Potential of Plant Polyphenols To Combat Oxidative Stress Andinflammatory Processes in Farm Animals

DOI: 10.1111/jpn.
12579
REVIEW ARTICLE
Potential of plant polyphenols to combat oxidative stress and

inflammatory processes in farm animals
D. K. Gessner, R. Ringseis and K. Eder
Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Giessen, Germany
Summary
Polyphenols are secondary plant metabolites which have been shown to exert antioxidative and antiinflamma
tory effects in cell culture, rodent and human studies. Based on the fact that conditions of oxidative stress and
inflammation are highly relevant in farm animals, polyphenols are considered as promising feed additives in the
nutrition of farm animals. However, in contrast to many studies existing with model animals and humans,
potential antioxidative and antiinflammatory effects of polyphenols have been less investigated in farm animals
so far. This review aims to give an overview about potential antioxidative and antiinflammatory effects in farm
animals. The first part of the review highlights the occurrence and the consequences of oxidative stress and
inflammation on animal health and performance. The second part of the review deals with bioavailability and
metabolism of polyphenols in farm animals. The third and main part of the review presents an overview of the
findings from studies which investigated the effects of polyphenols of various plant sources in pigs, poultry and
cattle, with particular consideration of effects on the antioxidant system and inflammation.
Keywords inflammation, pig, poultry, cattle, immune response, metabolism
Correspondence K. Eder, Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universit€at Giessen, Heinrich-Buff-Ring 26-32, 35392
Giessen, Germany. Tel: +49 641 9939230; Fax: +49 641 9939239; E-mail: klaus.eder@ernaehrung.uni-giessen.de
Received: 1 June 2016; accepted: 24 June 2016
2-related factor-2 (Nrf2) (Rahman et al., 2006; Sca-

Introduction
pagnini et al., 2011; Tangney and Rasmussen, 2013).
Since the ban of feed antibiotics by the EU in the In humans and experimental animal models, these
year of 2006, there is intensive search for feed addi- effects of plant polyphenols are well established. In
tives in farm animals which are able to maintain or contrast, in farm animals, the effects of plant
even improve animal health and animal perfor- polyphenols with respect to their antiinflammatory,
mance. Natural compounds produced by plants antioxidative and cytoprotective effects have been
might be relevant candidates in this respect. Plants less investigated so far. This study aims to give a
are producing a great variety of secondary metabo- comprehensive overview about effects of polyphe-
lites. Many of these secondary plant metabolites nols in farm animals with major emphasis on the
have been shown to exert a broad range of benefi- effect of polyphenols on inflammation and oxidative
cial effects on health in humans and rodent models stress, both of which are linked with each other. In
(e.g. Cornwell et al., 2004; Hooper et al., 2008; the first chapters, however, the role of oxidative
Lavecchia et al., 2013; Martin and Bolling, 2015). stress and inflammation in farm animals is high-
Among the great number of secondary plant lighted.
metabolites, the group of polyphenols might be most
promising due to its well-established antioxidative
Oxidative stress
and gene regulatory properties (Baur et al., 2006;
Chuang and McIntosh, 2011; Aguirre et al., 2014). Oxidative stress is known as the imbalance between
It has been well established that polyphenols are the formation of oxidants and their detoxification by
able to act antiinflammatory both in vitro and in vivo the antioxidant system and is traditionally recog-
by inhibiting the activation of nuclear factor kappa nized as detrimental to the body because it can
B (NF-jB) and to induce antioxidative and cytopro- cause damage to the cell constituents including
tective effects by inducing nuclear factor erythroid lipids, DNA, proteins and carbohydrates thus leading
Journal of Animal Physiology and Animal Nutrition 101 (2017) 605–628 © 2016 Blackwell Verlag GmbH 605
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Potential of plant polyphenols in farm animals D. K. Gessner, R. Ringseis and K. Eder
to tissue damage (Halliwell, 2007). Oxidants include laboratory animals, feeding a diet rich in oxidized
both radical and non-radical molecules, containing fatty acids also causes a strong reduction in plasma
either oxygen, nitrogen or chlorine, called reactive and tissue vitamin E concentrations and an increase
oxygen species (ROS), nitrogen or chlorine species in lipid peroxidation products in tissues (Liu and
respectively. The formation of oxidants can occur Huang, 1995; Eder et al., 2002; Keller et al., 2004).
during normal metabolism, for example superoxide Further dietary sources for the generation of oxidants
radicals are produced within the respiratory chain in are undesirable substances in food such as pesticides,
the mitochondria, during inflammatory reactions, for organic solvents or mycotoxins, because these com-
example superoxide radicals are formed by NADPH pounds induce the hepatic xenobiotic system gener-
oxidase from activated immune cells, and due to ating oxidants as by-products (Banerjee et al., 2001;
exogenous noxious agents, for example high con- Alpsoy and Yalvac, 2011).
centrations of free transition metals like iron and
copper which induce the formation of the highly
Link of oxidative stress with inflammation
reactive hydroxyl radicals from hydrogen peroxide
(Gutteridge, 1994). The antioxidant system, which is Oxidative stress is directly linked with inflammation
able to prevent oxidative stress through reducing the due to the fact that the above-mentioned oxidants are
formation and/or scavenging of oxidants, is com- activators of NF-jB, the key regulator of inflammation
prised of three components: (i) antioxidant enzymes, (Pantano et al., 2006). NF-jB is a protein complex
such as superoxide dismutase (SOD), glutathione which is present in almost all animal cell types and, in
peroxidase (GPX) and catalase (CAT); (ii) low molec- the inactive state, is bound to inhibitory proteins in
ular mass antioxidants, such as tocopherols (vitamin the cytosol. Upon stimulation by oxidants and several
E), ascorbic acid (vitamin C), carotenoids including other stimuli, such as cytokines, bacterial stimuli,
b-carotene, uric acid, glutathione, and polyphenols; viruses and ultraviolet radiation, the inhibitory pro-
and (iii) proteins that are able to sequestrate free teins are released from NF-jB which facilitates the
transition metals. The latter group of proteins active NF-jB to translocate into the nucleus and to
includes storage and transport proteins for metal activate the transcription of a large set of genes
ions, such as ferritin, ceruloplasmin and metalloth- involved in all aspects of inflammation (e.g. vasodila-
ionein (Halliwell, 1996). As amino acids and trace tion, chemotaxis, cell adhesion, leucocyte extravasa-
elements (copper, zinc, iron, selenium) are con- tion, phagocytosis). Thus, typical proteins encoded by
stituents of endogenous antioxidants (glutathione, NF-jB target genes are proinflammatory cytokines,
SOD, GPX, CAT) and different vitamins (thiamine, chemokines, inflammatory enzymes, adhesion mole-
riboflavin, niacin, folic acid) involved as coenzymes cules and various receptors (Hiscott et al., 1993;
in various antioxidant pathways, an inadequate sup- Barnes, 1997; Aggarwal, 2004). As several of the NF-
ply of these nutrients impairs the antioxidant jB-regulated proteins, such as cytokines and
defence system thereby inducing oxidative stress chemokines, stimulate the production of oxidants by
(Evans and Halliwell, 2001). activated neutrophils (respiratory burst) and in the
Oxidative stress can be induced by dietary factors, mitochondria, thereby, promoting oxidative stress, a
such as polyunsaturated fatty acids or oxidized fatty vicious cycle is triggered (Pillarisetti and Saxena,
acids representing an oxidative burden to the body 2004). If the vicious cycle cannot be broken due to
through the formation of lipid peroxidation products sustained and overwhelming production of oxidants,
and an increased consumption of endogenous the inflammatory process becomes chronic and the
antioxidants, in particular vitamin E. In broilers, for body0 s cells and tissues are damaged. This situation is
instance, it was observed that feeding a diet contain- the underlying cause of many chronic inflammatory
ing 6% linseed oil as a source of polyunsaturated disorders in humans, such as asthma, chronic obstruc-
fatty acids in combination with a low dietary vita- tive pulmonary disease, inflammatory bowel disease,
min E supply (15 mg vitamin E/kg diet) strongly rheumatoid arthritis and many others, also called free
depletes vitamin E and increases lipid peroxidation radical diseases (Ciz et al., 2012). However, such free
in tissues (Eder et al., 2005). Similarly, rats fed a radical diseases also occur in farm animals and exam-
diet with 10% fish oil in combination with a low ples are pneumonia, enteritis and sepsis in pigs, masti-
vitamin E supply (10 mg vitamin E/kg diet) had tis and pneumonia in ruminants and recurrent airway
increased levels of lipid peroxidation products and obstruction, exercise-induced pulmonary haemor-
markedly reduced levels of vitamin E in blood and rhage or joint disease in horses (Lykkesfeldt and
tissues (Ringseis and Eder, 2002). In pigs and different Svendsen, 2007).
606 Journal of Animal Physiology and Animal Nutrition 101 (2017) 605–628 © 2016 Blackwell Verlag GmbH
D. K. Gessner, R. Ringseis and K. Eder Potential of plant polyphenols in farm animals
a result of suppression of the cows’ own antioxidant

