The Biofunctions of Phytochemicals and Their Applications in Farm Animals: The Nrf2/Keap1 System as a Target

Engineering ›› 2017, Vol. 3 ›› Issue (5) : 738 -752. DOI: 10.1016/J.ENG.2017.03.011

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Si Qin ^a^,^b
, De-Xing Hou ^a^,^b^,^c

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2017-04-05	2017-05-18	2017-01-24
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2017-07-24

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Abstract

Reactive oxygen species (ROS) can be caused by mechanical, thermal, infectious, and chemical stimuli, and their negative effects on the health of humans and other animals are of considerable concern. The nuclear factor (erythroid-derived 2)-like 2/Kelch-like ECH-associated protein 1 (Nrf 2/Keap1) system plays a major role in maintaining the balance between the production and elimination of ROS via the regulation of a series of detoxifying and antioxidant enzyme gene expressions by means of the antioxidant response element (ARE). Dietary phytochemicals, which are generally found in vegetables, fruits, grains, and herbs, have been reported to have health benefits and to improve the growth performance and meat quality of farm animals through the regulation of Nrf 2-mediated phase II enzymes in a variety of ways. However, the enormous quantity of somewhat chaotic data that is available on the effects of phytochemicals needs to be properly classified according to the functions or mechanisms of phytochemicals. In this review, we first introduce the antioxidant properties of phytochemicals and their relation to the Nrf 2/Keap1 system. We then summarize the effects of phytochemicals on the growth performance, meat quality, and intestinal microbiota of farm animals via targeting the Nrf 2/Keap1 system. These exhaustive data contribute to better illuminate the underlying biofunctional properties of phytochemicals in farm animals.

Keywords

Phytochemical / Biofunction / Nrf2/Keap1 system / Growth performance / Meat quality / Intestinal microbiota

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Si Qin, De-Xing Hou. The Biofunctions of Phytochemicals and Their Applications in Farm Animals: The Nrf2/Keap1 System as a Target. Engineering, 2017, 3(5): 738-752 DOI:10.1016/J.ENG.2017.03.011

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Biofunctions of dietary phytochemicals in modulating the Nrf2/Keap1 system

Dietary phytochemicals

Phytochemicals are produced via primary or secondary plant metabolisms and originate in various kinds of fruits, vegetables, grains, and herbs, endowing them with the color, taste, smell, and other organoleptic properties of the plants [ 1]. They are produced to help plants thrive or to thwart competitors, predators, or pathogens. During the last two decades, dietary phytochemicals have been found to be strongly associated with human health and diseases through their biological functions [ 2, 3]. More than 10 000 kinds of dietary phytochemicals have been classified into carotenoids, isothiocyanates, and polyphenols based on their chemical structure. Among these, the best-investigated category is that of polyphenols, which mainly include phenolic acids, flavonoids, and stilbenes/lignans. Many epidemiological investigations and lab-based studies have demonstrated that most polyphenols are conducive to the chemoprevention of several chronic diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, cancer, and other inflammatory diseases [ 4].

Phytochemicals as modulators for the Nrf2/Keap1 system

When phytochemicals are ingested by humans and other animals, they are recognized as xenobiotics. As a result, they stimulate the genes of a series of antioxidant and detoxifying enzymes (ADEs) to express. Most of these genes contain a specific conserved nucleotide sequence of 5'-TA/CANNA/GTGAC/TNNNGCA/G-3' in their promoters, named antioxidant response element (ARE)/electrophile-responsive element (EpRE) [ 5]. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been demonstrated to strongly activate ARE/EpRE to enhance the gene expressions of a series of ADEs [ 6], such as NAD(P)H quinone dehydrogenase 1 (NQO1), glutathione reductase (GSR), and solute carrier family 7 member 11 (SLC7A11) [ 7]. Nrf2 is a transcription factor (TF) transcribed by the NFE2L2 gene in humans, with a basic leucine zipper (bZIP) protein that induces the gene expressions of phase II antioxidant proteins and detoxifying enzymes in order to protect against oxidative damage triggered by chronic inflammation and injury [ 2]. The crucial negative regulator of Nrf2 is Kelch-like ECH-associated protein 1 (Keap1), which maintains the dynamic balance of cytoplasmic Nrf2 by proteasomal degradation [ 8].

