberry and
chokeberry extracts. This was shown by measuring phospholipids’ hydro-
philic heads packaging in membrane after incubation with such mentioned
extracts. The reason of the more pronounced effect of apple may lay in its
high content of chlorogenic acid. The effect of mentioned plant extracts on
shape of erythrocytes was also investigated. As a result, the chokeberry
extract led to occurrence of most diverse forms and shapes of erythrocytes.
Based on the present shapes of cells, the authors concluded that plant
polyphenols concentrated in exterior layer of membranes, while they did

not rich interior layer (Iglic, Kralj-Iglic, & Hagerstand, 1998). The alter-
ations in phenolic structure can change their affinity to incorporate in mem-
branes. For instance, the addition of sugar units (such as glucose) leads to
weaker binding to membranes (Oszmia nski & Wojdylo, 2005).
Interactions of polyphenols with biological membranes also affect the
membrane bound transporter proteins and enzymes and this way changes
transmembrane potential of intracellular and extracellular molecules
(Hussain, Sulaiman, Alhaddad, & Alhadidi, 2016). Polyphenols are becom-
ing popular since they can interact with drug transporters, such as multidrug
resistance protein (MDR) and p-glycoprotein (P-gp), and alter their activity.
Reports suggested that natural polyphenols, as well as their synthetic analogs,
may affect MDR transporters that are in charge of chemotherapy resistance
(Bansal, Akhtar, Jaggi, Khar, & Talegaonkar, 2009). A well-studied poly-
phenol resveratrol showed potential to block P-gp efflux of doxorubicin
and docetaxel and improve their cytotoxic activities in solid tumors.
The mechanisms by which polyphenols may interact with uptake trans-
porters are not well defined, but some in vitro studies indicated that
polyphenols may change their configuration and functionality by acting
as competitive and noncompetitive ligands for either active or allosteric sites
(Rodriguez-Proteau et al., 2006). Polyphenols’ effects on modulation of
transporters and receptors involved in neurological processes, suggest their
potential implications in treatments of depression and other disorders.
In accordance, hesperidin and EGCG improve the activity of benzo-
diazepine by modulation of GABA-A receptor where they can bind
(Hanrahan, Chebib, & Johnston, 2011).
6.2.1 Impact of Polyphenols on Membrane Fatty Acid Profile:

Chokeberry Juice as Example
The determination of unsaturated fatty acids’ content in red blood cells
membranes is of great importance for the estimation of risk for CVD. It
has been shown that the amount of PUFA in erythrocytes inversely corre-
lates with the occurrence of high blood pressure. Additionally, omega-3
fatty acids content is negatively associated with the risk of CVD, rheumatoid
arthritis, and metabolic syndrome (Lee & Park, 2013; Piñeiro-Corrales,
Lago Rivero, & Culebras-Fernández, 2013; Simopoulos, 2013). In accor-
dance with the importance of omega-3 fatty acids, some authors suggested
the introduction of omega-3 index, defined as the sum of content of the
most important omega-3 fatty acids: DHA and EPA. This index is
considered to be a valuable indicator of risk of coronary heart disease devel-

opment and consequent death. Besides content of unsaturated fatty acids, the
ratio of omega-6 and omega-3 fatty acids’ content is also an important deter-
minant of health. The high ratio in membrane of erythrocytes contributes to
the development of inflammation and chronic diseases, while the decrease of
this ratio decreases the risk of these conditions (Simopoulos, 2006).
Owing to their incorporation in phospholipid bilayer of cell membranes,
regular intake of polyphenols could reduce the extent of membrane lipids’
oxidation and impact fatty acid profile. Thus, daily intake of polyphenol-
rich chokeberry juice for 12 weeks increased the relative amount of total
and omega-3 PUFA, as well as omega-3 index and DHA level in phospho-
lipids of erythrocytes membranes in healthy female volunteers (Kardum,
Petrovic-Oggiano, et al., 2014). This increase in omega-3 fatty acids was
followed by significant decrease of omega-6 and omega-3 ratio. Further-
more, the similar effect was observed in women with abdominal obesity after
4 weeks of regular chokeberry juice consumption. In this subject group,
favorable effect on fatty acid profile was accompanied with decrease in
SBP (Kardum, Takic, et al., 2014). However, these subjects consumed
chokeberry juice enriched with dietary fiber, and the observed effects could
be result of joint action of both active ingredients. Chokeberry belongs to
Rosaceae family and origins from east parts of North America and Canada.
Polyphenols are identified as the active ingredients (Konic-Ristic, Srdic-
Rajic, Kardum, & Glibetic, 2013). Chokeberry fruits and related products
are believed to have health-promoting effects, including impact on cardio-
vascular system, gastrointestinal and urinary tract, improving memory and
cognitive functions, and protection from bacteria and viruses (Chrubasik,
Li, & Chrubasik, 2010). The recent study showed that chokeberry juice
could be effective in treatment of cellulite, by acting on morphological
properties of skin and possibly circulation (Savikin et al., 2014).
The observed effects of chokeberry juice consumption on fatty acids
indicate its beneficial impact on cellular antioxidant defense. Additionally,
these changes in fatty acid profile suggest protective role of chokeberry juice
on cardiovascular health. The increase in content of omega-3 fatty acids has
hypotensive effect, leads to better fluidity and permeability of membranes,
and regulates the signaling pathway. On the other side, the lower amount of
omega-3 fatty acids increases the production of proinflammatory eicosanoids
and makes smooth muscle cells in arterial walls more sensitive to vasocon-
strictors’ influence (Novgorodtseva, Kantur, Karaman, Antonyuk, &
Zhukova, 2011). Besides chokeberry, recent study has shown that
pomegranate juice consumption can influence fatty acid composition and

level of lipid peroxidation. As Kojadinovic et al. (2017) reported, 6 weeks
consumption of pomegranate juice in subjects with metabolic syndrome sig-
nificantly decreased level of arachidonic acid, while it increased content of
MUFA. In addition, level of thiobarbituric reactive substance (TBARS), as
marker of lipid peroxidation significantly decreased. Accordingly, the
impact on fatty acid profile can be associated with antioxidant properties
of chokeberry, pomegranate, and other sources of polyphenols. In both
mentioned studies with female volunteers (Kardum, Petrovic-Oggiano,
et al., 2014; Kardum, Takic, et al., 2014), chokeberry juice consumption
raised activity of antioxidant enzymes in erythrocytes. In addition, there
was a clear correlation between relative content of some fatty acids and glu-
tathione peroxidase (GPx) activity, in group of healthy females. More pre-
cisely, the higher increase of GPx activity was accompanied by more
pronounced changes in the content of total and omega-3 fatty acids
(Kardum, Takic, et al., 2014). In these subjects, chokeberry juice consump-
tion also led to decrease in lipid peroxidation, measured as level of TBARS.
Further investigations are required to better understand interactions of
polyphenols and fatty acids in membranes, as well as its consequences on
human health. In accordance, the conduction of well-controlled human tri-
als with bigger intervention groups is needed, so as investigations on impact
of other polyphenol-rich items. Beside this, better understanding of mech-
anisms underlying effects on fatty acids could be achieved by in vitro exam-
ination with use of phenolic metabolites, present in circulation upon
polyphenol-rich foods ingestion.
7. INTESTINAL MICROBIOTA AND ITS ROLE IN

POLYPHENOLS–MACRONUTRIENT INTERACTIONS
As available literature data indicate the impact of polyphenols–
macronutrient interactions on human health can be mediated through their
effects on gut microbiota (Clemente-Postigo et al., 2013; Conlon & Bird,
2014; Sheflin, Melby, Carbonero, & Weir, 2017). For instance, consump-
tion of polyphenols can counteract dysbiosis caused by high intake of fats. In
addition, gut microbiota plays crucial role in metabolism of polyphenols, but
can also influence metabolism of macronutrients, especially some lipids and
dietary fibers. Accordingly, through the impact on their availability, gut
microbiota may indirectly affect the extent of polyphenols–macronutrients
interactions, which can further be reflected on their health effects.
7.1 Interactions Between Gut Microbiota and Macronutrients