Role of physiological levels of oxidants for stress
and cytoprotective system. Thus, it can be summa-
adaptation
rized that the classic view of ROS as generally harmful
Besides the harmful effects of sustained and over- products that destroy cellular structures is regarded as
whelming production of oxidants, it has been recog- outdated, whereas physiological ROS levels should be
nized in recent years that low levels of oxidants have considered as protective by stimulating defence mech-
physiological functions for stress adaptation. This is anisms that prevent cellular damage.
explained by the role of many oxidants as signalling
molecules of important intracellular pathways. For
General significance of inflammation and its
instance, several oxidants are activators of stress-sen-
regulation
sitive transcription factors such as Nrf2 (Zhang and
Hannink, 2003). Upon activation of Nrf2 the expres- Inflammation is the normal, protective and usually
sion of a great number of genes involved in cytopro- temporary response of the innate immune system to
tection, such as the above-mentioned antioxidant pathogens or injury. It is typified by redness, swelling,
enzymes, several enzymes involved in the detoxifica- heat and pain. These responses occur as a result of
tion of xenobiotics, and antiinflammatory genes, is increased blood flow, increased permeability across
induced (Kim et al., 2010). Thus, physiological levels blood capillaries which increases the movement of
of oxidants are even useful for the adaptation of the leucocytes and large molecules (e.g. antibodies,
body to cellular stress due to improving defence and cytokines) from the blood into the surrounding tissue.
detoxification mechanisms. In line with this, it has The aim of inflammation is to induce immunological
been proven that moderate production of ROS in the processes to eliminate invading pathogens and toxins
mitochondria improves health and even extends the and to repair damaged tissue (Bertoni et al., 2009).
life span of different model organisms (C. elegans and Inflammation is triggered by the production of a broad
mice), a phenomenon that has been named mito- spectrum of cytokines, chemokines, adhesion mole-
chondrial hormesis or abbreviated mitohormesis (Yun cules, eicosanoids and complement proteins (Newton
and Finkel, 2014). For instance, sirtuins, a family of and Dixit, 2012). These molecules form complex regu-
histone deacetylases, were found to promote C. elegans latory networks to promote increased blood flow to
longevity through generating a mitohormetic ROS sig- the infected tissue, immune cell infiltration and acti-
nal, whereas this effect of sirtuins is blocked by vation, and systemic responses, including increased
antioxidants (Schmeisser et al., 2013). Moreover, body temperature, increased heart rate and decreased
studies in humans demonstrated that supplementa- appetite (Bradford et al., 2015). At the molecular
tion with high doses of vitamins C and E prevents the level, the inflammatory process is mainly regulated by
health-promoting effects, such as improvements of NF-jB, the above-mentioned key regulator of inflam-
antioxidant defence and insulin sensitivity, of physical mation. The NF-jB is activated by ROS, which
exercise, during which substantial amounts of ROS explains the mechanistic link between oxidative stress
are formed in skeletal muscle (Ristow et al., 2009). and inflammation, but also by viruses, bacterial tox-
This clearly indicates that ROS play an essential role ins, proinflammatory cytokines and many other stres-
for inducing health-promoting effects in the body. sors. Upon activation, NF-jB target genes, such as
Also in agreement with this view is that the vast proinflammatory cytokines, chemokines, inflamma-
majority of placebo-controlled intervention trials in tory enzymes, adhesion molecules and various recep-
humans failed to demonstrate any health improve- tors are induced (Vendrame and Klimis-Zacas, 2015).
ments in response to supplementation with high doses
of antioxidants (vitamin C, E and b-carotene)
Consequences of inflammation
(Fortmann et al., 2013; Grodstein et al., 2013). More-
over, according to meta-analyses of large human Hepatic acute-phase response
intervention trials, supplementation of antioxidants One important secondary response to inflammation
even increases overall mortality (Bjelakovic et al., is the acute-phase response (APR) which is mainly
2014). The biological concept of mitohormesis also triggered by proinflammatory cytokines such as
applies to farm animals as evidenced from a recent interleukin (IL)-6, tumour necrosis factor-a (TNF-a)
study with dairy cows showing that supplementation or IL-1b. APR is characterized by an increased pro-
with vitamin E during the dry period increases clinical duction of more than 200 acute-phase proteins
mastitis incidence post-partum through the induction (APP), mainly in the liver (Venteclef et al., 2011).
of oxidative stress (Bouwstra et al., 2010a,b), likely as APP play major roles in several aspects of systemic
reaction to inflammation, such as opsonization of been shown to inhibit the anabolic effects of insulin
pathogens, scavenging of toxic substances and the on skeletal muscle (Klasing and Johnstone, 1991).
overall regulation of different stages of inflammation The aim of both muscle protein degradation and inhi-
(Ceciliani et al., 2012). While the concentrations of bition of muscle protein synthesis is to supply the liver
APP such as haptoglobin, ceruloplasmin, serum amy- with amino acids available for the synthesis of APP.
loid A and C-reactive protein in the blood are very During inflammation, the uptake of amino acids into
low under healthy condition, their concentrations the liver is increased, and it has been suggested that at
are greatly elevated during systemic inflammation least 60% of the amino acids required for synthesis of
(Bradford et al., 2015). Therefore, concentrations of APP are deriving from proteolysis in skeletal muscle
APP have gained widespread acceptance as markers (Andus et al., 1991; Johnson, 1997). Amino acids
of inflammation (Ceciliani et al., 2012). While APP deriving from muscle are moreover utilized for gluco-
play a central role in restoring tissue homoeostasis neogenesis – a process which is stimulated by
during the early phase of inflammation, the produc- increased glucocorticoid secretion – to supply immune
tion of several other proteins typically secreted by cells with fuels. Many immune cells, such as neu-
the liver such as albumin, apolipoproteins, transfer- trophils and macrophages, rely heavily on glucose to
rin or retinol-binding protein is reduced during meet their increased metabolic demands during
inflammation. The downregulation of the hepatic inflammation (Bradford et al., 2015). An increased
synthesis of these proteins, which are denominated rate of lipolysis, induced by an increased secretion of
as negative APP, increases the pool of free amino catecholamines – a process that is also controlled in
acids which are utilized partially for gluconeogenesis the hypothalamus –, is another metabolic alteration
and the production of APP (Ceciliani et al., 2012). which aims to supply the body with metabolic fuels to
meet the extraordinary energetic costs of increasing
body temperature (fever) and expanding the immune
Hypothalamic inflammation
responses (Thaler et al., 2010).
The production of cytokines is not only important for One key event occurring during inflammation,
the regulation of immunological responses against which is negatively linked with animal performance,
pathogens or toxins. Cytokines have also profound is the induction of anorexia. Systemic inflammation,
effects on several metabolic pathways that are directly triggered for example by injection of lipopolysaccha-
linked with performance of farm animals. Recent rides (LPS), causes an activation of neurons that pro-
studies have shown that circulating cytokines and duce the anorexigenic peptides pro-opiomelanocortin
inflammatory mediators increase production and and cocaine- and amphetamine-regulated transcript,
release of cytokines within the mediobasal hypothala- while the secretion of the orexigenic agouti-related
mus, creating a paracrine inflammatory milieu which peptide and neuropeptide Y is reduced, overall leading
initiates alterations in the activity of neuronal popula- to a reduced appetite (Burfeind et al., 2015). Besides
tions that regulate appetite, body temperature and effects on the release of orexigenic and anorexigenic
metabolic programs controlling body mass and energy peptides in the brain, central cytokines moreover have
homeostasis (Burfeind et al., 2015). Metabolic alter- profound effects on gastrointestinal secretions and
ations that are regulated in the hypothalamus during motility. Changes in this respect resemble those of
a proinflammatory condition mainly aim to shift satiated animals, such as a decrease in gastric secretion
energy and amino acids away from stores towards or an inhibition of gastric motility (Johnson, 1997).
metabolic responses that support the immune system. The loss of appetite in sick animals is not a maladap-
In this respect, accelerated muscle protein degradation tive response or the effect of debilitation, but rather
is one key event. Increased proteolysis in skeletal an organized, evolved strategy that facilitates recov-
muscle during inflammation is mediated by an activa- ery. Systemic inflammation causes a shift of the
tion of the ubiquitin proteasome system (UPS). Recent anabolic–catabolic balance towards catabolism mean-
studies suggest that the activation of the UPS is mainly ing that animals have a lower requirement of energy
due to increased concentrations of glucocorticoids as a and nutrients for anabolic processes. Thus, anorexia in
result of the activation of the hypothalamic–pituitary sick animals can be considered as a means to avoid
axis in the brain during proinflammatory conditions intake of nutrients that are unusable in their current
(Karrow, 2006; Burfeind et al., 2015). Besides gluco- physiological state (Johnson, 1998). Indeed, it has
corticoids, cytokines such IL-1, IL-6 or TNF-a are able been shown that survival of infected animals is posi-
to directly activate the UPS in skeletal muscle (Bowen tively related to anorexia and weight loss, at least in
et al., 2015). Cytokines such as IL-1 moreover have the short term (Murray and Murray, 1979). An
overview of hormonal and metabolic changes trig- gain-to-feed ratio (Webel et al., 1997; Liu et al., 2003;
gered by inflammation is given in Fig. 1. Campos et al., 2014; Wyns et al., 2015). Increases of
plasma non-esterified fatty acids (NEFA) and urea
concentrations after LPS challenge are indicative of an
Consequences of inflammation on performance of
increased lipolysis in adipose tissue and an increased
farm animals
protein breakdown in muscle (Johnson, 1997).
The effects of systemic inflammation on performance In pigs, besides several diseases associated with sys-
of important farm animal species, such as pigs, poultry temic inflammation, the weaning phase represents
and cattle, have been mostly investigated by injection one important stage in which a local inflammation in
of LPS or proinflammatory cytokines. the small intestine is occurring, which is called wean-
ing-associated intestinal inflammation. This inflam-
mation is characterized by an increased production of
Effects of inflammation on performance of pigs
cytokines and adverse changes in intestinal morphol-
Several studies have shown that typical responses to ogy, including reduced villus height, increased villus
LPS challenge in pigs are reduced feed intake, increase width, increased crypt depth and reduced absorptive
in body temperature (fever), strong increases in the capacity and brush border enzyme activity
concentrations of proinflammatory cytokines, APP (McCracken et al., 1995, 1999; Pi e et al., 2004). It has
and cortisol and reduction in the plasma concentra- been originally suggested that these effects are mainly
tion of insulin-like growth factor (IGF)-1. Reduced due to a depressed feed intake (McCracken et al.,
feed intake, increased energy requirement for the pro- 1995, 1999). Recent studies, however, have shown
duction of fever and hormonal changes shift the meta- that gut function is adversely affected by an activation
bolism into a more catabolic state which results in of the hypothalamic–pituitary–adrenal axis which is
reduced body weight gains and an impairment of the caused by weaning stress conditions, including
Decreased feed Hypothalamic Increased energy

