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Digestibility and metabolism of copper in diets for pigs and influence of dietary copper on growth performance, intestinal health, and overall immune status: a review


The current contribution reviews absorption and metabolism of copper (Cu), Cu deficiency, Cu toxicity, Cu bioavailability, and effects of pharmacological levels of Cu on growth performance and intestinal health of pigs. Copper is a micro mineral involved in metabolic reactions including cellular respiration, tissue pigmentation, hemoglobin formation, and connective tissue development. Copper is mostly absorbed in the upper gastrointestinal tract, particularly in the duodenum, but some Cu is absorbed in the stomach. One way to evaluate the efficacy of sources of Cu is to measure relative bioavailability where responses include tissue concentrations of Cu, concentrations of metalloproteins, and enzymatic activity of animals fed test diets containing graded levels of Cu. The requirement for Cu by pigs is 5 to 10 mg/kg diet, however, Cu can be included at growth-promoting levels (i.e., 75 to 250 mg/kg diet) in diets for weanling and growing pigs to reduce post-weaning diarrhea and improve growth performance. The consistently observed improvement in growth performance upon Cu supplementation is likely a result of increases in lipase activity, growth hormone secretion, and expression of genes involved in post-absorptive metabolism of lipids. The growth-promoting effects of dietary Cu have also been attributed to its bacteriostatic and bactericidal properties because Cu may change bacterial populations in the intestine, and thereby reduce inflammation caused by pathogens. However, further research is needed to determine potential interactions between Cu and non-nutritive feed additives (e.g., enzymes, probiotics, phytobiotics), and the optimum quantity of Cu as well as the optimum duration of feeding supplemental Cu in diets for pigs should be further investigated. These gaps needs to be addressed to maximize inclusion of Cu in diets to improve growth performance while minimizing diseases and mortality.


Minerals are inorganic elements needed by pigs for maintenance, growth, and reproduction [1]. Historically, mineral nutrition of domestic animals was considered of limited importance with the exception of common salt, which was recognized in Biblical times as a substance of value for human and animal consumption [2]. Discovery of the essentiality of minerals dates back to the late eighteenth century when it was recognized that deficiency of minerals caused certain diseases [1]. The nutritional significance of minerals was demonstrated in 1791 when Fordyce demonstrated that canaries require an adequate Ca supply for optimum health and egg production [3], but most of the early research with minerals was conducted to alleviate health problems [3].

Minerals have structural, physiological, catalytic, and regulatory functions in animals [4] and they are classified into 2 groups based on the amount that is required in the diet. Minerals needed by more than 100 mg/kg diet on a dry matter basis are called macro minerals, and this group includes Ca, Cl, K, Mg, Na, P, and S [1]. These minerals play a major role in acid-base balance, structural and regulatory functions in bones and teeth, and nerve transmission. Minerals that are required in quantities less than 100 mg/kg diet are called micro minerals, and primarily serve as components of enzymes, coenzymes, and hormones [5]. Micro minerals include Cr, Fe, I, Mn, Mo, Co, Se, Zn, and Cu [6].

Copper (Cu) is an essential component of several metalloenzymes including cytochrome C oxidase, lysyl oxidase, cytosolic Cu-Zn superoxide dismutase (SOD1), extracellular Cu-Zn superoxide dismutase 3 (SOD3), monoamine oxidase, and tyrosinase [7, 8]. Copper, therefore, plays a role in oxidation-reduction reactions, transport of oxygen and electrons, and protection against oxidative stress [8, 9]. Copper is involved in metabolic reactions including cellular respiration, tissue pigmentation, hemoglobin formation, and connective tissue development [10, 11]. Copper has been recognized as an essential mineral since 1928 when it was demonstrated that Cu is needed for red blood cell synthesis in rats. Rats suffering from anemia were fed animal or vegetable based diets supplemented with ash and were able to recuperate from the disease. It was subsequently discovered that ash contained Cu sulfide [12]. This discovery led to research that demonstrated the essentiality of Cu not only for preventing microcytic hypochromic anemia, but also for maintenance and growth [12, 13].