Gut microbiota has a crucial role in human health, while imbalance in its
composition or structure may cause intestinal, metabolic, and autoimmune
diseases (Valdes et al., 2015). The overall diet as well as intake of individual
macronutrients can affect the composition, diversity, and activity of gut
microbiota. Studies have shown that diet rich in fats decreases the number
of Bifidobacterium species, while intake of saturated and MUFA positively
correlates with the species from Bacteroides genus (Brinkworth, Noakes,
Clifton, & Bird, 2009; Wu, Chen, et al., 2011). On the other side, the high
intake of omega-3 fatty acids was associated with the increase in beneficial
Lactobacillus species as well as with better function and structure of intestinal
epithelial barrier (Willemsen et al., 2008). The intake of omega-6 fatty acids,
on the contrary, was correlated with the decrease in number of
Bifidobacterium species as well as with the impaired functions of immune sys-
tem (Simões et al., 2013). Taking into account these findings, it is evident
that balanced intake of different fatty acids acts beneficially on gut micro-
biota, and thus contributes to overall health. However, literature data are
still not consistent. In vitro studies showed that some fatty acids, such as
LA, gamma-linolenic, ALA, arachidonic, and DHA can inhibit the growth
of some species from Lactobacillus genus and their binding to intestine
mucosa (Kankaanp€a€a, Yang, Kallio, Isolauri, & Salminen, 2004). On the
other side, it was detected that adding essential fatty acids LA and ALA in
a medium that contains different Bifidobacterium species leads to their conver-
sion to conjugated LA. It has been suggested that this conjugated fatty acid
can have both beneficial and adverse effects on human health. For instance,
one study indicated that conjugated LA and ALA could act as inhibitory on
cancer, atherosclerosis, obesity, and insulin resistance (Belury, 2002). Still, it
remains unclear whether gut microbiota can produce significant amounts of
conjugated fatty acids that would exert these systematic effects. The diet rich
in fats can increase the amount of bile acids and fats that reach the colon,
while the type of fatty acids influence the spectrum of created bile acids,
and indirectly the function of microbiota (Devkota et al., 2012). Also, die-
tary pattern with high intake of fat can facilitate translocation of bacterial
lipopolysaccharides, well-established promoters of chronic inflammation
(Sheflin et al., 2017). On the other side, there is increased number of findings
suggesting that gut microbiota and its interactions with foods can regulate
metabolism of lipids. It was estimated that gut microbiota may metabolize
fats by converting PUFA into diacylglycerols (which are then absorbed)
and primary bile acids into secondary ones. Gut microbiota may also
influence enterohepatic circulation of bile acids, and absorption of fats in

small intestines (Fava et al., 2013). Bacterial species, depending on their type
and intake of food, can affect incorporation of fatty acids in lipid droplets in
enterocytes. For instance, in satiety, Firmicutes species stimulate the entry of
fatty acids in enterocytes and also the creation of lipid droplets, formed dur-
ing fat digestion (Semova et al., 2012).
As opposed to most nutrients that are absorbed in duodenum, dietary
fibers, often referred as nondigestible polysaccharides, remain unaltered
until reaching the colon. Since they represent the main source of energy
for colonic microbiota, they are recently called microbiota-accessible car-
bohydrates (Daı̈en, Pinget, Tan, & Macia, 2017). As a result of fermen-
tation of dietary fibers by microbiota, short chain fatty acids (SCFA) are
released. These SCFA play important role in health and disease. People
with higher intake of dietary fibers have much more diverse gut micro-
biota and larger amount of SCFA in comparison to people with lower
intake. Low diversity of microbiota is associated with diseases typical
for Western society, such as diabetes, rheumatoid arthritis, inflammatory
bowel disease, and asthma (Daı̈en et al., 2017). As human diet almost
never includes individual and chemically distinct dietary fiber, but rather
mixture of these structures in food items, it is important to evaluate the
impact of their combinations present in various food sources. Thus, stud-
ies that included various whole cereal grains, such as whole grain maize
and whole grain wheat cereal, showed that they lead to increase in ben-
eficial Bifidobacterium species (Carvalho-Wells et al., 2010; Costabile,
Klinder, & Fava, 2008).
Higher intake of particular macronutrient is often associated with lower
intake of other macronutrients, while this combination results in alterations
of gut microbiota’ composition and diversity, leading to different
enterotypes (Sheflin et al., 2017). Prevotella enterotype, for instance, has been
associated with high consumption of complex carbohydrate, while Bacte-
roides enterotype has been associated with frequent intake of animal proteins
and saturated fats (David et al., 2014). The impact of diets rich in proteins on
gut microbiota is not extensively investigated, but is of great importance due
to their increased popularity. Although some findings indicated that high-
protein diet can lead to production of bacterial metabolites associated with
inflammation and increased risk of colorectal cancer (Sheflin, Whitney, &
Weir, 2014), the impact of this diet can also depend on other factors. These
include body composition, level of physical activity, but also the types and
amounts of dietary fats. Thus, in professional athletes, protein consumption
was positively associated with the better bacterial diversity, while they
exerted lower levels of inflammation markers and better metabolism com-
paring with the control subject (Clarke et al., 2014).
7.2 Interactions Between Gut Microbiota and Polyphenols

Gut microbiota and polyphenols interact in both directions, meaning that
microbiota affects metabolism and bioavailability of polyphenols, while phe-
nolic metabolites influence the growth of some bacterial species. Numerous
studies have been conducted to determine the impact of polyphenol-rich
foods on gut microbiota. For example, some research suggested bifidogenic
effects of tea, while other reported no effect of tea consumption on human
gut microbiota, indicating that phenolic profile determines the nature of this
effect ( Janssens et al., 2016; van Duynhoven et al., 2013). The similar effect
on increase in Bifidobacterium, as well as in Lactobacillus species was reported
for cocoa, chocolate, and berries consumption. Study in mice reported the
same for apples enriched in flavonoids, but observed effect could also be due
to the considerable amount of dietary fiber (Espley et al., 2014). It has been
well established that high-caloric diets, such as high-fat diet, causes imbal-
ance of gut microbiota, while various compounds such as prebiotics and
probiotics modulate this dysbiosis (defined as disruption of ecological
equilibrium in the gut). In addition, Etxeberria et al. (2015) proposed that
polyphenols, as plant bioactive compounds, may reverse dysbiosis induced
by high-fat sucrose (HFS) diet. They tested the impact of supplementation
with one of two polyphenols: transresveratrol and quercetin or both on
microbiota composition in rats fed with HFS diets. As a result, administ-
ration of individual compounds, as well as both compounds together
reduced levels of insulin in serum. Additionally, quercetin supplementation
showed impact on gut microbiota composition, by attenuation Firmicutes/
Bacteroidetes ratio and inhibition of bacterial species that have been associated
with obesity. Thus, quercetin administration was effective in decreasing the
HFS diet-induced dysbiosis, while transresveratrol alone or combined with
quercetin had low impact on bacterial profile. Still, transresveratrol caused
changes at intestinal level, manifested as alterations in mRNA expression
of tight-junction proteins and genes associated with inflammation.
Human intervention study with proanthocyanidin-rich grape seed
extract resulted in increased number of Bifidobacterium after 2 weeks, while
another 20-day long study showed the same effect for moderate consump-
tion of red wine (Queipo-Ortuño et al., 2012; Yamakoshi et al., 2001).
Furthermore, Shinohara, Ohashi, Kawasumi, Terada, and Fujisawa (2010)