intake inflammation requirement
Activation of
Fig. 1 A simplified overview of the
Anorexia hypothalamic– Fever
hormonal and metabolic changes triggered by pituitary axis
inflammation. Local inflammation leads to the
production and release of cytokines which
directly stimulate proteolysis in muscle by an Cytokines
activation of the ubiquitin proteasome
system (UPS) and lipolysis in adipose tissue.
Local
Adrenal cortex Adrenal medulla
Cytokines produced in peripheral tissues are Inflammation
moreover able to induce inflammation in the
hypothalamus. Central inflammation leads to Cortisol Cytokines Cytokines Catecholamines
the induction of anorexia and the production of
fever and moreover causes activation of
the hypothalamic–pituitary axis. This in turn
stimulates the release of cortisol from the Protein degradation Lipolysis
adrenal cortex and catecholamines from the induced by UPS
adrenal medulla which enhances proteolysis in
Muscle Adipose tissue
muscle and lipolysis in adipose tissue. The
overall aim of these metabolic changes is (I) to
supply the liver with amino acids available for Loss of Fatty acids as Loss of
Amino acids
the production of acute-phase proteins (APP) muscle mass fuels for tissues fat mass
and the production of glucose utilized by
activated leucocytes and (II) to supply the body
with fatty acids as metabolic fuels for tissues in
Production of APP
a condition with an increased energy
Gluconeogenesis
requirement. Decreased feed intake, increased Blood circulation
energy requirement, loss of muscle and fat
mass are directly linked with a reduced Glucose supply
Liver for leucocytes
performance in farm animals.
psychosocial (maternal deprivation), immunological, feed intake, a reduction in body weight gain and an
infectious, metabolic and nutritional stress. Down- increase in the feed conversion ratio were typically
stream events of hypothalamic–pituitary–adrenal axis observed in broilers subjected to LPS injection (Korver
activation include an increased secretion of corti- et al., 1998; Shen et al., 2010; Tan et al., 2014). LPS
cotrophin-releasing factor and glucocorticoids, and an injection in broilers caused also a strong increase in
activation of intestinal mast cells, all of which might plasma concentration of cortisol, shifting the metabo-
be involved in disruption of the intestinal barrier lism in a more catabolic state (Shini et al., 2008).
(Smith et al., 2010; Pohl et al., 2015). The compro- Broilers injected with LPS moreover had increased rel-
mised intestinal barrier allows the passage of luminal ative weights (organ weight/body weight) of liver,
antigens into the lamina propria where an inflamma- spleen and intestine (Korver et al., 1998).
tory response can be initiated. Villus atrophy in this
stage might be caused by an activation of matrix met-
Effects of inflammation on performance of dairy cattle
alloproteinases which are induced by proinflamma-
tory cytokines (McCracken et al., 1999). A Several studies in the last years have shown that most
disturbance of the barrier integrity moreover favours of the high-yielding dairy cows experience a proin-
the transepithelial passage of micro-organisms and flammatory condition during the peripartal phase
thus promotes bacterial infections and diarrhoea. (Bertoni et al., 2008; Bradford et al., 2015). The
Noteworthy, adverse effects of weaning stress on gut proinflammatory condition is caused by various stim-
function are not limited to the weaning phase. Rather, uli, such as LPS, cytokines and ROS released in the
weaning stress triggers long-term defects in intestinal course of infectious diseases, such as mastitis or metri-
barrier function (Smith et al., 2010). Therefore, the tis (Bradford et al., 2015). Although this inflammation
weaning-associated intestinal inflammation process is is mostly of subclinical nature, it is of impact for health
negatively linked with health and growth perfor- and performance of cows during early lactation. Stud-
mance of piglets, and controlling this process is a chal- ies with dairy cows, which were subjected to systemic
lenge in managing post-weaning health and optimum inflammation induced by injection of either LPS or
growth performance (Pi e et al., 2004). proinflammatory cytokines, typically found a decrease
Recent studies have shown that lactation is another in food intake (Yuan et al., 2013) and a strong reduc-
metabolic condition which is associated with the tion in milk yield (Kushibiki et al., 2003; Trevisi et al.,
development of inflammation in the liver of pigs 2009; Yuan et al., 2013). In addition to the impair-
(Rosenbaum et al., 2012a,b). It is likely that the ment of animal0 s performance, it was reported that
induction of inflammation in the liver of lactating the induction of inflammation was associated with an
sows – which was also associated with the develop- increase in the concentration of NEFA as a result of
ment of stress of the endoplasmic reticulum (ER increased rate of lipolysis in adipose tissue and
stress), a condition triggered by inflammation – might increased concentration of b-hydroxybutyrate as a
be due to oxidative stress caused by the high meta- result of a stimulation of ketogenesis in the liver and
bolic activity or the occurrence of infectious diseases the development of a fatty liver (Trevisi et al., 2009;
such as mastitis or metritis which are commonly Bradford et al., 2015). Moreover, cows subjected to
observed in sows after parturition (Gessner et al., TNF-a-induced inflammation had an increased inci-
2015a,b). Physiological consequences of inflammatory dence of various diseases, such as ketosis, mastitis, res-
conditions in lactating sows have been less investi- piratory diseases, metritis and milk fever (Yuan et al.,
gated so far. However, with respect to animal welfare 2013). Conversely, inhibition of the proinflammatory
and performance, prevention of proinflammatory condition during the peripartal phase in dairy cows by
conditions in lactation sows should be given more early post-partum treatment with non-steroidal anti-
consideration. inflammatory drugs led to a significant increase in
milk yield over the whole lactation period and caused
a reduction in somatic cell count in milk being indica-
Effects of inflammation on performance of poultry
tive of an improved udder health (Carpenter et al.,
Like in pigs, LPS-induced systemic inflammation in 2016). According to these findings, investigations aim-
broilers commonly leads to a strong increase in the ing to prevent the proinflammatory condition during
production of various proinflammatory cytokines and the peripartal phase, either by optimization of feeding
to an increase in body temperature (De Boever et al., regimes pre-partum (Khan et al., 2015; Zhou et al.,
2009, 2010; Zhang et al., 2010; Shen et al., 2010). 2015; Vailati-Riboni et al., 2016) or by administration
With respect to animal performance, a decrease in of potential antiinflammatory feed supplements
(Gessner et al., 2015a,b; Hashemzadeh-Cigari et al., their oestrogen agonist and antagonist properties
2015; Winkler et al., 2015), are of great relevance. (Kitts et al., 1999). The last group of non-flavonoid-
type polyphenols are the stilbenoids, from which
resveratrol is the most famous compound due to its
Potential of plant polyphenols to combat oxidative
lifespan prolonging effects (Valenzano et al., 2006)
stress and inflammatory processes in farm animals
and which have two phenol rings connected by a two-
Structure and classes of polyphenols carbon methylene bridge.
Polyphenols are secondary plant metabolites synthe-
sized by plants to provide protection against invasive
Occurrence of polyphenols
pathogens, such as bacteria, viruses and fungi, and to
prevent damage to DNA and photosynthetic apparatus Polyphenolic compounds occur in almost all plants,
due to ultraviolet radiation. The polyphenols comprise but their distribution at the tissue level and the
a large group of more than 8000 different compounds cellular or subcellular level is not uniform. For
with the phenol ring being the common structural instance, the outer layers of plants contain higher
feature. According to the number of phenol rings and polyphenol levels than the inner layers or insol-
the structural elements that bind these rings to one uble polyphenolic compounds are associated with
another, the polyphenols can be divided into the fla- the cell wall, whereas soluble ones are found in
vonoid-type and the non-flavonoid-type polyphenols the cell vacuoles (Wink, 1997). Moreover, the con-
(Tangney and Rasmussen, 2013). centrations and the proportions of polyphenolic
The flavonoid-type polyphenols comprise the lar- compounds in plants are greatly affected by ripe-
gest group of polyphenols with more than 4000 com- ness at the time of harvest, edaphic factors such as
pounds identified and share as a common structure soil type, sun exposure, air temperature and rain-
two benzene rings connected by three carbon atoms fall, processing and storage (Manach et al., 2004).
forming an oxygenated heterocycle. Based on the type With regard to the latter, it can be generally stated
of the heterocycle, the following flavonoid subclasses that the concentration of polyphenolic compounds
can be distinguished: flavonols, flavones, flavan-3-ols, in plant material decreases with increasing storage
flavanones, anthocyanins and isoflavones (Beecher, time and when high temperatures are present dur-
2003). Examples of frequently studied flavonoids are ing storage and processing because of the high sus-
the flavonols quercetin and myricetin, the flavones ceptibility of polyphenols to oxidation. Collectively,
orientin, vitexin and homoorientin, the flavan-3-ols these factors explain that the concentrations and
catechin, epicatechin, epigallocatechin and their gal- the type of polyphenols vary greatly in plants and
late esters, the flavanone naringenin, the anthocyanin the plant products (e.g. extracts) manufactured
cyanidin and the isoflavones genistein and daidzein. from.
Isoflavones have an oestrogen-like structure and thus Typical polyphenol-rich plant materials are fruits,
are able to bind to oestrogen receptors (Uifalean et al., vegetables, leaves, legume seeds and beans. Corre-
2015). Almost all dietary flavonoids exist in glycosidic spondingly, humans regularly consuming black and
form, mostly in O-glycosidic form, but C-glycosylated green tea, tropical fruits and berries, spinach, onion,
flavonoids, particularly flavones, are also abundant in soybeans, fruit juices and wine have a high intake
plants (Xiao and Jiang, 2015). of polyphenols (Tangney and Rasmussen, 2013).
Phenolic acids, which comprise one group of non- Due to economic considerations, relevant sources
flavonoid-type polyphenols, are frequent in cereals of polyphenols for farm animals are agroindustrial
and can be subdivided into cinnamic acids, such as by-products from juice, wine and beer making, such
ferulic, caffeic, coumaric and sinapic acid, and the less as pomace, peels, seeds, stems and brewery waste,
abundant hydroxyl benzoic acids, such as gallic and and from processing of grains, seeds and nuts, such
vanillic acid. Typically, the cinnamic acids are bound as hulls (rice, buckwheat, almond) and husks
to arabinoxylans of the plant cell wall which impairs (coconut).
their bioavailability (Andreasen et al., 2001). A sec-
ond group of non-flavonoid-type polyphenols are the