The molecular mechanisms of Nrf2-ARE activation are summarized in the schematic diagram in Fig. 1. As shown in this diagram, the mechanisms of the regulating Nrf2/Keap1 system can be divided into Keap1-dependent and Keap1-independent mechanisms. Under basal conditions, Keap1 inhibits Nrf2 by functioning as an E3 ubiquitin ligase with the cullin 3-RING box protein 1 (Cul3-Rbx1) system for the constant ubiquitination and proteasomal degradation of Nrf2. Under induced status, electrophiles, oxidants, or phytochemicals can influence the Keap1 structure/residues, in the forms of cysteine modification, ubiquitination, phosphorylation, and succination, causing Nrf2 to escape from the Keap1-dependent ubiquitination system [ 9]. Alternatively, stress inducement may stimulate the phosphorylation of certain protein kinases, such as mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), PKR-like endoplasmic reticulum kinase (PERK), glycogen synthase kinase 3 (GSK3), or Nrf2 itself, thus regulating the activity of a series of TFs or certain nuclear proteins such as positive Brahma-related gene 1 (BRG1), nuclear receptor coactivator amplified in breast cancer 1 (AIB1), and Maf, as well as negative p53, p65, and cFos [ 6, 8]. Moreover, phytochemicals may cause epigenetic modifications to affect the mRNA transcription of NFE2L2or Keap1, such as DNA methylation, histone modification, and microRNA tuning. All of the above result in the accumulation of Nrf2 in the nucleus to heterodimerize with small Maf or CREB-binding protein (CBP) and to bind to ARE, which finally activates the expression of its downstream ADEs genes [ 6, 10].

Molecular mechanism underlying Nrf2 regulation by dietary phytochemicals

An extremely large number of studies performed in vitro and in vivo have revealed that many dietary phytochemicals have powerful abilities in regulating the Nrf2/Keap1 system [ 2– 4]. However, the molecular mechanisms underlying this huge quantity of data are not well classified. Here, based on the current research status, we review the molecular mechanisms of Nrf2 regulation by dietary phytochemicals and classify them into Keap1-dependent and Keap1-independent mechanisms.

Keap1-dependent pathway

Several models have been suggested to explain the inhibitory regulation of Nrf2 by Keap1. Most of the ARE inducers can target and modify the cysteines of Keap1 to affect Nrf2-ARE signaling. It is interesting that the location of the Keap1 cysteine that is targeted differs, depending on the type of the inducer [ 9, 10]. The essential cysteine residues generally involve C288, C273, and C151 [ 11]. After the discovery of Keap1 as an E3 ligase substrate adaptor of the Cul3-Rbx1-containing ubiquitination system, the “Keap1 dissociation and Cul3-Rbx1 ubiquitination” model was developed to explain the major Nrf2 regulation mechanism [ 12]. Moreover, several other important models such as the “Keap1 hinge-and-latch,” “Keap1 phosphorylation,” “Keap1 ubiquitination,” and “Keap1 succination” models reveal that modifications of Keap1 caused by a variety of stimuli constitute a primary mechanism in the modulation of the Nrf2/Keap1 system [ 13– 17].