reported an increase in the number of bifidobacteria as a result of two apples
per day intake in 2-week period, while lecithinase-positive clostridia were
reduced. A drink enriched in cocoa flavanols showed similar effect on
bifidiobacteria increase and clostridia decrease, along with increase in
lactobacilli population, after 4 weeks of supplementation (Tzounis et al.,
2011). In another study, the moderate coffee consumption had no effect
on fecal profile of dominant microbiota, but still, an increase of
Bifidobacterium species proportion was detected ( Jaquet, Rochat, Moulin,
Cavin, & Bibiloni, 2009). Investigation of 6-week long consumption of wild
blueberry drink revealed significant increase in Bifidobacterium relatively to
total eubacteria, with no changes in other species (Vendrame et al., 2011).
8. CONCLUDING REMARKS
Interactions between polyphenols and macronutrients can reflect on
absorption and metabolism of interacting compounds, which may have dif-
ferent consequences on human health. Additionally, these interactions can
occur in food items, and impact their organoleptic properties, as well as sta-
bility, while polyphenols may protect other food compounds, especially
lipids, from oxidation.
Since polyphenols have limited bioavailability, further research on their
encapsulation in microparticles made of proteins, lipids, or carbohydrates is
highly recommended. This could lead to development of products with
controlled release of polyphenols, as well as targeted and more pronounced
health effects. Finally, in order to completely understand the health conse-
quences of polyphenols–macronutrients interactions, further well-designed
and controlled human trials should be encouraged.
REFERENCES
Acosta, N., Sánchez, E., Calderón, L., Cordoba-Diaz, M., Cordoba-Diaz, D., Dom, S., et al.
(2015). Physical stability studies of semi-solid formulations from natural compounds
loaded with chitosan microspheres. Marine Drugs, 13, 5901–5919.
Adam, A., Crespy, V., Levrat-Verny, M. A., Leenhardt, F., Leuillet, M., Demigne, C., et al.
(2002). The bioavailability of ferulic acid is governed primarily by the food matrix rather
than its metabolism in intestine and liver in rats. The Journal of Nutrition, 132, 1962–1968.
Adisakwattana, S., Jiphimai, P., Prutanopajai, P., Chanathong, B., Sapwarobol, S., &
Ariyapitipan, T. (2010). Evaluation of α-glucosidase, α-amylase and protein glycation
inhibitory activities of edible plants. International Journal of Food Sciences and Nutrition,
61, 295–305.
Bahadoran, Z., Mirmiran, P., & Azizi, F. (2013). Dietary polyphenols as potential
nutraceuticals in management of diabetes: A review. Journal of Diabetes and Metabolic
Disorders, 12, 43.
Banihani, S. A., Makahleh, S. M., El-Akawi, Z., Al-Fashtaki, R. A., Khabour, O. F.,
Gharibeh, M. Y., et al. (2014). Fresh pomegranate juice ameliorates insulin resistance,
enhances beta-cell function, and 1783 decreases fasting serum glucose in type 2 diabetic
patients. Nutrition Research (New York, NY), 34, 862–867.
Bansal, T., Akhtar, N., Jaggi, M., Khar, R. K., & Talegaonkar, S. (2009). Novel formulation
approaches for optimising delivery of anticancer drugs based on P-glycoprotein modu-
lation. Drug Discovery Today, 14, 1067–1074.
Belury, M. A. (2002). Dietary conjugated linoleic acid in health: Physiological effects and
mechanisms of action. Annual Review of Nutrition, 22, 505–531.
Bittner, S. (2006). When quinones meet amino acids: Chemical, physical and biological con-
sequences. Amino Acids, 30, 205–224.
Bonarska-Kujawa, D., Pruchnik, H., Oszmia nski, J., Sarapuk, J., & Kleszczy
nska, H. (2011).
Changes caused by fruit extracts in the lipid phase of biological and model membranes.
Food Biophysics, 6, 58–67.
Bordenave, N., Hamaker, B. R., & Ferruzzi, M. G. (2014). Nature and consequences of
non-covalent interactions between flavonoids and macronutrients in foods. Food & Func-
tion, 5, 18–34.
Br€aunlich, M., Slimestad, R., Wangensteen, H., Brede, C., Malterud, K. E., & Barsett, H.
(2013). Extracts, anthocyanins and procyanidins from Aronia melanocarpa as radical
scavengers and enzyme inhibitors. Nutrients, 5, 663–678.
Brinkworth, G. D., Noakes, M., Clifton, P. M., & Bird, A. R. (2009). Comparative effects of
very low-carbohydrate, high-fat and high-carbohydrate, low-fat weight-loss diets on
bowel habit and faecal short-chain fatty acids and bacterial populations. British Journal
of Nutrition, 101, 1493–1502.
Carvalho-Wells, A. L., Helmolz, K., Nodet, C., Molzer, C., Leonard, C., McKevith, B.,
et al. (2010). Determination of the in vivo prebiotic potential of a maize-based whole
grain breakfast cereal: A human feeding study. British Journal of Nutrition, 104,
1353–1356.
Chrubasik, C., Li, G., & Chrubasik, S. (2010). The clinical effectiveness of chokeberry:
A systematic review. Phytotherapy Research, 24, 1107–1114.
Clarke, S. F., Murphy, E. F., O’Sullivan, O., Lucey, A. J., Humphreys, M., Hogan, A., et al.
(2014). Exercise and associated dietary extremes impact on gut microbial diversity. Gut,
63, 1913–1920.
Clemente-Postigo, M., Queipo-Ortuño, M. I., Boto-Ordoñez, M., Coin-Arag€ uez, L.,
Roca-Rodriguez, M. M., Delgado-Lista, J., et al. (2013). Effect of acute and chronic
red wine consumption on lipopolysaccharide concentrations. American Journal of Clinical
Nutrition, 97, 1053–1061.
Conlon, M. A., & Bird, A. R. (2014). The impact of diet and lifestyle on gut microbiota and
human health. Nutrients, 7, 17–44.
Coonrod, D., Brick, M. A., Byrne, P. F., DeBonte, L., & Chen, Z. (2008). Inheritance of
long chain fatty acid content in rapeseed (Brassica napus L.). Euphytica, 164, 583–592.
Costabile, A., Klinder, A., & Fava, F. (2008). Whole-grain wheat breakfast cereal has a pre-
biotic effect on the human gut microbiota: A double-blind, placebo-controlled, cross-
over study. British Journal of Nutrition, 99, 110–120.
Covas, M. I., Konstantinidou, V., & Fitó, M. (2009). Olive oil and cardiovascular health.
Journal of Cardiovascular Pharmacology, 54, 477–482.
Coward, L., Smith, M., Kirk, M., & Barnes, S. (1998). Chemical modification of isoflavones
in soyfoods during cooking and processing. American Journal of Clinical Nutrition, 68,
S1486–S1491.
Crauste, C., Rosell, M., Durand, T., & Vercauteren, J. (2016). Omega-3 polyunsaturated
lipophenols, how and why? Biochimie, 120, 62–74.
Crozier, A., Borges, G., & Ryan, D. (2010). The glass that cheers: Phenolic and polyphenolic
constituents and the beneficial effects of moderate red wine consumption. Biochemistry,
32, 4–9.
Crozier, A., McDonald, M. S., Lean, M. E. J., & Black, C. (1997). Quantitative analysis of the
flavonoid content of tomatoes, onions, lettuce and celery. Journal of Agricultural and Food
Chemistry, 45, 590–595.
Cyboran, S., Oszmia nski, J., & Kleszczy
nska, H. (2012). Interaction between plant polyphe-
nols and the erythrocyte membrane. Cellular and Molecular Biology Letters, 17, 77–88.
Czank, C., Cassidy, A., Zhang, Q., Morrison, D. J., Preston, T., Kroon, P. A., et al. (2013).
Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: A (13)C-
tracer study. American Journal of Clinical Nutrition, 97, 995–1003.
Daı̈en, C. I., Pinget, G. V., Tan, J. K., & Macia, L. (2017). Detrimental impact of microbiota-
accessible carbohydrate-deprived diet on gut and immune homeostasis: An overview.
Frontiers in Immunology, 8, 548.
David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E.,
Wolfe, B. E., et al. (2014). Diet rapidly and reproducibly alters the human gut micro-
biome. Nature, 505, 559–563.
de Bock, M., Derraik, J. G., Brennan, C. M., Biggs, J. B., Morgan, P. E., Hodgkinson, S. C.,
et al. (2013). Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in
middle-aged overweight men: A randomized, placebo-controlled, crossover trial. PLoS
One, 8, e57622.
De Ferrars, R. M., Czank, C., Zhang, Q., Botting, N. P., Kroon, P. A., Cassidy, A., et al.