Bioavailability of polyphenols in monogastric animals
lignans, which are also diphenolic compounds with a
1,4-diarylbutane structure formed by dimerization of The bioavailability of dietary compounds describes the
two cinnamic acid residues, and several representa- degree to which they become available in intact form
tives, such as secoisolariciresinol, pinoresinol and syr- to the target tissues following ingestion into the gas-
ingaresinol, are considered as phytoestrogens due to trointestinal tract. Generally it can be assumed that
the bioavailability of polyphenolic compounds from Moreover, it has to be pointed that there are large
the small intestine is very low. Based on estimations sex-related (Mugford and Kedderis, 1998; Renaud
from Faria et al. (2014), less than 5% to 10% of plant et al., 2011; Liu et al., 2013; Ruiz et al., 2013;
polyphenols are absorbed in the small intestine. This Dellinger et al., 2014; Prokopec et al., 2015) and spe-
is explained mainly by the fact that almost all cies-dependent (Matal et al., 2008; Yamazaki et al.,
polyphenols in plants exist as esters, glycosides or 2011; Helke and Swindle, 2013; Saengtienchai et al.,
polymers, and many polyphenols are associated with 2014) differences in xenobiotic metabolism which lar-
cell wall constituents, such as arabinoxylans, with gely explains that the spectrum of polyphenol
proteins or with other organic compounds such as metabolites, their tissue distribution and concentra-
organic acids and lipids (Andreasen et al., 2001; tions in blood following ingestion of polyphenols or
Bunzel et al., 2004). On the other hand, the capacity polyphenol mixtures can differ markedly between
for hydrolysis and liberation from the plant matrix, species and between males and females (Weinert
respectively, by either digestive or microbial enzymes et al., 2012; Margalef et al., 2016). This is a clear hin-
in the small intestine is generally limited due to either drance for the ability to transfer data from male-to-
lack of appropriate enzyme activity or the low micro- female animals and from one species to another one.
bial colonization. Enzymatic hydrolysis of esters and The large proportion of polyphenols, which passes
glycosides and the release from cell wall constituents through the small intestine without being absorbed
is a prerequisite step for the absorption of polyphenols (approximately 90% to 95% of ingested polyphenols;
because only the aglycones and few glycosides (e.g. Faria et al., 2014), together with conjugated polyphe-
mono- and diglucosides), but not more complex, poly- nol metabolites excreted from the liver via the bile
meric polyphenols can be absorbed in the small intes- enter the colon and are biotransformed with the help
tine (Murota et al., 2002; Cermak et al., 2003; Zubik of enzymatic activities of the colon microbiota to vari-
and Meydani, 2003; Manach et al., 2004). A further ous polyphenol metabolites. For instance, the conju-
reason for the low bioavailability of many polyphenols gated polyphenol metabolites excreted via the bile are
in target tissues following absorption is that polyphe- deconjugated by microbial glucuronidases and sul-
nolic compounds are recognized as xenobiotics by the phatases into their aglycones, which can be further
body0 s biotransformation system. Thus, polyphenols degraded by microbial enzymes leading to various
are extensively biotransformed by classic detoxifica- metabolites (Hein et al., 2008). In the case of
tion pathways (methylation, glucuronidation, sulpha- degradation of flavonols, flavones, flavanones and fla-
tion) in enterocytes and liver to a large number of van-3-ols, for instance, a large number of different
hydrophilic conjugated (methylated, glucuronidated metabolites, such as dihydroxyphenylacetic acids,
and sulphated) metabolites (Kuhnle et al., 2000; Vai- hydroxyphenylacetic acids, hydroxyphenylpropionic
dyanathan and Walle, 2002), which can partially acids, dihydroxybenzoic acid, trihydroxybenzoic acid,
reach blood and tissues, but are also rapidly excreted dihydroxyphenylethanol, dihydroxybenzaldehyde
via urine and bile (Hackman et al., 2008). As the phenylvalerolactones, phloroglucinol, hydrocaffeic
result of low absorption, extensive biotransformation acid, phloretic acid, benzoic acid, phenyllactic acid and
and excretion of metabolites, concentrations of vanillic acid, are formed (Meselhy et al., 1997; D eprez
polyphenols such as quercetin in plasma and tissues et al., 2000; Rechner et al., 2004; Hein et al., 2008).
after supplementation remain relatively low. Even The polyphenol metabolites in the colon can have
long-term supplementation of polyphenols does not different fates: one part is absorbed into the circulation
lead to an accumulation in plasma or tissues (Bieger after being conjugated once again in the enterocyte
et al., 2008; Reinboth et al., 2010). Moreover, the and the liver. Once absorbed into the circulation, the
diverse potential health benefits of polyphenols, such bioavailability of polyphenol metabolites in target tis-
as antiinflammatory, antioxidative, anticarcinogenic, sues depends on their binding affinity to albumin,
antiatherogenic and immunomodulatory effects, which was shown to differ according to the chemical
observed in studies with laboratory animals in structure of polyphenolic compounds (Dangles et al.,
response to isolated polyphenols and/or polyphenol 2001) and thus influences delivery of polyphenol
mixtures cannot be simply ascribed to the polyphenols metabolites to tissues and the rate of clearance from
themselves, but rather to their metabolites originating the circulation. Another part of polyphenol metabo-
from biotransformation. This is a significant limitation lites can serve as either growth-promoting substrates
for the ability to translate results from cell culture or antimicrobial substances for bacteria of the colon
studies, in which incubations were performed only microbiota. In this context it is worth mentioning that
with the parent compounds, to the in vivo situation. several studies have shown that polyphenol
metabolites can modulate the composition of the increasing following the administration of four differ-
colon microbiota in a desirable manner due to simul- ent polyphenol-rich plant extracts (rosemary, grape,
taneously promoting the growth of beneficial bacteria citrus, marigold) via a rumen cannula (Gladine et al.,
in a pre-biotic-like manner, while inhibiting that of 2007). Those studies indicate that at least a part of the
pathogenic bacteria (Axling et al., 2012; China et al., isoflavones present in the diet is protected against
2012; Queipo-Ortu~ no et al., 2012; Etxeberria et al., degradation in the rumen and is available in the small
2013, 2015; Moreno-Indias et al., 2016). This modula- intestine, the site of absorption of polyphenols.
tion of the colon microbiota is considered a key mech- Besides, few reports exist demonstrating that feeding
anism underlying the overall health-promoting effects polyphenol-enriched feeding rations to heifers modu-
of polyphenols, because the resulting eubiotic micro- lates several parameters of rumen fermentation (pH
biota contributes to gut health, intact gut barrier func- and concentration of fermentation products in rumen
tion, and a properly working intestinal immune fluid) and rumen bacterial community (Balcells et al.,
system, all of which are important to protect the ani- 2012; De Nardi et al., 2016). With regard to the latter,
mal from translocation of pathogens or other infec- it was reported in one study that feeding a flavonoid-
tious noxious into the circulation. The remaining part rich plant extract increases the numbers of lactate-
of non-absorbed and non-metabolized polyphenol consuming and propionate-producing bacteria (Bal-
metabolites is excreted via the faeces. A schematic cells et al., 2012) and in another study that a daily
illustration of absorption and metabolism of plant dose of a commercial polyphenol-essential oil mixture
polyphenols in farm animals is shown in Fig. 2. as part of a total mixed ration enhances the abun-
Summarizing the above, it can be stated that the dance of many taxa belonging to Bacteroidetes, Firmi-
bioavailability of plant polyphenols is critically influ- cutes and Tenericutes phyla (De Nardi et al., 2016).
enced by their chemical structure (e.g. glycosylation, These reports indicate that, such as in monogastrics,
esterification and polymerization) and associations the composition of the microbiota in the rumen of
with other plant cell constituents (fibre, protein). ruminants is modulated by plant polyphenols.
Correspondingly, the most abundant polyphenols in
plants or plant extracts are not necessarily those
Effects of polyphenols on oxidative stress and
with the highest bioavailability. A second important
inflammation in studies with farm animals
message is that the two-way interaction between
polyphenols and colon microbiota, meaning the bio- A large number of studies with either cell cultures
transformation of polyphenols by the gut microbiota (e.g. intestinal cells, immune cells, endothelial and
to polyphenol metabolites and the modulation of smooth muscle cells, adipocytes) or experimental ani-
microbiota composition by polyphenol metabolites, mal models of inflammation (intestinal inflammation,
is likely a key mechanism explaining many health- systemic inflammation associated with obesity, meta-
promoting effects of polyphenols. bolic syndrome and atherosclerosis) convincingly
demonstrated that isolated polyphenolic compounds
or polyphenol-rich plant extracts (e.g. green tea, hop,
Bioavailability of polyphenols in ruminants
cocoa, grape) suppress experimentally induced
In contrast to the great number of studies with mono- inflammation processes (Martın et al., 2004; Romier
gastric animals, studies on the bioavailability of et al., 2009; Biasi et al., 2011; Gonz
alez et al., 2011;
polyphenols in ruminants are very scarce. There are, Song et al., 2011; Gessner et al., 2012; Gupta et al.,
however, few studies which indicate that at least a 2014). Effects of polyphenols against inflammation
small part of polyphenols are absorbed from the diet are mediated by complex cellular mechanisms, most
in ruminants. Gohlke et al. (2013a) have recently of which are linked with an inhibition of NF-jB, the
shown that quercetin aglycon intraduodenally admin- master regulator of inflammation. Polyphenols are
istered in lactating dairy cows is absorbed at a rate able to block the activation of NF-jB by inhibiting
similar to that observed in pigs. In dairy cows, it has phosphorylation and proteasomal degradation of IjB,
moreover been shown that the administration of feed- an effect which is at least in part due to the antioxi-
stuffs rich in isoflavones (genistein, daidzein) such as dant properties of polyphenols (Vendrame and Kli-
soybean meal or red glover silage causes an increase mis-Zacas, 2015). Polyphenols are able to directly
in the concentrations of those isoflavones in blood scavenge ROS and moreover induce the activation of
and milk (H€ ojer et al., 2012; Cools et al., 2014). In Nrf2 which in turn leads to an activation of various
sheep, it was observed that concentrations of different antioxidant enzymes (Na and Surh, 2008). Both,
polyphenols, such as epicatechin, in plasma are direct scavenging of ROS and activation of Nrf2 helps
Dietary polyphenols Tissues