The objective of this contribution is to review current understanding of digestibility, absorption, and metabolism of Cu, Cu deficiency, Cu toxicity, Cu bioavailability, and relationships between Cu and other nutrients. Effect of pharmacological levels of Cu on growth performance, gut microbiome, and intestinal health of pigs will also be discussed.

Digestibility, absorption, and metabolism of copper

Mineral digestibility reflects the dissolution and absorption of minerals from the gastrointestinal lumen. Digestibility and absorption of minerals is difficult to accurately determine due to endogenous mineral secretions into the gastrointestinal tract via pancreatic juice, bile, and mucosal cells [14]. Digestibility of Cu and Zn is also difficult to assess due to interference of homoeostatic regulation, which normally limits absorption of these minerals when animals are fed beyond the requirement [15]. The digestibility of Cu for growing pigs range from 30% to 55% [15, 16], and the relatively low digestibility of Cu is due to antagonisms between Cu and other microminerals [17]. Low pH in the stomach may reduce digestibility of Cu by causing dissociation of inorganic salts of dietary Cu [18]. As pH increases in the small intestine, Zn and Cu can be trapped in insoluble hydroxide precipitates, rendering these minerals unavailable for absorption [19]. The dietary source of Cu also affects its digestibility in pigs [15]. Chelation of dietary trace minerals with proteinates (i.e., peptides, amino acids) improve apparent total tract digestibility and retention of Cu in pigs by preventing formation of insoluble complexes along the gastrointestinal tract [16, 20].

Copper is mostly absorbed in the upper gastrointestinal tract, particularly in the duodenum, but some Cu is absorbed in the stomach [21]. In non-ruminants, Cu is primarily absorbed through a transcellular saturable process [22], but Cu can be absorbed through solvent drag, which involves movement of Cu through the tight junction pores [23]. Solvent drag allows free mineral ions to be solubilized in water through water dipole-ion interaction. Minerals suspended in water can be absorbed when water passes through the pores within the protein meshwork forming the tight junction [23].

Copper exist in two forms of valency depending on its state of oxidation. Most dietary Cu is in the Cu2+ form, but for Cu to be absorbed, it must be reduced to Cu+, which is catalyzed by a Cu-reductase enzyme that is expressed by glands at the brush border [24]. This metalloreductase belongs to the Steap protein family, and is a ferrireductase that stimulates cellular uptake of Fe and Cu [25]. Following the reduction of dietary Cu2+ into Cu+, Cu+ crosses the apical membrane and enters the enterocyte through Cu transport protein 1 (CTR1). Copper transport protein 1, which has a high affinity for Cu, is the main Cu transporter in enterocytes. Copper transport protein 1 is present in most tissues with significant quantities in the liver [26] because of the high need for Cu in hepatic cells. The amount of CTR1 in the apical membrane decreases via degradation in endosomal compartments if Cu is in excess of the requirement [27]. Other Cu transporters involved in Cu uptake are Cu transport protein 2 (CTR2) and divalent metal transporter (DMT1), but their affinity for Cu is less than that of CTR1 [28]. The DMT1 is located mainly on the brush border and transports Cu, Fe, Zn, and Mn across the apical membrane [29]. Thus, CTR1, CTR2, and DMT1 are the transport proteins specifically involved in increasing cellular Cu concentration if the body is in need of Cu.

Upon uptake of Cu+ from the apical membrane, Cu+ is transferred to chaperone proteins [30]. Chaperone proteins are involved in maintaining homeostatic Cu concentration in the body, and are associated with specific metalloenzymes and other Cu-containing proteins [27]. One of the chaperone proteins delivers Cu+ to Cu/Zn-superoxide dismutase, which is an antioxidant enzyme. Another chaperone protein is the cytochrome C oxidase Cu chaperone (COX17), which transports Cu+ in the mitochondria to cytochrome C oxidase, which is involved in energy transfer from NADH or FADH2 to ATP [29]. Other chaperone proteins include antioxidant protein 1 (ATOX1), which delivers Cu through the cytosol to the Golgi apparatus of intestinal cells [31]. Copper is then transferred to the Cu transporting ATPase 1 protein (ATP7A), which can bind and translocate 6 Cu+ ions into the basolateral membrane [32]. This ATPase also sequesters excess Cu to avoid Cu toxicity [33]. At the basolateral membrane, Cu+ is then converted to Cu2+ via a Cu oxidase for release into the interstitial space.