(2014). The pharmacokinetics of anthocyanins and their metabolites in humans. British
Journal of Pharmacology, 171, 3268–3282.
Del Rio, D., Borges, G., & Crozier, A. (2010). Berry flavonoids and phenolics: Bioavailabil-
ity and evidence of protective effects. British Journal of Nutrition, 104, S67–S90.
Devkota, S., Wang, Y., Musch, M. W., Leone, V., Fehlner-Peach, H., & Nadimpalli, A.
(2012). Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis
in IL10-/- mice. Nature, 487, 104–108.
Dower, J. I., Geleijnse, J. M., Gijsbers, L., Schalkwijk, C., Kromhout, D., & Hollman, P. C.
(2015). Supplementation of the pure flavonoids epicatechin and quercetin affects some
1886 biomarkers of endothelial dysfunction and inflammation in (pre)hypertensive
adults: A randomized double-blind, placebo-controlled, crossover trial. Journal of Nutri-
tion, 145, 1459–1463.
Draijer, R., van Dorsten, F. A., Zebregs, Y. E., Hollebrands, B., Peters, S., Duchateau, G. S.,
et al. (2016). Impact of proteins on the uptake, distribution, and excretion of phenolics in
the human body. Nutrients, 8, pii: 814.
Duda-Chodak, A., Tarko, T., Satora, P., & Sroka, P. (2015). Interaction of dietary com-
pounds, especially polyphenols, with the intestinal microbiota: A review. European Jour-
nal of Nutrition, 54, 325–341.
Espley, R. V., Butts, C. A., Laing, W. A., Martell, S., Smith, H., McGhie, T. K., et al. (2014).
Dietary flavonoids from modified apple reduce inflammation markers and modulate gut
microbiota in mice. Journal of Nutrition, 144, 146–154.
Etxeberria, U., Arias, N., Boque, N., Macarulla, M. T., Portillo, M. P., Martı́nez, J. A., et al.
(2015). Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and
quercetin in high-fat sucrose diet-fed rats. Journal of Nutritional Biochemistry, 26, 651–660.
Fava, F., Gitau, R., Griffin, B. A., Gibson, G. R., Tuohy, K. M., & Lovegrove, J. A. (2013).
The type and quantity of dietary fat and carbohydrate alter faecal microbiome and
short-chain fatty acid excretion in a metabolic syndrome ‘at-risk’ population. International
Journal of Obesity, 37, 216–223.
Feringa, H. H., Laskey, D. A., Dickson, J. E., & Coleman, C. I. (2011). The effect of grape
seed extract on cardiovascular risk markers: A meta-analysis of randomized controlled
trials. Journal of the American Dietetic Association, 111, 1173–1181.
Ferrer-Gallego, R., Soares, S., Mateus, N., Rivas-Gonzalo, J., Escribano-Bailón, M. T., &
de Freitas, V. (2015). New anthocyanin–human salivary protein complexes. Langmuir,
31, 8392–8401.
Frazier, R. A., Deaville, E. R., Green, R. J., Stringano, E., Willoughby, I., Plant, J., et al.
(2010). Interactions of tea tannins and condensed tannins with proteins. Journal of Phar-
maceutical and Biomedical Analysis, 51, 490–495.
Galati, G., & O’Brien, P. J. (2004). Potential toxicity of flavonoids and other dietary pheno-
lics: Significance for their chemopreventive and anticancer properties. Free Radical Biol-
ogy and Medicine, 37, 287–303.
Gibis, M., Ruedt, C., & Weiss, J. (2016). In vitro release of grape-seed polyphenols encap-
sulated from uncoated and chitosan-coated liposomes. Food Research International, 88,
105–113. https://doi.org/10.1016/j.foodres.2016.02.010.
Gibis, M., Thellmann, K., Thongkaew, C., & Weiss, J. (2014). Interaction of polyphenols
and multilayered liposomal-encapsulated grape seed extract with native and heat-treated
proteins. Food Hydrocolloids, 41, 119–131.
Giroux, H. J., De Grandpre, G., Fustier, P., Champagne, C. P., St-Gelais, D., Lacroix, M.,
et al. (2013). Production and characterization of Cheddar-type cheese enriched 401 with
green tea extract. Dairy Science and Technology, 93, 241–254.
Gnoni, G. V., & Paglialonga, G. (2009). Resveratrol inhibits fatty acid and triacylglycerol
synthesis in rat hepatocytes. European Journal of Clinical Investigation, 39, 211–218.
Grosso, G., Stepaniak, U., Topor-Madry, R., Szafraniec, K., & Pajak, A. (2014). Estimated
dietary intake and major food sources of polyphenols in the Polish arm of the HAPIEE
study. Nutrition, 30, 1398–1403.
Guo, Y., Mah, E., Davis, C. G., Jalili, T., Ferruzzi, M. G., Chun, O. K., et al. (2013). Dietary
fat increases quercetin bioavailability in overweight adults. Molecular Nutrition & Food
Research, 57, 896–905.
Gurinovic, M., Mileševic, J., Novakovic, R., Kadvan, A., Djekic-Ivankovic, M., Šatalic, Z.,
et al. (2015). Improving nutrition surveillance and public health research in Central and
Eastern Europe/Balkan countries using the Balkan food platform and dietary tools. Food
Chemistry, 193, 173–180.
Hanrahan, J. R., Chebib, M., & Johnston, G. A. (2011). Flavonoid modulation of GABA(A)
receptors. British Journal of Pharmacology, 163, 234–245.
Hartley, L., Flowers, N., Holmes, J., Clarke, A., Stranges, S., Hooper, L., et al. (2013). Green
and black tea for the primary prevention of cardiovascular disease. Cochrane Database of
Systematic Reviews, 6, CD009934.
Holmes, E., Kinross, J., Gibson, G. R., Burcelin, R., Jia, W., Pettersson, S., et al. (2012).
Therapeutic modulation of microbiota–host metabolic interactions. Science Translational
Medicine, 4, 137rv6.
Hooper, L., Kay, C., Abdelhamid, A., Kroon, P. A., Cohn, J. S., Rimm, E. B., et al. (2012).
Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: A systematic
review and meta-analysis of randomized trials. American Journal of Clinical Nutrition,
95, 740–751.
Hussain, S. A., Sulaiman, A. A., Alhaddad, H., & Alhadidi, Q. (2016). Natural polyphenols:
Influence on membrane transporters. Journal of Intercultural Ethnopharmacology, 5, 97–104.
Iglic, A., Kralj-Iglic, V., & Hagerstand, V. H. (1998). Amphiphile induced echinocyte–
spheroechinocyte transformation of red blood cell shape. European Biophysics Journal,
27, 335–339.
Jakobek, L. (2015). Interactions of polyphenols with carbohydrates, lipids and proteins. Food
Chemistry, 175, 556–567.
Janssens, P. L., Penders, J., Hursel, R., Budding, A. E., Savelkoul, P. H., & Westerterp-
Plantenga, M. S. (2016). Long-term green tea supplementation does not change the
human gut microbiota. PLoS One, 11, e0153134.
Jaquet, M., Rochat, I., Moulin, J., Cavin, C., & Bibiloni, R. (2009). Impact of coffee con-
sumption on the gut microbiota: A human volunteer study. International Journal of Food
Microbiology, 130, 117–121.
J€
obstl, E., Howse, J. R., Fairclough, J. P., & Williamson, M. P. (2006). Noncovalent cross-
linking of casein by epigallocatechin gallate characterized by single molecule force
microscopy. Journal of Agricultural and Food Chemistry, 54, 4077–4081.
Jung, M. H., Seong, P. N., Kim, M. H., Myong, N. H., & Chang, M. J. (2013). Effect of
green tea extract microencapsulation on hypertriglyceridemia and cardiovascular tissues
in high fructose-fed rats. Nutrition Research and Practice, 7, 366–372.
Kankaanp€a€a, P., Yang, B., Kallio, H., Isolauri, E., & Salminen, S. (2004). Effects of polyun-
saturated fatty acids in growth medium on lipid composition and on physicochemical
surface properties of lactobacilli. Applied and Environmental Microbiology, 70, 129–136.
Kardum, N., Konic Ristic, A., Zec, M., Kojadinovic, M., Petrovic-Oggiano, G.,
Zekovic, M., et al. (2017). Design, formulation and sensory evaluation of a
polyphenol-rich food placebo: An example of aronia juice for food intervention studies.
International Journal of Food Sciences and Nutrition, 68, 742–749.
Kardum, N., Milovanovic, B., Šavikin, K., Zdunic, G., Mutavdžin, S., Gligorijevic, T., et al.
(2015). Beneficial effects of polyphenol-rich chokeberry juice consumption on blood
pressure level and lipid status in hypertensive subjects. Journal of Medicinal Food, 18,
1231–1238.
Kardum, N., Petrovic-Oggiano, G., Takic, M., Glibetic, N., Zec, M., Debeljak-Martacic, J.,
et al. (2014). Effects of glucomannan-enriched, aronia juice-based supplement on cellular