Polyphenol
metabolites
Liver
Species- and sex-specific
Small intestine biotransformation:
Hydrolysis of most glucuronidation,
Aglycones
glycosides by intestinal methylation,
Epithelial cells Biotransformation

enzymes sulphation
Polyphenol
metabolites
Absorption
(5-10 %)
Large intestine
Hydrolysis of glycosides
and deconjugation of
conjugated Kidney
polyphenol metabolites by Aglycones renal
microbial enzymes excretion
of
Pre-biotic effects
metabolites
Antimicrobial effects
Unabsorbed polyphenols and

polyphenol metabolites Polyphenol
metabolites
Faeces Urine
Fig. 2 Overview of absorption and metabolism of plant polyphenols in monogastric farm animals. In monogastric animals, a small part (5–10%) of
plant polyphenols, which mainly exist as esters, glycosides or polymers, becomes absorbed in the small intestine after being hydrolysed by either
digestive or microbial enzymes. Since polyphenols are recognized as xenobiotics by the body0 s biotransformation system, most polyphenols are exten-
sively biotransformed by classic detoxification pathways (methylation, glucuronidation, sulphation) in the enterocyte and the liver to a large number of
hydrophilic conjugated (methylated, glucuronidated and sulphated) metabolites, which can partially reach blood and tissues, but are also rapidly
excreted via urine and bile. The large proportion of polyphenols, which passes through the small intestine without being absorbed (approximately 90%
to 95% of ingested polyphenols), together with conjugated polyphenol metabolites excreted from the liver via the bile enter the colon and are biotrans-
formed and/or deconjugated with the help of enzymatic activities of the colon microbiota to various polyphenol metabolites. The polyphenol metabo-
lites in the colon can then be partially absorbed into the circulation after being conjugated once again in the enterocyte and the liver, partially serve
as either growth-promoting substrates (pre-biotic effect) or antimicrobial substances for bacteria of the colon microbiota and the remaining part of
non-absorbed and non-metabolized polyphenol metabolites is excreted via the faeces. In ruminants, plant polyphenols are hydrolysed and biotrans-
formed by enzymatic activities of the rumen microbiota and the resulting aglycones and polyphenol metabolites are partially absorbed through the
rumen epithelium. Non-absorbed polyphenols passing into the small intestine can be biotransformed like in monogastric animals.
to prevent the development of oxidative stress which activation of Nrf2, leading to the induction of so-called
triggers proinflammatory pathways by activating NF- vitagenes, such as genes encoding antioxidant
jB, mitogen-activated protein kinases and activating enzymes, biotransformation enzymes and heat-shock
protein 1 (Chuang and McIntosh, 2011). Moreover, proteins, thereby preserving cellular homeostasis dur-
polyphenols are able to activate transcription factors ing stressful conditions and conferring resistance to a
such as peroxisome proliferator-activated receptor c more severe stress (Calabrese et al., 2012). Due to
which is antagonizing inflammation by blocking NF- this, the stress-inducing phytochemicals not only pro-
jB activation (Chuang and McIntosh, 2011). A simpli- tect the cell against higher doses of the same agent,
fied overview of some key mechanisms by which but also against other agents or even less-specific
polyphenols prevent inflammation is shown in Fig. 3. stressors including oxidative, metabolic, inflamma-
The activation of Nrf2 by polyphenols is one exam- tory, and thermal stress (Son et al., 2008), all of which
ple of hormetic pathways which are typically activated play an important role in farm animals. Interestingly,
by polyphenols and many other phytochemicals. In the activation of the cytoprotective Nrf2 pathway in
the context of polyphenols, the hormesis concept response to such unspecific stressors like ROS and
states that high doses of certain polyphenols are toxic, reactive nitrogen species stimulates autophagy (Ishii
whereas subtoxic doses ingested by animals consum- et al., 2002), which is a conserved lysosomal ‘self-
ing plants induce mild cellular stress responses, like digestion’ pathway for the degradation of long-lived
Proinflammatory stimuli,
such as LPS, ROS,
viruses, cytokines Transrepression Polyphenols
of NF-κB
P P
IκBα
PPARγ
NF-κB
Inactive NF-κB
NF-κB
Nrf2
Proteasomal
degradation Active NF-κB
of IκBα
Nuclear
ROS Nuclear
translocation of
translocation of
active NF- κB
Nrf2
NF-κB – DNA Transcription of Transcription of