An enormous number of dietary phytochemicals have been found to modify the cysteines of Keap1 to regulate the Nrf2/Keap1 system. As displayed in Table 1 [ 18– 80], sulforaphane, resveratrol, catechol estrogens, quercetin, carnosic acid, baicalein, glyceollins, oridonin, falcarindiol, piceatannol, xanthohumol, and 6-(methylsulfinyl)hexyl isothiocyanate were reported to activate the Nrf2/Keap1 system. Of these, quercetin works in the “Keap1 dissociation” model [ 18] and baicalein works in the “Keap1 ubiquitination” model; it is noteworthy that baicalein also works in the “Keap1 hinge-and-latch” model [ 26]. In addition, sulforaphane works in the “Keap1 hinge-and-latch” model in human Keap1, whereas it works in the “Keap1 dissociation” model in animal Keap1 [ 56– 59]. These data suggest that Keap1 modification by phytochemicals varies, and that the cell model used is an important factor.

Keap1-independent pathway

Aside from Keap1, a large number of other factors have been proven to play significant roles in the regulation of the Nrf2/Keap1 system. As shown in Fig. 1, these factors can be mainly classified into epigenetic modifications, the phosphorylation of protein kinases, and the regulation of TFs.

As shown in Table 1, the phosphorylation of extracellular signal-regulated kinase (ERK) can be promoted by quercetin [ 19], sulforaphane/phenethyl isothiocyanate (PEITC) [ 58, 60], hydroxytyrosol [ 51], resveratrol [ 39], luteolin [ 20], procyanidin B2 [ 21], hesperidin [ 23], oleanolic acid [ 44], epigallocatechin-3-gallate (EGCG) [ 34], epicatechin [ 35], eupatilin [27], rottlerin [32], acteoside [46], and celastrol [47]. The activation of p38 MAPK can occur from treatments of quercetin [ 19], procyanidins [37], sulforaphane [ 57], procyanidin B2 [ 21], fisetin [ 22], rottlerin [ 32], carnosic acid [ 40], celastrol [ 47], sesamin/episesamin [ 53], EGCG [ 33], and kahweol [ 49]. The activity of c-Jun N-terminal kinase (JNK) has been reported to be induced by treatments of alantolactone [45], hydroxytyrosol [ 52], PEITC [ 60], kaempferol [ 36], genipin [ 64], and indole-3-carbinol/3,3'-diindolylmethane [ 61, 62]. The activity of PI3K can be stimulated by procyanidins [37], sulforaphane [ 58], hydroxytyrosol [ 51], resveratrol [ 39], chlorophyllin [ 54], genipin [ 64], isoorientin [ 28], butin [ 29], guggulsterone [ 65], alantolactone [ 45], phytoestrogen puerarin [ 30], berberine [ 50], acteoside [ 46], EGCG [ 34], and epicatechin [ 35].

Several lines of research have found that the Nrf2/Keap1 system can be regulated by dietary phytochemicals through modulation of other transcriptional factors or nuclear proteins. Jun dimerization protein 2 (JDP2) was found to be strongly associated with sulforaphane-induced Nrf2 activation, and it was shown that JDP2 positively promotes Nrf2-ARE activation caused by sulforaphane [ 81]. Another study reported that sulforaphane inhibited the Nrf2 signaling pathway at the transcription level via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); NF-κB promotes histone deacetylase 3 (HDAC3) to cause local hypoacetylation and competes against Nrf2 transactivation with CBP to inhibit Nrf2 signaling [ 82].

Some dietary phytochemicals are considered to be potent epigenetic modifiers, including isothiocyanates, tea polyphenols, genistein, and curcumin [ 83]. Sulforaphane, 3,3'-diindolylmethane, curcumin, and Zligustilide were shown to inhibit the expressions of DNA methyltransferase (DNMT) and HDAC, resulting in the demethylation of Nrf2 promoter and the reactivation of Nrf2 signaling in the prostate of TRAMP mice or in TRAMP C1 cells [ 59, 62, 84, 85]. Moreover, apigenin, sulforaphane, and tanshinone IIA were reported to demethylate excessively methylated 5'-C-phosphate-G-3' (CpG) sites in the Nrf2 promoter region in mouse skin epidermal JB6 P+ cells, which was associated with the reactivation of Nrf2 signaling, the expression of Nrf2 target genes, the suppression of TPA-induced transformation, and the inhibition of protein expression of DNMTs and HDACs [ 86– 88]. These findings suggest that phytochemicals can regulate Nrf2 expression epigenetically; however, the exact effects of these special Nrf2 modulators on cancer and other chronic diseases need to be clarified by further study.