antioxidant enzymes and membrane lipid status in subjects with abdominal obesity. The
Scientific World Journal, 2014, 869250.
Kardum, N., Takic, M., Šavikin, K., Zec, M., Zdunic, G., Spasic, S., et al. (2014). Effects of
polyphenol-rich chokeberry juice on cellular antioxidant enzymes and membrane lipid
status in healthy women. Journal of Functional Foods, 9, 89–97.
Katare, C., Saxena, S., Agrawal, S., Joseph, A. Z., Subramani, S. K., Yadav, D., et al. (2014).
Lipid-lowering and antioxidant functions of bottle gourd (Lagenaria siceraria) extract in
human dyslipidemia. Journal of Evidence-Based Complementary & Alternative Medicine, 19,
112–118.
Khalesi, S., Sun, J., Buys, N., Jamshidi, A., Nikbakht-Nasrabadi, E., & Khosravi-Boroujeni, H.
(2014). Green tea catechins and blood pressure: A systematic review and meta2084
analysis of randomised controlled trials. European Journal of Nutrition, 53, 1299–1311.
Kojadinovic, M. I., Arsic, A. C., Debeljak-Martacic, J. D., Konic-Ristic, A. I.,
Kardum, N. D., Popovic, T. B., et al. (2017). Consumption of pomegranate juice
decreases blood lipid peroxidation and levels of arachidonic acid in women with meta-
bolic syndrome. Journal of the Science of Food and Agriculture, 97, 1798–1804.
Konic-Ristic, A., Kroon, P. A., & Glibetic, M. (2015). Modulation of platelet function with
dietary polyphenols: A promising strategy in the prevention of cardiovascular disease.
Agro Food Industry Hi-Tech, 26, 15–19.
Konic-Ristic, A., Srdic-Rajic, T., Kardum, N., & Glibetic, M. (2013). Biological activity of
Aronia melanocarpa antioxidants pre-screening in an intervention study disign. Journal of
the Serbian Chemical Society, 78, 429–443.
Kroon, P. A., Clifford, M. N., Crozier, A., Day, A. J., Donovan, J. L., Manach, C., et al.
(2004). How should we assess the effects of exposure to dietary polyphenols in vitro?
American Journal of Clinical Nutrition, 80, 15–21.
Landete, J. M. (2011). Ellagitannins, ellagic acid and their derived metabolites: A review about
source, metabolism, functions and health. Food Research International, 44, 1150–1160.
Lee, Y. A., Cho, E. J., Tanaka, T., & Yokozawa, T. (2007). Inhibitory activities of
proanthocyanidins from persimmon against oxidative stress and digestive enzymes
related to diabetes. Journal of Nutritional Science and Vitaminology, 53, 287–292.
Lee, H. C., Jenner, A. M., Low, C. S., & Lee, Y. K. (2006). Effect of tea phenolics and their
aromatic fecal bacterial metabolites on intestinal microbiota. Research in Microbiology, 157,
876–984.
Lee, A. L., & Park, Y. (2013). The association between n-3 polyunsaturated fatty acid levels
in erythrocytes and the risk of rheumatoid arthritis in Korean women. Annals of Nutrition
and Metabolism, 63, 88–95.
Li, G., Zhang, Y., Thabane, L., Mbuagbaw, L., Liu, A., Levine, M. A., et al. (2015). Effect of
green tea supplementation on blood pressure among overweight and obese adults:
A systematic review and meta-analysis. Journal of Hypertension, 33, 243–254.
Madhan, B., Subramanian, V., Rao, J. R., Nair, B. U., & Ramasami, T. (2005). Stabilization
of collagen using plant polyphenol: Role of catechin. International Journal of Biological Mac-
romolecules, 37, 47–53.
Manach, C., Williamson, G., Morand, C., Scalbert, A., & Remesy, C. (2005). Bioavailability
and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies.
American Journal of Clinical Nutrition, 81, S230–S242.
Martı́nez-González, M. A., Garcı́a-Arellano, A., Toledo, E., Salas-Salvadó, J., Buil-
Cosiales, P., Corella, D., et al. (2012). A 14-item mediterranean diet assessment tool
and obesity indexes among high-risk subjects: The PREDIMED trial. PLoS One, 7,
e43134.
Maruo, S., Kuriyama, I., Kuramochi, K., Tsubaki, K., Yoshida, H., & Mizushina, Y. (2011).
Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity,
cancer cell growth and inflammatory response. Bioorganic and Medicinal Chemistry, 19,
5803–5812.
McAnlis, G. T., McEneny, J., Pearce, J., & Young, I. S. (1999). Absorption and antioxidant
effects of quercetin from onions, in man. European Journal of Clinical Nutrition, 53, 92–96.
Mellou, F., Loutrari, H., Stamatis, H., Roussos, C., & Kolisis, F. N. (2006). Enzymatic ester-
ification of flavonoids with unsaturated fatty acids: Effect of the novel esters on vascular
endothelial growth factor release from K562 cells. Process Biochemistry, 41, 2029–2034.
Miranda, A. M., Steluti, J., Fisberg, R. M., & Marchioni, D. M. (2016). Dietary intake and
food contributors of polyphenols in adults and elderly adults of Sao Paulo: A population-
based study. British Journal of Nutrition, 115, 1061–1070.
Mitjavila, M. T., & Moreno, J. J. (2012). The effects of polyphenols on oxidative stress and
the arachidonic acid cascade. Implications for the prevention/treatment of high preva-
lence diseases. Biochemical Pharmacology, 84, 1113–1122.
Molinar-Toribio, E., Ramos-Romero, S., Fuguet, E., Taltavull, N., Mendez, L.,
Romeu, M., et al. (2017). Influence of omega-3 PUFAs on the metabolism of
proanthocyanidins in rats. Food Research International, 97, 133–140.
Mozafari, M. R., Johnson, C., Hatziantoniou, S., & Demetzos, C. (2008). Nanoliposomes
and their applications in food nanotechnology. Journal of Liposome Research, 18, 309–327.
Mullen, W., Edwards, C. A., Serafini, M., & Crozier, A. (2008). Bioavailability of
pelargonidin-3-O-glucoside and its metabolites in humans following the ingestion of
strawberries with and without cream. Journal of Agricultural and Food Chemistry, 56,
713–719.
Novgorodtseva, T. P., Kantur, T. A., Karaman, Y. K., Antonyuk, M. V., & Zhukova, N. V.
(2011). Modification of fatty acids composition in erythrocytes lipids in arterial hyper-
tension associated with dyslipidemia. Lipids in Health and Disease, 10, 18.
Nunes, C., Almeida, L., & Laranjinha, J. (2008). 3,4-Dihydroxyphenylacetic acid (DOPAC)
modulates the toxicity induced by nitric oxide in PC-12 cells via mitochondrial dys-
functioning. Neurotoxicology, 29, 998–1007.
Nunes, C., Barbosa, R. M., Almeida, L., & Laranjinha, J. (2011). Nitric oxide and DOPAC-
induced cell death: From GSH depletion to mitochondrial energy crisis. Molecular and
Cellular Neuroscience, 48, 94–103.
O’Connor, S., Chouinard-Castonguay, S., Gagnon, C., & Rudkowska, I. (2017). Prebiotics
in the management of components of the metabolic syndrome. Maturitas, 104, 11–18.
Ortega, N., Reguant, J., Romero, M. P., Macià, A., & Motilva, M. J. (2009). Effect of fat
content on the digestibility and bioaccessibility of cocoa polyphenol by an in vitro diges-
tion model. Journal of Agricultural and Food Chemistry, 57, 5743–5749.
Oszmia nski, J., & Wojdylo, A. (2005). Aronia melanocarpa phenolics and their antioxidant
activity. European Food Research and Technology, 221, 809–813.
Ottaviani, J. I., Borges, G., Momma, T. Y., Spencer, J. P., Keen, C. L., Crozier, A., et al.
(2016). The metabolome of [2-(14)C](-)-epicatechin in humans: Implications for the
assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci-
entific Reports, 6, 29034.
Ozeki, Y., Matsuba, Y., Abe, Y., Umemoto, N., & Sasaki, N. (2011). Pigment biosynthesis.
I. Anthocyanins. In A. Ashihara, A. Crozier, & A. Komamine (Eds.), Plant metabolism and
biotechnology (pp. 155–181). Chichester, UK: Wiley.
Paini, M., Daly, S. R., Aliakbarian, B., Fathi, A., Tehrany, E. A., Perego, P., et al. (2015). An
efficient liposome based method for antioxidants encapsulation. Colloids and Surfaces. B,
Biointerfaces, 136, 1067–1072.
Parsaeyan, N., Mozaffari-Khosravi, H., & Mozayan, M. R. (2012). Effect of pomegranate
juice 2295 on paraoxonase enzyme activity in patients with type 2 diabetes. Journal of
Diabetes and Metabolic Disorders, 11, 11.
Pekkinen, J., Rosa, N. N., Savolainen, O. I., Keski-Rahkonen, P., Mykk€anen, H.,
Poutanen, K., et al. (2014). Disintegration of wheat aleurone structure has an impact