binding proinflammatory antioxidative
genes enzymes
NF-κB Nrf2
Fig. 3 A simplified overview of key mechanisms by which polyphenols prevent inflammation. Proinflammatory stimuli such as lipopolysaccharides
(LPS), reactive oxygen species (ROS), viruses or cytokines are activating nuclear factor kappa B (NF-jB), which is the central regulator of inflammation.
Activation occurs by phosphorylation and release of the inhibitory jB (IjB) subunit which is degraded by the proteasome. The activated NF-jB translo-
cates into the nucleus and initiates the transcription of a broad spectrum of proinflammatory genes. Polyphenols are able to block activation of NF-jB
directly by inhibition of the phosphorylation of IjB and by scavenging ROS. Moreover, polyphenols are able to inhibit activation of NF-jB in an indirect
manner, by activation of PPARc which causes transrepression of NF-jB and by activating nuclear factor erythroid 2-related factor (Nrf2). Nrf2, a redox-
sensitive transcription factor, stimulates the transcription of antioxidative enzymes which are helpful to eliminate ROS.
cellular proteins and organelles generating amino deposition, improves the lipid profile and glucose
acids, fatty acids and nucleotides which can be recy- metabolism and prevents the development of
cled for protein synthesis and ATP generation during atherosclerotic lesions in the aorta of pigs (Burgess
stressful conditions. Through this autophagic ‘self- et al., 2011; Azorın-Ortu~
no et al., 2012). Other stud-
cleaning’, the cell0 s ability to process damaged ies observed that resveratrol favourably influences risk
proteins, which can trigger apoptosis, and damaged factors for coronary heart disease and improves
mitochondria, a source of apoptotic proteins and toxic myocardial function in porcine models of metabolic
ROS, and to cope with the consequences of cellular syndrome and myocardial ischaemia (Robich et al.,
stress is enhanced (Lee et al., 2012). As consequence 2010; Burgess et al., 2011; Chu et al., 2011).
of the activation of autophagy by hormetic phyto- In contrast to studies with biomedical background,
chemicals, such as epigallocatechin gallate (Kim et al., the number of studies dealing with effects of
2013), but also by caloric restriction (Lempi€ ainen polyphenols on the antioxidant status and inflamma-
et al., 2013), oxidative stress, ER stress and inflammation in pigs as farm animal species is relatively lim-
tory stress are reduced thus making autophagy an ited, with more studies focusing on potential
important biological process contributing to cellular antioxidant effects of polyphenols. One of these stud-
and organismic health (Lee et al., 2012). ies has shown that supplementation of the flavonol
quercetin (at a level of 10 mg/kg body weight/day) is
able to increase plasma and liver concentrations of a-
tocopherol and reduce plasma lipid peroxidation
inflammation in studies with pigs
products in growing pigs fed fish oil in combination
There are several studies which considered the effects with a low dietary vitamin E supply (7 mg/kg diet)
of polyphenols on pathophysiological processes of var- (Luehring et al., 2011) indicating that quercetin
ious diseases in pigs as an animal model for humans. exerts a tocopherol-sparing effect at a low vitamin E
For instance, it has been shown that the stilbenoid intake. In pigs treated with subcutaneous LPS injec-
resveratrol or resveratrol-rich grape extract lowers fat tion, supplementation of the diet with ampelopsin (at
a level of 400 mg/kg diet), which is also known as seed and grape marc meal extract also caused an
dihydromyricetin, the most common flavonoid in dry increase in the villus height-to-crypt depth ratio, sug-
tender stems and leaves, ameliorated the antioxida- gesting that plant polyphenols could influence
tive capacity in plasma and lowered concentrations of intestinal microarchitecture in a beneficial manner.
malondialdehyde (MDA) in the liver (Hou et al., In another study, two polyphenol-rich plant extracts
2014). This study suggested that the flavonoid ampe- were used, either grape seed and grape marc meal
lopsin improves the antioxidative status in pigs extract or hop extract, both at dietary levels of 10 g/
subjected to inflammation and oxidative stress. In a kg diet. Both plant extracts were able to lower the
study with gilts which were treated with zear- expression of several proinflammatory genes in vari-
alenone, a mycotoxin known to induce oxidative ous parts of the intestine (duodenum, ileum, colon)
stress, supplementation of isoflavones lowered MDA (Fiesel et al., 2014). The apparent digestibility of
concentration in plasma (Wang et al., 2012). This nutrients was not changed by the treatment in that
finding suggests that isoflavones are able to counter- study. However, supplementation of both grape seed
act oxidative stress induced by mycotoxin treatment. and grape marc meal extract and hop extract lowered
In contrast to pigs which were either fed diets with the abundance of some potentially pathogenic bacte-
insufficient dietary vitamin E levels or subjected to ria (Streptococcus spp., Clostridium cluster XIVa) and
prooxidative treatments, plant polyphenols had less concentrations of volatile fatty acids in faecal sam-
effect on the antioxidative status in pigs without ples. These findings suggest that polyphenols exerted
prooxidative treatment. In the study of Augustin an antimicrobial effect on pathogenic bacteria in the
et al. (2008), supplementation of a green tea extract intestine of pigs. In both of the above-mentioned
rich in catechins did not increase tocopherol concen- studies, feeding polyphenol-rich plant extracts caused
trations in plasma and various tissues and did not an improvement of the gain-to-feed ratio in pigs, an
increase the antioxidative capacity in pigs fed a diet effect which could be due to an inhibition of proin-
with an adequate supply of vitamin E. In another flammatory processes in the intestine or to antimicro-
study, supplementation of grape seed and grape marc bial effects. A very recent study from Jang et al.
extract with a total polyphenol content of 60 mg/g at (2016) reported that feeding different doses of cocoa
a level of 10 g/kg diet did also not influence concen- powder (2.5, 10 and 20 g) containing 51, 205 and
trations of tocopherols and thiobarbituric acid-reac- 410 mg flavanols, respectively, to pigs for 4 weeks
tive substances (TBARS) in plasma and liver and the decreased gene expression of TNF-a and Toll-like
antioxidative capacity of plasma in piglets (Gessner receptors -2, -4 and -9 in the ileal Peyer0 s patches,
et al., 2013). In the study of Zhang et al. (2014), sup- mesenteric lymph nodes and the proximal colon.
plementation of a basal diet with a mixture of Interestingly, it has been shown in in vitro studies
polyphenols extracted from apple, grapes, green tea that the antiinflammatory potential of cocoa
and olive leaves (at a level of 1 g/kg diet) reduced polyphenols is attributed mainly to the monomeric
concentration of MDA in plasma of weaned piglets compounds, such as catechin and epicatechin,
but had no effect on the total antioxidative capacity whereas the intermediate or large-sized oligomers,
and activities of several antioxidant enzymes in the procyanidins, which are also abundant in cocoa
plasma. The overall conclusion of the few studies per- powder, have proinflammatory activities as evi-
formed so far is that supplementation of polyphenols denced by an increased secretion of TNF-a from
improves the antioxidative status and ameliorates macrophages (Mao et al., 2002; Park et al., 2000). In
oxidative stress in pigs subjected to prooxidative the context of the above-mentioned study from Jang
treatment. In pigs without prooxidative treatment, et al. (2016), this possibly indicates that the anti-
polyphenols have either no or only marginal effects inflammatory effects of the monomeric compounds
on the antioxidant status. in cocoa powder dominated over the proinflamma-
Regarding potential effects of polyphenols on tory actions of procyanidins. Performance data were
inflammation in pigs, very few studies are available not shown in this study, but the authors stated that
considering the effects of polyphenol-rich plant body weights were not influenced. Besides inhibiting
extracts on the expression of proinflammatory genes proinflammatory gene expression in the intestine,
in the intestine. In the study from Gessner et al. this study revealed that feeding the cocoa powder
(2013), the diet containing grape seed and grape increases the abundance of some beneficial bacterial
marc meal extract caused a downregulation of vari- strains, such as Lactobacillus and Bifidobacterium spp.,
ous proinflammatory genes in the duodenum of in the proximal colon and faeces. These bacteria are
growing pigs. In that study, supplementation of grape known to inhibit the growth of pathogenic bacteria
by the production of lactic acid by fermentation of animals (Larrosa et al., 2009; Qiao et al., 2014; Etxe-
sugars, reducing the intestinal pH and thus making berria et al., 2015), it can be postulated that a key
the environment unfavourable for the growth of mechanism of this beneficial effect of polyphenol-rich
pathogens, competition for receptors on the intestinal diets in pigs is their contribution to gut health by
epithelium and production of antimicrobial com- exerting a pre-biotic activity favouring the growth of
pounds (Alakomi et al., 2000; Servin, 2004). In line beneficial bacteria while inhibiting the growth of
with findings in pigs, it was reported in a study with pathogenic bacteria. This beneficial modulation of the
healthy humans that consumption of cocoa-derived gut microbiota is known to enhance gut barrier func-
flavanols has a pre-biotic effect stimulating the tion, decrease the translocation of bacterial compo-