It is interesting that several lines of study reported that some flavonoids work as inhibitors of the Nrf2/Keap1 system in certain cancer cell lines and play an important role in overcoming cancer drug resistance (Table 1) [ 66– 80]. For example, luteolin, apigenin, chrysin, 4-methoxychalcone, pentamethoxyflavone, and EGCG have been found to play different roles in Nrf2-ARE regulation in normal cells and in cancer cells. In normal cells, they work as activators for Nrf2-ARE regulation to prevent chronic diseases, whereas in cancer cells, they work as inhibitors for Nrf2-ARE regulation to overcome cancer drug resistance. This dual action of phytochemicals on the Nrf2/Keap1 system in normal and cancer cells is attracting considerable attention regarding its health benefits [ 89].

The effects of phytochemicals on the growth performances, meat quality, and intestinal microbiota of farm animals by targeting the Nrf2/Keap1 system

The source of phytochemicals for farm animals is generally agroindustrial byproducts, such as skins, stems, seeds, pomace, nuts, hulls, and waste from the production of juice, wine, or beer, in order to reduce feed cost [ 90]. Table 2 summarizes the effects of phytochemicals on the growth performances, meat quality, and intestinal microbiota of farm animals [ 91– 135].

Growth performances

Several lines of study have reported the effects of phytochemicals on the growth performances of farm animals including pigs, poultry, and cattle.

In pigs, stilbenoid resveratrol and grape extract with a rich concentration of resveratrol were found to lower fat deposition, improve glucose metabolism and myocardial function, and prevent the progression of atherosclerotic lesions and coronary heart disease [ 91– 93]. Although an improvement in growth performance was found in pig feed based on polyphenol-rich grape seed and marc meal, the activity of TF Nrf2 and the expressions of ARE-associated antioxidant genes or detoxifying enzymes showed no significant change [ 94, 95].

In broilers and laying hens, phytochemicals were found to have a significant effect on improving growth performances. The supplementation of proanthocyanidin extract from grape seed was reported to lower the mortality of broilers infected with Eimeria tenella and improve their weight gain [ 96]. The broiler diet, which contained thymol (200 mg·kg⁻¹ diet), gallic acid (5 g·kg⁻¹ diet), and tannic acid (5 g·kg⁻¹ diet), was found to improve the feed utilization and final body weight [ 97]. Grape pomace concentrate (60 g·kg⁻¹ diet) was found to improve feed efficiency [ 98]. Green tea polyphenols in the broiler diet improved the feed conversion ratio in liver and muscle treated with corticosterone, but impaired the feed efficiency without corticosterone treatment [ 99]. Resveratrol (1% of diet) impaired the body weight gains of broiler birds as well as their feed conversion ratios [ 100]. Dietary quercetin (0.2–0.6 g·kg⁻¹ diet) was found to increase the laying rate and decrease the feed-to-egg ratio [ 101]. Tea polyphenols (5–15 mg·kg⁻¹ diet) were reported to prevent the adverse effect of vanadium on egg quality [ 102].

In dairy cows, pomegranate-extracted polyphenols decreased the digestibility of protein and fat due to the suppression of these nutrients by high tannins content [ 103]. The supplementation of dairy cow feed with polyphenol-rich grape seed and marc extract was found to improve milk performance [ 104]. Plant products were shown to cause a reduction of fatty liver formation and an improvement in milk performance in cows [ 105].

Although direct proof of the link between phytochemical-caused improvements on the growth performance of farm animals and the Nrf2/Keap1 system has not yet been fully established, significant improvements in antioxidant and anti-inflammatory properties caused by phytochemicals-based feedings have been extensively observed in many studies, and may be strongly associated with the Nrf2/Keap1 system.