on the bioavailability of phenolic compounds and other phytochemicals as evidenced
by altered urinary metabolite profile of diet-induced obese mice. Nutrition and Metabo-
lism, 11, 1–15.
Perez-Jimenez, J., Fezeu, L., Touvier, M., Arnault, N., Manach, C., Hercberg, S., et al.
(2011). Dietary intake of 337 polyphenols in French adults. American Journal of Clinical
Nutrition, 93, 1220–1228.
Petzke, K. J., Schuppe, S., Rohn, S., Rawel, H. M., & Kroll, J. (2005). Chlorogenic acid
moderately decreases the quality of whey proteins in rats. Journal of Agricultural and Food
Chemistry, 53, 3714–3720.
Piñeiro-Corrales, G., Lago Rivero, N., & Culebras-Fernández, J. M. (2013). Role of
omega-3 fatty acids in cardiovascular disease prevention. Nutrición Hospitalaria, 28, 1–5.
Pinto, P., & Santos, C. N. (2017). Worldwide (poly)phenol intake: Assessment methods and
identified gaps. European Journal of Nutrition, 56, 1393–1408.
Possemiers, S., Bolca, S., Verstraete, W., & Heyerick, A. (2011). The intestinal microbiome:
A separate organ inside the body with the metabolic potential to influence the bioactivity
of botanicals. Fitoterapia, 82(1), 53–66.
Queipo-Ortuño, M. I., Boto-Ordóñez, M., Murri, M., Gomez-Zumaquero, J. M.,
Clemente-Postigo, M., Estruch, R., et al. (2012). Influence of red wine polyphenols
and ethanol on the gut microbiota ecology and biochemical biomarkers. American Journal
of Clinical Nutrition, 95, 1323–1334.
Rashidinejad, A., Birch, E. J., Hindmarsh, J., & Everett, D. W. (2017). Molecular interac-
tions between green tea catechins and cheese fat studied by solid-state nuclear magnetic
resonance spectroscopy. Food Chemistry, 215, 228–234.
Rashidinejad, A., Birch, E. J., Sun-Waterhouse, D., & Everett, D. W. (2017). Addition of
milk to tea infusions: Helpful or harmful? Evidence from in vitro and in vivo studies on
antioxidant properties. Critical Reviews in Food Science and Nutrition, 57, 3188–3196.
Rawel, H. M., Czajka, D., Rohn, S., & Kroll, J. (2002). Interactions of different phenolic
acids and flavonoids with soy proteins. International Journal of Biological Macromolecules,
30, 137–150.
Reboredo-Rodrı́guez, P., Figueiredo-González, M., González-Barreiro, C., Simal-Gándara, J.,
Salvador, M. D., Cancho-Grande, B., et al. (2017). State of the art on functional virgin
olive oils enriched with bioactive compounds and their properties. International Journal of
Molecular Sciences, 18, pii: E668.
Ribnicky, D. M., Roopchand, D. E., Poulev, A., Kuhn, P., Oren, A., Cefalu, W. T., et al.
(2014). Artemisia dracunculus L. polyphenols complexed to soy protein show enhanced
bioavailability and hypoglycemic activity in C57BL/6 mice. Nutrition, 30, S4–S10.
Rice-Evans, C., Miller, M., & Paganga, G. (1997). Antioxidant properties of phenolic com-
pounds. Trends in Plant Science, 2, 152–159.
Rodriguez-Mateos, A., Heiss, C., Borges, G., & Crozier, A. (2014). Berry (poly)phenols and
cardiovascular health. Journal of Agricultural and Food Chemistry, 62, 3842–3851.
Rodriguez-Mateos, A., Vauzour, D., Krueger, C. G., Shanmuganayagam, D., Reed, J.,
Calani, L., et al. (2014). Bioavailability, bioactivity and impact on health of dietary fla-
vonoids and related compounds: An update. Archives of Toxicology, 88, 1803–1853.
Rodriguez-Proteau, R., Mata, J. E., Miranda, C. L., Fan, Y., Brown, J. J., & Buhler, D. R.
(2006). Plant polyphenols and multidrug resistance: Effects of dietary flavonoids on drug
transporters in Caco-2 and MDCKII-MDR1 cell transport models. Xenobiotica, 36,
41–58.
Rohn, S., Rawel, H. M., & Kroll, J. (2002). Inhibitory effects of plant phenols on the activity
of selected enzymes. Journal of Agricultural and Food Chemistry, 50, 3566–3571.
Sahebkar, A., Serban, C., Ursoniu, S., Wong, N. D., Muntner, P., Graham, I. M., et al.
(2015). Lipid and blood pressure meta-analysis collaboration group. Lack of efficacy
of resveratrol on C-reactive protein and selected cardiovascular risk factors—Results
from a systematic review and meta-analysis of randomized controlled trials. International
Journal of Cardiology, 189, 47–55.
Sahoo, N., Sahoo, R. K., Biswas, N., Guha, A., & Kuotsu, K. (2015). Recent advancement
of gelatin nanoparticles in drug and vaccine delivery. International Journal of Biological Mac-
romolecules, 81, 317–331.
Saura-Calixto, F. (2011). Dietary fiber as a carrier of dietary antioxidants: An essential phys-
iological function. Journal of Agricultural and Food Chemistry, 59, 43–49.
Savikin, K., Menkovic, N., Zdunic, G., Pljevljakušic, D., Spasic, S., Kardum, N., et al.
(2014). Dietary supplementation with polyphenol-rich chokeberry juice improves skin
morphology in cellulite. Journal of Medicinal Food, 17, 582–587.
Scalbert, A., Manach, C., Morand, C., Remesy, C., & Jimenez, L. (2005). Dietary polyphe-
nols and the prevention of diseases. Critical Reviews in Food Science and Nutrition, 45,
287–306.
Schramm, D. D., Karim, M., Schrader, H. R., Holt, R. R., Kirkpatrick, N. J.,
Polagruto, J. A., et al. (2003). Food effects on the absorption and pharmacokinetics of
cocoa flavanols. Life Sciences, 73, 857–869.
Semova, I., Carten, J. D., Stombaugh, J., Mackey, L. C., Knight, R., Farber, S. A., et al.
(2012). Microbiota regulate intestinal absorption and metabolism of fatty acids in the
zebrafish. Cell Host & Microbe, 12, 277–288.
Sen, T., Cawthon, C. R., Ihde, B. T., Hajnal, A., DiLorenzo, P. M., de La Serre, C. B., et al.
(2017). Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity.
Physiology and Behavior, 173, 305–317.
Serra, A., Macià, A., Romero, M. P., Valls, J., Blade, C., Arola, L., et al. (2010). Bioavail-
ability of procyanidin dimmers and trimers and food matrix effect in in vitro and in vivo
models. British Journal of Nutrition, 103, 944–952.
Shang, J., Chen, L. L., Xiao, F. X., Sun, H., Ding, H. C., & Xiao, H. (2008). Resveratrol
improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase.
Acta Pharmacologica Sinica, 29, 698–706.
Sheflin, A. M., Melby, C. L., Carbonero, F., & Weir, T. L. (2017). Linking dietary patterns
with gut microbial composition and function. Gut Microbes, 8, 113–129.
Sheflin, A. M., Whitney, A. K., & Weir, T. L. (2014). Cancer-promoting effects of microbial
dysbiosis. Current Oncology Reports, 16, 406.
Shinohara, K., Ohashi, Y., Kawasumi, K., Terada, A., & Fujisawa, T. (2010). Effect of apple
intake on fecal microbiota and metabolites in humans. Anaerobe, 16, 510–515.
Shishikura, Y., Khokhar, S., & Murray, B. S. (2006). Effects of tea polyphenols on emulsi-
fication of olive oil in a small intestine model system. Journal of Agricultural and Food Chem-
istry, 54, 1906–1913.
Shpigelman, A., Israeli, G., & Livney, Y. D. (2010). Thermally-induced protein polyphenol
co-assemblies: Beta lactoglobulin-based nanocomplexes as protective nanovehicles for
EGCG. Food Hydrocolloids, 24, 735–743.
Shrime, M. G., Bauer, S. R., McDonald, A. C., Chowdhury, N. H., Coltart, C. E., &
Ding, E. L. (2011). Flavonoid-rich cocoa consumption affects multiple cardiovascular risk
factors in a 2411 meta-analysis of short-term studies. Journal of Nutrition, 141, 1982–1988.
Simeonov, S. B., Botushanov, N. P., Karahanian, E. B., Pavlova, M. B., Husianitis, H. K., &
Troev, D. M. (2002). Effects of Aronia melanocarpa juice as part of the dietary regimen
in patients with diabetes mellitus. Folia Medica, 44, 20–23.
Simões, C. D., Maukonen, J., Kaprio, J., Rissanen, A., Pietil€ainen, K. H., & Saarela, M.
(2013). Habitual dietary intake is associated with stool microbiota composition in mono-
zygotic twins. Journal of Nutrition, 143, 417–423.
Simopoulos, A. P. (2006). Evolutionary aspects of diet, the omega-6/omega-3 ratio and
genetic variation: Nutritional implications for chronic diseases. Biomedicine and Pharma-
cotherapy, 60, 502–507.
Simopoulos, A. P. (2013). Dietary omega-3 fatty acid deficiency and high fructose intake in