growth of beneficial bacterial strains while inhibiting nents into the circulation and stimulate the host
that of potentially pathogenic ones (Tzounis et al., immune system (Mosele et al., 2015). In line with
2011). Thus, these findings indicate that flavanol-rich this, it was reported that the modulation of the colon
cocoa powder contributes to gut health through mod- microbiota by plant polyphenols correlated with
ulation of the colon microbiota composition and reduced levels of systemic inflammatory markers,
reducing expression of inflammatory genes in the such as C-reactive protein, and decreased expression
intestine. In agreement with the modulation of of inflammatory genes in tissues (Axling et al., 2012;
intestinal microbial populations by polyphenol-rich Queipo-Ortu~ no et al., 2012; Moreno-Indias et al.,
diets in pigs (Fiesel et al., 2014; Jang et al., 2016), a 2016). With regard to the improvements of systemic
very recent study from Magistrelli et al. (2016) found antioxidative status and the reduction in ROS levels
that feeding cocoa husk meal (75 g/kg diet), a by polyphenol-rich diets observed in some studies
polyphenol-rich waste from agroindustry represent- with pigs (Luehring et al., 2011; Hou et al., 2014;
ing the integuments of the cocoa beans, to male pigs Wang et al., 2012), we postulate that these effects are
for 3 weeks increased faecal abundance of Bac- unlikely to be mediated by direct antioxidant effects of
teroides–Prevotella and Faecalibacterium prausnitzii. Both polyphenols, because of their poor bioavailability, but
bacterial populations are considered beneficial for the are secondary due to the improvements of gut health
intestine due to the production of large amounts of and consequently less translocation of proinflamma-
butyrate, which stimulates growth and differentiation tory and prooxidative stimuli. However, undoubtedly,
of enterocytes and exerts antiinflammatory effects. further studies are warranted to get more evidence of
Unfortunately, these authors did not report on the potential beneficial effects of plant polyphenols in
effect of the cocoa husk meal-enriched diet on pigs.
inflammatory parameters in the intestine. Perfor-
mance data of the pigs such as feed intake, weight
gain and gain-to-feed ratio were not influenced by
inflammation in studies with poultry
feeding of the cocoa husk meal. One limitation of the
study form Magistrelli et al. (2016) is that the inclu- Similar to pigs, the number of studies dealing with
sion of the large amount of cocoa husk meal into the effects of polyphenols in broilers and laying hens is
cereal-based test diet not only increase the polyphe- limited and only a few of these studies focused on the
nol content but also nearly doubled the percentage of antioxidant system or inflammation. In the study of
acid detergent lignin. Thus, it is unclear to which Goni et al. (2007), supplementation of 5, 15 or 30 g
extent the change of the intestinal microbial popula- grape pomace per kg diet had no effect on growth per-
tions can be ascribed to cocoa polyphenols. Studies formance and digestibility of amino acids and also did
dealing with the effects of plant polyphenols on the not influence the antioxidant capacity in plasma and
expression of proinflammatory genes in tissues other MDA concentration in breast and thigh muscle. How-
than intestine have not yet been published. However, ever, the susceptibility of lipids in breast and thigh
we have recently observed that supplementation of muscle during refrigerated storage was reduced by
grape seed and grape marc meal extract or hop grape pomace supplementation in that study. In a fol-
extract does not influence the expression of proin- low-up study from the same group, doses of 15, 30
flammatory genes in the liver of pigs (Gessner et al., and 60 g of grape pomace concentrate per kg diet
unpublished data). were tested in broilers (Brenes et al., 2008). In this
In conclusion, the few studies published so far sug- experiment, doses of 30 and 60 g/kg diet caused a
gest that polyphenols are able to suppress inflamma- moderate increase in the antioxidant capacity in
tion in the small intestine of pigs. Considering similar serum. In agreement with the study of Goni et al.
effects of polyphenol-enriched diets in laboratory (2007), supplementation of grape pomace concentrate
caused a reduced formation of MDA in breast meat no consistent effect of quercetin on the antioxidant
during refrigerated storage. In the study of Wang et al. status was found; while the activity of SOD in the liver
(2008), supplementation with grape seed proantho- was increased, the concentration of MDA, Trolox
cyanidin extract improved weight gains and lowered equivalent antioxidative capacity and the activity of
the mortality of broilers infected with Eimeria tenella, GPX were not influenced by quercetin supplementa-
but had less effect on antioxidative parameters (MDA tion. In a very recent study from Yuan et al. (2016),
concentration, activity of SOD) in plasma. An the effect of different doses of tea polyphenols (600
improved performance and also reduced oxidative and 1000 mg/kg diet) on production performance,
stress in broilers fed different polyphenols was egg quality and hepatic antioxidant status was investi-
reported in a study from Starcevic et al. (2015). The- gated in laying hens treated with different concentra-
ses authors found that the inclusion of different phe- tions of dietary vanadium (5, 10 and 15 mg
nolic compounds into the broiler diet, either thymol vanadium/kg diet) for 8 weeks. This study found that
(200 mg/kg diet), tannic acid (5 g/kg diet) or gallic the high concentrations of vanadium caused reduced
acid (5 g/kg diet), improved feed utilization and/or albumen quality, bleaching effect on eggshell colour
final body weight (only tannic acid) and improved and oxidative stress in the liver, while the tea
oxidative stability (decreased concentration of polyphenols prevented the adverse effect of vanadium
TBARS) in liver and breast muscle. In a study of on egg quality and increased the activity of GPX in the
Viveros et al. (2011), broiler diets were supplemented liver being indicative of induction of the antioxidant
with either 60 g/kg diet of grape pomace concentrate defence system. To sum up, most of the studies with
or grape seed extract. Supplementation with grape broilers and laying hens revealed increases of perfor-
pomace concentrate improved the feed efficiency in mance and moderate improvements of antioxidant
broilers, an effect that could be explained by beneficial status or oxidative stability of tissues by plant
effects on the intestinal microbial population (in- polyphenols. Nevertheless, two studies even reported
creased abundance of Enterococcus, decreased abun- an impairment of performance of broilers fed polyphe-
dance of Clostridium) and an increase in the villus nol-enriched diets.
height-to-crypt depth ratio. Interestingly, these effects With regard to potential effects of polyphenols on
were not observed in broilers supplemented with inflammation in broilers, only one study is available
grape seed extract, suggesting that polyphenols from so far. That study investigated the effect of tea
different sources exert different biological effects. In polyphenols (0.03–0.09 g/kg body weight) on the
the study of Eid et al. (2003), supplementation of expression of various proinflammatory cytokines (IL-
green tea polyphenols improved the feed conversion 1B, IL-4, IL-6, IL-10, TNF, IFN-c) in the intestine of
ratio and lowered TBARS concentrations in muscle broilers (Li et al., 2015). It was found that most of
and liver of broilers treated with corticosterone. In these genes were downregulated by tea polyphenols.
contrast, green tea polyphenols did not lower TBARS Unfortunately, no performance data were reported in
concentrations in muscle and liver and even impaired that study. Therefore, it remains unclear whether
the feed efficiency in broilers which were not treated downregulation of proinflammatory genes by tea
with corticosterone. In the study of Sridhar et al. polyphenols was associated with an increase in animal
(2015), supplementation of resveratrol (at a level of performance. In the study of Huang et al. (2013),
1% of diet) improved the antioxidative status of broilers were fed diets supplemented with either 50 or
serum in broilers, both without and with further treat- 100 mg of green tea polyphenols per kg body weight.
ment with aflatoxin B1. In that study, dietary treat- This study did not consider pathways of inflammation.
ment with resveratrol, however, impaired body However, it was found that broilers supplemented
weight gains and feed conversion ratio. In a study with green tea polyphenols have a reduced deposition
with Hessian laying hens, the effect of different doses of body fat, probably as a result of a reduced rate of de
of dietary quercetin (0.2, 0.4 and 0.6 g quercetin/kg novo-fatty acid synthesis and an increased rate of b-
diet) on performance, egg quality, caecal microflora oxidation. In overall, the few studies performed so far
populations and antioxidant status was investigated indicate that polyphenols might exert beneficial
(Liu et al., 2014). This study demonstrated an effects in the intestine of broilers, like in pigs. It is
increased performance (increased laying rate, likely that effects of polyphenols in this respect could
decreased feed-to-egg ratio) and improvements of cae- be mediated by favourable effect on the microbial
cal microflora status (decrease in the abundance of composition. However, future studies are warranted
total aerobes and coliforms, increased abundance of to get more evidence of potential beneficial effect of
Bifidobacteria) in laying hens fed quercetin. However, polyphenols in poultry.
Regarding potential antiinflammatory effects of