Meat quality

A very large number of studies were performed to study the effects of phytochemicals on meat quality, with a focus on antioxidant properties, anti-inflammatory properties, and sensory performances such as color, texture, and flavor [ 106– 133].

Antioxidant properties

The antioxidant properties of phytochemicals in farm animals, meat, and meat products have been extensively studied, forming a basis for an understanding of other functions of phytochemicals.

Phytochemicals supplementation was reported to improve the redox status and reduce excessive oxidative stress in pigs treated by peroxidation, by reducing plasma lipid peroxidation and lowering malondialdehyde (MDA) level. However, phytochemicals had no such effects in the case of non-pro-oxidative treatment [ 94, 106, 107]. Plant phytochemicals in the diet also moderately improved the antioxidant status in broilers and laying hens through the reduction of MDA and thiobarbituric acid reactive substance (TBARS) concentrations, and the induction of glutathione peroxidase (GPx) activity [ 96, 98, 102]. However, the antioxidant status was found to be less influenced in dairy cattle by phytochemicals supplementation, although the activity of superoxide dismutase (SOD) increased occasionally [ 104, 105].

In meat and meat products, lipid oxidation is found to be the primary cause of quality loss. During the digestion–absorption–metabolism process, a number of oxidative compounds and stresses emerge and accumulate in the organism or tissues, adversely limiting the shelf-life and affecting the quality of the meat or meat products, including texture, color, flavor, nutritive value, and safety [ 136]. The toxic effects of synthetic antioxidants and consumers’ interest in natural products have accelerated the development of natural phytochemicals as better choices than additives [ 137]. For example, the addition to pork patties of phytochemicals, such as extracts of grape skin, green tea, rosemary, and coffee, was observed to reduce lipid oxidation and the values of TBARS and hexanal at doses of 50–200 ppm [ 108]. In raw or cooked goat meat patties, extracts of red peony, white peony, moutan peony, rehmannia, sappan wood, and angelica were found to reduce lipid oxidation, at doses of 0.5%–2.0% [ 109]. In raw beef patties, ground beef, and buffalo meat patties, extracts of olive leaf, date pits, and rosemary leaf were found to reduce TBARS value, lipid oxidation, and oxymyoglobin oxidation, respectively [ 110– 112]. In pork and beef sausages, adzuki bean extract and grape seed extract were found to reduce lipid oxidation and TBARS values [ 113, 114]. The antioxidant properties of green tea extract, rosemary extract, and grape seed extract are well studied and their application in meat and meat products has been reviewed in a report [ 130].

Anti-inflammatory properties

Diets containing grape seed, marc extract, and hop extract were found to downregulate the expressions of various pro-inflammatory genes in the small intestine of growing pigs [ 95]. Cocoa powder in pig feed also decreased the gene expressions of Toll-like receptors and tumor necrosis factor (TNF)-α [ 117].

The anti-inflammatory effect of tea polyphenols on poultry was reported by investigating the expressions of a series of pro-inflammatory cytokines in the intestine of broilers. The results showed that tea polyphenols (0.03–0.09 g·kg⁻¹ body weight) caused a downregulation of the gene expressions of TNF-α, interleukin (IL)-4, IL-10, IL-1β, and interferon (IFN)-γ [ 118].

Feeding cattle with pomegranate-extract polyphenols (5–10 g·d⁻¹) increased the secretion of IL-4 and IFN-γ in peripheral blood mononuclear cells and improved the total immunoglobulin G (IgG) responses to the vaccination of ovalbumin [ 119]. Feeding dairy cows grape seed and marc extract stimulated a significant downregulation of the marker of endoplasmic reticulum stress, fibroblast growth factor (FGF)-21, as well as decreasing fat accumulation in the liver [ 104].

Sensory performance

Sensory performance is generally used to evaluate the color, flavor, and taste of meat or meat products. Phytochemicals have been found to affect the sensory performance of meat significantly.