the development of metabolic syndrome, brain metabolic abnormalities, and non-
alcoholic fatty liver disease. Nutrients, 5, 2901–2923.
Singhal, A., Jain, H., Singhal, V., Elias, E. J., & Showkat, A. (2011). Colon-targeted quer-
cetin delivery using natural polymer to enhance its bioavailability. Pharmacognosy
Research, 3, 35–39.
Skoczynska, A., Jedrychowska, I., Poreba, R., Affelska-Jercha, A., Turczyn, B.,
Wojakowska, A., et al. (2007). Influence of chokeberry juice on arterial blood pressure
and lipid parameters in men with mild hypercholesterolemia. Pharmacological Reports, 59,
177S–182S.
Stalmach, A., Williamson, G., & Crozier, A. (2014). Impact of dose on the bioavailability of
coffee chlorogenic acids in humans. Food & Function, 5, 1727–1737.
Taguchi, C., Fukushima, Y., Kishimoto, Y., Suzuki-Sugihara, N., Saita, E., Takahashi, Y.,
et al. (2015). Estimated dietary polyphenol intake and major food and beverage sources
among elderly Japanese. Nutrients, 7, 10269–10281.
Takahashi, A., Okazaki, Y., Nakamoto, A., Watanabe, S., Sakaguchi, H., Tagashira, Y., et al.
(2014). Dietary anthocyanin-rich Haskap phytochemicals inhibit postprandial hyperlip-
idemia and hyperglycemia in rats. Journal of Oleo Science, 63, 201–209.
Thimothe, J., Bonsi, I. A., Padilla-Zakour, O. I., & Koo, H. (2007). Chemical characteri-
zation of red wine grape (Vitis vinifera and vitis interspecific hybrids) and pomace phe-
nolic extracts and their biological activity against streptococcus mutans. Journal of
Agricultural and Food Chemistry, 55, 10200–10207.
Tresserra-Rimbau, A., Medina-Remón, A., Perez-Jimenez, J., Martı́nez-González, M. A.,
Covas, M. I., Corella, D., et al. (2013). Dietary intake and major food sources of poly-
phenols in a Spanish population at high cardiovascular risk: The PREDIMED study.
Nutrition, Metabolism, and Cardiovascular Diseases, 23, 953–959.
Tuck, K. L., Freeman, M. P., Hayball, P. J., Stretch, G. L., & Stupans, I. (2001). The in vivo fate
of hydroxytyrosol and tyrosol, antioxidant phenolic constituents of olive oil, after intrave-
nous and oral dosing of labeled compounds to rats. Journal of Nutrition, 131, 1993–1996.
Tzounis, X., Rodriguez-Mateos, A., Vulevic, J., Gibson, G. R., Kwik-Uribe, C., &
Spencer, J. P. (2011). Prebiotic evaluation of cocoa-derived flavanols in healthy humans
by using a randomized, controlled, double-blind, crossover intervention study. American
Journal of Clinical Nutrition, 93, 62–72.
Valdes, L., Cuervo, A., Salazar, N., Ruas-Madiedo, P., Gueimonde, M., & González, S.
(2015). The relationship between phenolic compounds from diet and microbiota:
Impact on human health. Food & Function, 6, 2424–2439.
van Duynhoven, J., Vaughan, E. E., van Dorsten, F., Gomez-Roldan, V., de Vos, R.,
Vervoort, J., et al. (2013). Interactions of black tea polyphenols with human gut micro-
biota: Implications for gut and cardiovascular health. American Journal of Clinical Nutrition,
98, 1631S–1641S.
Vauzour, D., Rodriguez-Mateo, A., Corona, G., Oruna-Concha, M. J., & Spencer, J. P. E.
(2010). Polyphenols and human health: Prevention of disease and mechanisms of action.
Nutrients, 2, 1106–1131, 3.
Vendrame, S., Guglielmetti, S., Riso, P., Arioli, S., Klimis-Zacas, D., & Porrini, M. (2011).
Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the
human gut. Journal of Agricultural and Food Chemistry, 59, 12815–12820.
Vogiatzoglou, A., Mulligan, A. A., Lentjes, M. A., Luben, R. N., Spencer, J. P.,
Schroeter, H., et al. (2015). Flavonoid intake in European adults (18 to 64 years). PLoS
One, 10, e0128132.
Von Staszewski, M., Jara, F. L., Ruiz, A. L. T. G., Jagus, R. J., Carvalho, J. E., &
Pilosof, A. M. R. (2012). Nanocomplex formation between b-lactoglobulin or
caseinomacropeptide and green tea polyphenols: Impact on protein gelation and poly-
phenols antiproliferative activity. Journal of Functional Foods, 4, 800–809.
Wainstein, J., Ganz, T., Boaz, M., Bar Dayan, Y., Dolev, E., Kerem, Z., et al. (2012). Olive
leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats. Journal of
Medicinal Food, 15, 605–610.
Wang, Y., Liu, J., Chen, F., & Zhao, G. (2013). Effects of molecular structure of polyphenols
on their noncovalent interactions with oat b-glucan. Journal of Agricultural and Food Chem-
istry, 61, 4533–4538.
Wegrzyn, T. F., Farr, J. M., Hunter, D. C., Au, J., Wohlers, M. W., Skinner, M. A., et al.
(2008). Stability of antioxidants in an apple polyphenol-milk model system. Food Chem-
istry, 109, 310–318.
Willemsen, L. E., Koetsier, M. A., Balvers, M., Beermann, C., Stahl, B., & van Tol, E. A.
(2008). Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4
mediated permeability in vitro. European Journal of Nutrition, 47, 183–191.
Wu, G. D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y. Y., Keilbaugh, S. A., et al.
(2011). Linking long-term dietary patterns with gut microbial enterotypes. Science,
334, 105–108.
Wu, Y., Lin, Q., Chen, Z., & Xiao, H. (2011). The interaction between tea polyphenols and
rice starch during gelatinization. Food Science and Technology International, 17, 569–577.
Xie, Y., Kosinska, A., Xu, H., & Andlauer, W. (2013). Milk enhances intestinal absorption of
green tea catechins in in vitro digestion/Caco-2 cells model. Food Research International,
53, 793–800.
Xue, J., Tan, C., Zhang, X., Feng, B., & Xia, S. (2014). Fabrication of epigallocatechin-3-
gallate nanocarrier based on glycosylated casein: Stability and interaction mechanism.
Journal of Agricultural and Food Chemistry, 62, 4677–4684.
Yamakoshi, J., Tokutake, S., Kikuchi, M., Kubota, Y., Konishi, H., & Mitsuoka, T. (2001).
Effect of proanthocyanidin-rich extract from grape seeds on human fecal flora and fecal
odor. Microbial Ecology in Health and Disease, 13, 25–31.
Yamashita, Y., Okabe, M., Natsume, M., & Ashida, H. (2012). Comparison of anti-
hyperglycemic activities between low- and high-degree of polymerization procyanidin
fractions from cacao liquor extract. Journal of Food and Drug Analysis, 20, 283–288.
Yan, Y., Hu, J., & Yao, P. (2009). Effects of casein, ovalbumin, and dextran on the astrin-
gency of tea polyphenols determined by quartz crystal microbalance with dissipation.
Langmuir, 25, 397–402.
Zamora-Ros, R., Knaze, V., Rothwell, J. A., Hemon, B., Moskal, A., Overvad, K., et al.
(2016). Dietary polyphenol intake in Europe: The European prospective investigation
into cancer and nutrition (EPIC) study. European Journal of Nutrition, 55, 1359–1375.
Zern, T. L., West, K. L., & Fernandez, M. L. (2003). Grape polyphenols decrease plasma
triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs.
Journal of Nutrition, 133, 2268–2272.
Zhang, Y. B., Chen, W. H., Guo, J. J., Fu, Z. H., Yi, C., Zhang, M., et al. (2013). Soy iso-
flavone supplementation could reduce body weight and improve glucose metabolism in
non-Asian postmenopausal women—A meta-analysis. Nutrition, 29, 8–14.
Zhao, Y., Asimi, S., Wu, K., Zheng, J., & Li, D. (2015). Black tea consumption and serum
cholesterol concentration: Systematic review and meta-analysis of randomized con-
trolled trials. Clinical Nutrition, 34, 612–619.
Zhong, Y., Chiou, Y. S., Pan, M. H., Ho, C. T., & Shahidi, F. (2012). Protective effects of
epigallocatechin gallate (EGCG) derivatives on azoxymethane-induced colonic carcino-
genesis in mice. Journal of Functional Foods, 4, 323–330.
Zhong, Y., Chiou, Y. S., Pan, M. H., & Shahidi, F. (2012). Anti-inflammatory activity of
lipophilic epigallocatechin gallate (EGCG) derivatives in LPS-stimulated murine macro-
phages. Food Chemistry, 134, 742–748.
Zhu, B., Wang, X., & Li, L. (2010). Human gut microbiome: The second genome of human
body. Protein & Cell, 1, 718–725.
Zujko, M. E., Witkowska, A. M., Waskiewicz, A., & Sygnowska, E. (2012). Estimation of
dietary intake and patterns of polyphenol consumption in Polish adult population.
Advances in Medical Sciences, 57, 375–384.