polyphenols in cattle, there are only very few studies
inflammation in studies with cattle
available so far. In a study from Oliveira et al. (2010),
The focus of most of the studies dealing with effects of the effect of polyphenols from pomegranate extract on
polyphenols in dairy cattle was on the production health, nutrient digestion and immune competence
of methane. According to these studies, certain types was investigated in Holstein calves. The calves received
of polyphenols, particularly tannins, are able to sup- either 5 or 10 g pomegranate extract per day through-
press ruminal methanogenesis, both under in vitro and out the first 70 days of age. Feeding the pomegranate
in vivo conditions. The suppression of ruminal extract polyphenols impaired digestibility of crude pro-
methanogenesis was found to be mainly due to a tein and fat, increased the secretion of IFN-c and IL-4
reduction in the number of protozoa and toxic effects by peripheral blood mononuclear cells and improved
of tannins on methanogens (Patra and Saxena, 2009; total IgG responses to ovalbumin vaccination. These
Cieslak et al., 2013). With regard to an effect of results led the authors to suggest that feeding pomegra-
polyphenols on the antioxidant status of dairy cattle, nate extract polyphenols suppresses nutrient digestibil-
only few studies with divergent results exist. In an ity, likely because of the high tannin content, but
earlier study from Colitti and Stefanon (2006), feeding enhances mitogen-induced cytokine production and
grape polyphenols at a dose of 10 g/day to heifers dur- response to vaccination, which might be beneficial for
ing the transition period, it was observed that the leu- immune competence and health of calves. In the study
cocyte mRNA concentration of the Nrf2 target gene from Gessner et al. (2015a), feeding a polyphenol-rich
SOD increased after calving. This indicated that grape grape seed and grape marc meal extract in dairy cows
polyphenols may induce cytoprotective mechanisms caused a consistent reduction (25–65%) of the mRNA
after calving to cope with oxidative and inflammatory concentrations of a large set of genes involved in
stress. In the study of Shabtay et al. (2008), supple- inflammation and ER stress in the liver, even though
mentation of pomegranate peel as a source of flavo- the effects were not statistically significant. Moreover,
noids increased the concentration of a-tocopherol in feeding grape seed and grape marc meal extract to
plasma of Holstein–Friesian bull calves. In that study, dairy cows in that study caused a significant downreg-
however, no other indices of the antioxidant system ulation of fibroblast growth factor (FGF)-21, a key
were reported. In dairy cows, feeding of anthocyanin- marker of ER stress and a surrogate marker of liver fat
rich corn silage did not influence the antioxidative accumulation. In this study, supplementation of the
capacity of plasma (Hosoda et al., 2012), despite a polyphenol-rich product also improved milk perfor-
marked increase in the activity of SOD in plasma. Sim- mance, which could be – at least in part – the result of
ilarly, supplementation of a polyphenol-rich plant a suppression of inflammation and ER stress in the
extract did not improve concentrations of MDA, a- liver. In the study from Winkler et al. (2015), the
tocopherol and total antioxidative status of plasma in effect of feeding a polyphenol-rich plant product was
dairy cows (Gobert et al., 2009). In the study of also investigated on genes of inflammation and ER
Gohlke et al. (2013b), 4-week intraduodenal supple- stress in the liver of dairy cows. Feeding the polyphe-
mentation of quercetin did not influence mRNA con- nol-rich plant product caused a downregulation of a
centrations of various antioxidant enzymes in the set of genes involved in inflammation and ER stress,
liver of dairy cows. In a recent study of our group, which, however, failed to be significant for most genes.
supplementation of polyphenol-rich grape seed and However, in the group of cows supplemented with the
grape marc meal extract at a dietary level of 1% also plant product, there was also a significant downregula-
did not improve the plasma antioxidant status of dairy tion of FGF21, a reduced fat content in the liver and
cows (as assessed by determination of a-tocopherol, b- an increased milk performance. As dry matter intake
carotene, TBARS and total antioxidative capacity in was not different between cows supplemented with
plasma) (Gessner et al., 2015a). In another study, the plant product and control cows, it has been sug-
feeding a polyphenol-rich plant product consisting of gested that the plant product improved the utilization
green tea and curcuma extract also did not exert of energy for milk production. One plausible explana-
antioxidant effects in dairy cows (Winkler et al., tion for this might be a potential reduction in ER,
2015). Collectively, it can be stated that, like in most inflammatory and metabolic stress in the liver by the
studies with monogastric animals, the antioxidant sta- polyphenols from the plant product.
tus of dairy cattle is less influenced by supplementa- Overall, the few studies in dairy cows published so
tion of feed rations with polyphenols from plant far show that plant sources rich in polyphenols could
sources. have the potential to lower inflammation and ER
stress in the liver during the transition period and polyphenols has less effect on the antioxidant capacity,
even improve milk performance. An interesting obser- at least in healthy animals. The reason for this might
vation of the few studies is the downregulation of be that, due to their low rate of absorption and their
hepatic FGF21, because of its role for liver fat accumu- fast degradation in the body by the xenobiotic system,
lation, a frequent phenomenon in high-yielding dairy systemic concentrations of polyphenols when com-
cows. Future studies have to clarify whether a modu- pared with other antioxidants in plasma such as ascor-
lation of the rumen microbiota by plant polyphenols bic acid, tocopherols, albumin, uric acid and
(Patra and Saxena, 2009; Cieslak et al., 2013) might glutathione are very low (Surai, 2014). Direct antioxi-
contribute to the improvements of the inflammatory dant effects of polyphenols are expected to occur
status in dairy cows and the significant improvements in vivo only in the gut, because of the markedly higher
of milk performance. However, given that rumen dis- concentration of polyphenols in the intestinal lumen
orders, such as subacute rumen acidosis and abomasal compared with systemic concentrations and the direct
displacement (Plaizier et al., 2008; Zebeli and exposition of polyphenols to the intestinal epithelium
Metzler-Zebeli, 2012; Guzelbektes et al., 2010), which following ingestion of polyphenol-rich diets. Accord-
frequently occur during parturition and contribute to ingly, the view that plant polyphenols are able to
the systemic inflammatory condition during early replace other, much better bioavailable antioxidants in
condition, are accompanied by a marked impairment the diet, such as tocopherols, and to improve the total
of the rumen microbial community and an increased antioxidant system of the body, should be considered
translocation of inflammatory stimuli, such as LPS as doubtful. The replacement of tocopherols in the diet
and cytokines, this is not unlikely. with plant polyphenols is also questionable because
polyphenols can act as antioxidants in vivo only in
blood and cytosol due to their hydrophilic structure
Conclusions and future perspectives
and thus cannot replace the unique antioxidant func-
Increasing evidence from studies with pigs, poultry tion of vitamin E, which due to its lipophilic structure
and cattle indicates that plant polyphenols are helpful is integrated in the biological membranes and there
to attenuate both local and systemic inflammatory effectively neutralizes fatty acid radicals and other ROS
conditions, which are of particular relevance during (Surai, 2014). Unlike in healthy animals, improve-
the weaning phase in monogastric species and during ments of systemic antioxidative status and the reduc-
the periparturient period in dairy cattle, and through tion in ROS levels by plant polyphenols were observed
this improve animal0 s performance. The main reason in some studies with challenged or stressed animals
for improvements of animal0 s performance, such as (Luehring et al., 2011; Hou et al., 2014; Wang et al.,
increases in gain-to-feed ratio and milk yield, in 2012). These effects could be explained by the systemic
response to plant polyphenols is that the inflammatory antiinflammatory action of polyphenols, which might
condition reduces feed intake, increases energy be caused mainly by improvements of gut health and
requirement for the production of fever and induces reduced translocation of proinflammatory and proox-
several hormonal changes shifting the metabolism into idative stimuli into the circulation. However, regarding
a more catabolic state in farm animals. Given the gen- the relatively low number of studies performed with
erally poor absorption of polyphenols from the intes- farm animals, there is no doubt that more studies are
tine and the mutual interaction between polyphenols necessary to substantiate this hypothesis with experi-
and gut microbiota (biotransformation of polyphenols mental data.
to metabolites by the microbiota and modulation of A further issue, which has not been addressed in
the microbiota by polyphenols), it can be postulated the present review due to a lack of studies with farm
that a key mechanism underlying the antiinflamma- animals but which should receive attention in the
tory action of polyphenols is their contribution to a future, is the in vitro antiviral activity of certain
stable intestinal microbiota and gut health, both of polyphenols, such as epigallocatechin-3-gallate
which are associated with enhanced gut barrier func- (Ciesek et al., 2011; Calland et al., 2012), delphinidin
tion and decreased translocation of bacterial compo- (Calland et al., 2015) and many others (Date and Des-
nents and prooxidative stimuli into the circulation tache, 2015), against many viruses including hepatitis
(Landete, 2012; Mosele et al., 2015). It is well known C, herpes simplex, influenza and even Ebola (Hsu,
that polyphenols have pronounced antioxidative prop- 2015). It has been demonstrated that the antiviral
erties in vitro, such as scavenging of ROS, chelating of properties of many polyphenols are mediated by
metal ions and induction of antioxidant enzymes inhibiting an early and critical step of virus infection,
(Fraga, 2007). Nevertheless, supplementation of plant namely the virus entry by acting directly on the viral
particle and preventing its attachment to the cell sur- With regard to several adverse effects of plant
face (Calland et al., 2015). Since infectious diseases polyphenols, such as formation of complexes with
with involvement of viral pathogens, such as mastitis trace elements, rendering them less available for
or metritis, are considered to contribute to the absorption (Afsana et al. 2004; Gaffney et al. 2004),
proinflammatory condition observed in dairy cows and inhibition of digestive enzymes (Cermak et al.,
(Bradford et al., 2015), it is conceivable that the anti- 2004; Williamson, 2013; Buchholz and Melzig, 2015),
inflammatory action of polyphenols in farm animals is future studies with farm animals are necessary to clar-
partially due to inhibition of the entry of viral patho- ify which dose of polyphenols is appropriate to induce
gens. This, however, is a matter of speculation and beneficial effects without significantly impairing
needs to be clarified in future studies. nutrient digestibility.
Holm, C.; Molin, G.; Berger, K., 2012: Bertoni, G.; Trevisi, E.; Han, X.; Bionaz,
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Potential of Plant Polyphenols To Combat Oxidative Stress Andinflammatory Processes in Farm Animals

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Potential of Plant Polyphenols To Combat Oxidative Stress Andinflammatory Processes in Farm Animals

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DOI: 10.1111/jpn.

Potential of plant polyphenols to combat oxidative stress and

Received: 1 June 2016; accepted: 24 June 2016

2-related factor-2 (Nrf2) (Rahman et al., 2006; Sca-

a result of suppression of the cows’ own antioxidant

Decreased feed Hypothalamic Increased energy

Dietary polyphenols Tissues

Epithelial cells Biotransformation

Unabsorbed polyphenols and

NF-κB – DNA Transcription of Transcription of

Regarding potential antiinflammatory effects of

Larrosa, M.; Ya~ n

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