The homeostatic regulation of Cu absorption primarily involves the action of specific transporters and chaperone proteins [34]. The rate of Cu absorption is influenced by the Cu status of the animal, and Cu digestibility may be increased if animals are Cu-deficient [35]. If animals are deficient in Cu, there is an increase in the synthesis of Cu transport proteins and a Cu-ATPase pump is used to move Cu across the basolateral membrane into the extracellular fluid [35]. If the Cu concentration of the animal is adequate, the amount of Cu transport proteins for uptake is low, and the liver can synthesize metalloenzymes and store Cu for future use. If dietary Cu is provided in excess of the requirement, enterocytes produce a sulfhydryl-rich protein called metallothionein, which binds to the freely ionized Cu. This results in a subsequent reduction of Cu absorption, which helps prevent Cu toxicity [36, 37]. Metallothionein binds other metals such as Zn and Cd [37, 38]. Supplementing animals with greater quantities of Cu increases gene and protein expression of Cu specific transporters and chaperone proteins [39] because high concentration of Cu triggers ATP7A to become more active in releasing Cu+ at a higher rate [40]. However, research is needed to determine how pharmacological concentrations of Cu modulate expression of Cu transporters and chaperone proteins at the transcription level as well as at the level of translation.

In the hepatic portal vein, most of the absorbed Cu2+ is bound to albumin and transcuprein [41] for transport to the liver, where it is taken up by hepatocytes as Cu+ using Cu reductase. The CTR1 protein then moves Cu+ across the hepatocyte cell membrane. For Cu to be transported from the liver to peripheral tissues, Atox1 delivers Cu to the transmembrane Golgi complex. Copper is then transferred to the Cu transporting ATPase 2 protein (ATP7B) [32]. The Cu bound to ATP7B can then be utilized to produce Cu-containing proteins for export from the liver. Most Cu in serum is contained in ceruloplasmin, which is the major protein carrier for export of Cu from liver to target organs [42].

Ceruloplasmin is involved in Fe metabolism by having ferroxidase activity, which catalyzes the conversion of Fe2+ to Fe3+ [43]. The biological role of ceruloplasmin in pigs was reported by Ragan et al. [44] who demonstrated the impact of ceruloplasmin on plasma Fe in pigs fed diets deficient in Cu. Deficiency of Cu resulted in reduced concentration of serum ceruloplasmin with a subsequent manifestation of anemia in pigs. Iron deficiency was only corrected by administration of homologous ceruloplasmin or Cu to Cu-deficient pigs [44]. Porcine ceruloplasmin can be classified as ceruloplasmin I or ceruloplasmin II [45]. Ceruloplasmin I has greater copper content and specific enzymatic activity compared with ceruloplasmin II. Newly born piglets typically have high concentrations of liver Cu with ceruloplasmin II as the predominant form of ceruloplasmin. As pigs grow older, the concentration of ceruloplasmin I increases whereas ceruloplasmin II concentration remains constant [45].