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CHAPTER THREE

Polyphenols and Their

(Rice-Evans, Miller, & Paganga, 1997). Besides their direct antioxidant

2. PHENOLIC COMPOUNDS AS PART OF THE

C6–C3–C6 structure, and nonflavonoids. The flavonoids of dietary rele-

different parts of the world. According to literature data, polyphenols’ intake

3. BIOAVAILABILITY OF PHENOLIC COMPOUNDS:

circulation, polyphenols may undergo the phase II of metabolism, which

3.1 Role of Microbiota in Metabolism of Polyphenols

4. INTERACTIONS OF POLYPHENOLS WITH OTHER

4.1 Interactions of Polyphenols With Food Proteins

may prevent dental caries formation. This effect is based on polyphenols’

4.2 Interactions of Polyphenols With Food Lipids

4.3 Interactions of Polyphenols With Food Carbohydrates

5. INTERACTIONS OF POLYPHENOLS WITH

5.2 Impact of Proteins on Polyphenols’ Bioavailability

5.2.1 Proteins as Carriers of Polyphenols

5.3 Polyphenols’ Impact on Metabolism of Fats and Fatty Acids

as well as decreased accumulation in aorta, indicating the antiatherosclerotic

5.3.1 Impact of Polyphenols on Fats’ Emulsification and Absorption

amounts of polyphenols (Del Rio et al., 2010). The capture of polyphenols

5.4 Impact of Lipids on Absorption of Polyphenols

5.4.1 Liposomes as Carriers of Polyphenols

subclass in liposomes by ultrasound sonication, as a method for obtaining

5.5 Polyphenols’ Impact on Metabolism of Carbohydrates

5.6 The Impact of Carbohydrates on Polyphenols’

naturally colonizing intestines. Transport of polyphenols to the colon could

5.6.1 Encapsulation of Polyphenols by Carbohydrates

6. INTERACTIONS OF POLYPHENOLS WITH OTHER

proinflammatory mediators’ synthesis. For instance, mixture of EGCG and

6.1 Impact of Poylphenols on Cardiovascular Health

6.2 Interactions of Poylphenols With Lipids and Proteins

compound. Phospholipids are polar, ionic molecules composed of 1,2-

polyphenols concentrated in exterior layer of membranes, while they did

6.2.1 Impact of Polyphenols on Membrane Fatty Acid Profile:

considered to be a valuable indicator of risk of coronary heart disease devel-

pomegranate juice consumption can influence fatty acid composition and

7. INTESTINAL MICROBIOTA AND ITS ROLE IN

7.1 Interactions Between Gut Microbiota and Macronutrients

influence enterohepatic circulation of bile acids, and absorption of fats in

7.2 Interactions Between Gut Microbiota and Polyphenols

Furthermore, Shinohara, Ohashi, Kawasumi, Terada, and Fujisawa (2010)

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