For example, 0.5%–2.0% of white peony extract increased the redness value (a* value) in raw and cooked meat patties [ 109]; 300–500 ppm of rosemary extract maintained the red color of raw frozen sausage [ 120]; 300 mg·kg⁻¹ meat of green tea extract decreased the a* value in raw patties and eliminated rancid flavor in cooked patties [ 121, 122]; 0.01%–0.02% of grape seed extract reduced visual green discoloration of beef patties [ 123]; 10% of myrtle extract prevented color changes in beef patties [ 124]; 2.7–10.8 mg·(100 g)⁻¹ of Eleutherine americana extract increased a* value in cooked pork [ 125]; 0.2% of adzuki bean extract increased a* value but decreased lightness (L* value) and yellowness (b* value) in cured or uncured cooked pork sausages [ 126]; 500–6000 ppm of green tea extract increased a* value whereas grape seed extract decreased a* value in raw and cooked goat meat, and pepper extract was helpful in maintaining a* value in cooked pork [ 127, 128]; 5 mL·(500 g)⁻¹ meat of curry leaf extract decreased the L* value and a* value while increasing the b* value in raw ground pork [ 129]; and 130 ppm of rosemary leaf extract stabilized the color in raw and cooked ground buffalo meat patties [ 130].

In addition, plum products exhibited minor effect on flavor but caused color change in many meat and poultry products, and grape seed extract led to a significant change in color in meat products [ 137].

Intestinal microbiota

Studies focusing on the effect of phytochemicals on the intestinal microbiota in vivo have increased markedly in recent years. It is considered that intestinal microbiota are the first targets of dietary phytochemicals, and that they show many links to health. Thus, many health-promoting effects of phytochemicals may be attributed to their modulation of the intestinal microbiota [ 138]. For example, only 5%–10% of polyphenols can be absorbed in the small intestine; 90%–95% enter the colon and are bio-transformed with the aid of the enzymatic colon microbiota into a series of polyphenolic metabolites [ 90]. The polyphenolic metabolites are able to partially re-absorb into the systematic circulation after conjugation once again in the liver and the enterocyte, and partially serve as antimicrobial substances or growth-promoting substrates. On the other hand, polyphenols or their metabolites can affect the composition and density of the colon microbiota in a profitable manner, including promotion of the growth of beneficial bacteria in a prebiotic-like manner and inhibition of certain pathogenic bacteria [ 139, 140].

Limited studies were performed to specifically investigate the effects of polyphenols on the intestinal microbiota in farm animals. Cocoa powder feeding was found to increase the abundance of several bacterial strains in pigs, including Lactobacillus, Bifidobacterium spp., Bacteroides-Prevotella, and Faecalibacterium prausnitzii [ 117, 134]. A few studies revealed that polyphenols may exhibit favorable effects in the intestine of broilers. Grape pomace concentrate supplementation in broiler feed was found to have a beneficial effect on the intestinal microbial population by increasing the abundance of Enterococcus and decreasing that of Clostridium [ 98]. Quercetin feeding in laying hens was reported to improve the caecal microflora status by decreasing the total number of aerobes and coliforms and increasing that of Bifidobacterium [ 101]. Tea polyphenols were found to increase the amount of lactobacilli and decrease that of the total bacteria, Bacteroidaceae, and Clostridium(C.) perfringens in pigs; however, they decreased Bifidobacterium spp., Lactobacillus spp., and C. perfringens in calves [ 102, 135].

A recent review summarized the impact of polyphenols on the intestinal microbiota in rat and human models, and revealed that polyphenols or polyphenol-rich sources are able to affect the relative abundance of different bacterial groups by reducing the abundances of the potential pathogens C. perfringens and C. histolyticum, as well as that of Gram-negative Bacteroides spp., and by increasing the populations of certain beneficial strains, such as clostridia, bifidobacteria, and lactobacilli [ 108].

Based on the effects of phytochemicals on bacterial strains in several lines of studies, the antioxidant and anti-inflammatory properties of phytochemicals may be linked to improvements in gut health [ 141, 142].

Detrimental effects of phytochemicals in farm animals

Although the biofunctional properties of phytochemicals are powerful and promising for farm animals, detrimental effects of phytochemicals have also been reported in some cases. For example, high consumption of polyphenols can inhibit the absorption of nutrients [ 143, 144] and cause toxic effects. Moreover, a high dose of quercetin was observed to be related to chronic nephropathy in rats and to reduce the life expectancy in mice [ 145]. Excess administration of green tea polyphenols was reported to disrupt kidney function in mice [ 146] and enhance tumor development in the colon of male rats [ 147]. Excess intake of caffeic acid caused kidney and gastrointestinal tumors in mice and rats [ 148]. Although these data were obtained from experimental animals, they suggest that the administration of a high dose of phytochemicals should be avoided in farm animals.

Although the anti-inflammatory, antioxidative, and cytoprotective properties of phytochemicals have been less studied in farm animals, an extremely large number of such studies have been done using human and experimental animal models. Thus, the biofunctions of phytochemicals in farm animals are also considered to occur through modulating the Nrf2/Keap1 system, which is a central modulator in combating oxidative stress and chronic inflammation [ 90].

Future perspectives

Several lines of studies have reported that the Nrf2/Keap1 system can regulate the general energy metabolism system by inhibiting gluconeogenesis [ 149]; modulate the activities of several lipases involved in the degradation of triglycerides/phospholipids [ 150] as well as enzymes involved in fatty acid oxidation, lipid biosynthesis, fatty acid desaturation, and fatty acid transport [ 150]; affect redox-sensitive metabolic systems such as the AMP-activated protein kinase pathway [ 151]; and adjust mitochondrial metabolism processes such as glucose oxidation and substrate entry, and ATP production [ 152, 153]. EGCG has been shown to affect the general energy metabolism system in rats and in humans [ 154]. However, no data are available regarding farm animals, and the underlying molecular mechanism remains unclear. Thus, further studies are required to clarify the impact of phytochemicals on the energy metabolism system in farm animals.

Although extensive data have been accumulated on the biofunctions of phytochemicals in humans and in experimental animals, most of these data focus on the chemopreventive effects of phytochemicals on chronic diseases such as cancer, cardiovascular disease, and metabolic syndrome. The molecular data have been deeply mined to clarify how dietary phytochemicals modulate signaling pathways and gene expressions for homeostasis. On the other hand, the biofunctions of phytochemicals in farm animals have been paid a great deal of attention regarding growth performance, meat quality, and the use of phytochemicals as an antibiotic replacer or substituter, although the molecular data on mechanisms that have been obtained from farm animals are fewer than those obtained from humans and experimental animals. It appears to be difficult to compare the differences in the mechanisms of phytochemicals in farm animal nutrition and in human nutrition. However, the results from studies on the antioxidant properties and mechanisms of phytochemicals in farm animals are almost the same as the results of similar studies in humans, with the Nrf2/Keap1 system acting as an axis. Therefore, it is possible to take advantage of the phytochemical data from humans and experimental animals and apply them to farm animals.

Phytochemicals have multiple biofunctions for human and other animal health. The modulation of the Nrf2/Keap1 system by phytochemicals may play a central role in their multiple biofunctions because the Nrf2/Keap1 system is linked to antioxidant functions, anti-inflammation functions, and many other functions. The relatively low absorption ratio of most phytochemicals in the small intestine shifts the research field from a focus on direct antioxidant properties to a focus on indirect pro-oxidant properties, biotransformation, signaling transduction, and gene expression regulation. Although the limited studies on the effects of phytochemicals on the intestinal microbiota of farm animals are currently insufficient to show the significant improvements in growth performance, antioxidant parameters, and inflammatory parameters, these findings will pave the way for further studies to understand the health-promoting effects of dietary phytochemicals.

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