Deficiency and toxicity of copper

Animals deprived of Cu develop critical dysfunctions and hypocuprosis [46,47,48,49]. Microcytic anemia is a sign of Cu deficiency due to its role in Fe metabolism, specifically in hemoglobin formation and development [47, 50, 51]. Ceruloplasmin, which functions physiologically as a copper-dependent ferroxidase to promote transferrin formation, is essential for the catalysis of Fe2+ to Fe3+ [42]. Pigs suffer from bone abnormalities and unusual leg conditions with various degrees of crookedness if dietary Cu is deficient because of deficiency in monoamine oxidase, which is needed for cartilage formation [48, 49]. Depigmentation, failure of hair keratinization, and cardiovascular disorders have also been demonstrated as signs of Cu deficiency [52, 53]. More than 60% of pigs fed Cu-deficient diets died from coronary artery disease [54] characterized by intimal lesions in muscular arteries of Cu-deficient pigs [55]. Integrity of arteries in the cardiovascular system relies heavily on the quality and quantity of collagen and elastin, and Cu-dependent oxidases (i.e., benzylamine oxidase and lysyl oxidase) are needed for collagen and elastin metabolism [56]. Pigs with hypocuprosis have impaired humoral response [57]. Copper plays an important role in the development and function of T and B cells, neutrophils, and macrophages [58, 59], and deficiency of Cu affects the immune system because of deficiency in cytochrome C oxidase and superoxide dismutase [57]. Low concentration of cytochrome C oxidase results in impairment of the respiration burst in neutrophils, and subsequently a decrease in immunological function [60].

The clinical signs and symptoms that are typically observed in pigs with Cu deficiency have always been associated with the role of Cu as a component of metalloenzymes needed for several metabolic reactions such as cellular respiration, hemoglobin formation, cartilage formation, and keratinization [48]. A reduction in growth performance and feed intake occurs when Cu is deficient in diets for all species; however, an unusual leg condition develops specifically in Cu-deficient pigs [61]. Pigs fed diets that are deficient in Cu have signs of central nervous system disorders such as ataxia, posterior paresis, and horizontal nystagmus, and these observations is possibly due to a deficiency of cytochrome C oxidase needed for phospholipid synthesis [58, 62]. Deficiency in Cu may be related to the degree of saturation of the animals’ lipid reserves and cholesterol profile because dietary Cu is believed to influence lipid metabolism in animals [63, 64]. Addition of increasing levels of dietary Cu as CuSO4 reduced the concentration of serum polyunsaturated fatty acids in pigs fed diets containing 5% fat as stabilized medium-chain triglycerides, whereas the concentration of serum polyunsaturated fatty acids increased in pigs fed diets without added fat [65]. Copper supplementation may also affect carcass fatty acid composition of pigs because supplementation of Cu in diets resulted in increased proportion of unsaturated fatty acids in the outer backfat, inner backfat, and perinephric backfat of pigs [66, 67]. Deficiency of Cu causes hypercholesteremia and hypertriglyceridemia [68], and the reason for these conditions has been attributed to the role of Cu in increasing lipoprotein lipase and triolein hydrolase activities [64]. The effect of Cu deficiency on accumulation of long chain fatty acids has been attributed to increased expression of fatty acid synthase with reduced concentration of ceruloplasmin in the serum [69] because Cu is needed for ceruloplasmin to function. As Cu concentration increases, and is greater relative to the requirement, ceruloplasmin activity increases [70], which inhibits lipid peroxidation by inhibiting glutathione peroxidase and catalase [71].

Pigs are less sensitive to Cu toxicity than ruminants [5]. Sheep and lambs can only tolerate a Cu level of 20 mg/kg and 100 mg/kg (dry matter basis), respectively [72, 73]. Differences in the tolerance level for Cu among species can be attributed to the capacity of the animal to excrete Cu in the bile, and in general, pigs excrete more Cu compared with ruminants [5]. Pigs also absorb Cu more efficiently compared with ruminants [74, 75]. If the dietary level of Cu is in excess of the requirement, Cu accumulates in the liver and other vital organs. This may result in increased concentration of unbound free ionized Cu, which is a strong oxidant leading to haemolysis [76]. In pigs, Cu can be toxic if more than 250 mg/kg of diet is fed for an extended period because this leads to hemolysis of red blood cells characterized by jaundice and necrosis [76, 77]. Inclusion of 750 mg of Cu per kg of diet in growing pigs resulted in increased Cu and aspartate transaminase (AST) concentrations in the serum [78], and the observed increase in serum AST concentration indicates damage to tissues where AST is abundant (i.e., kidney, liver) [79]. Signs of jaundice were observed in pigs when fed diets with 750 mg/kg of Cu, which was proposed to be a result of liver damage due to the relationship between the increased serum AST concentration and the degree of jaundice [78]. However, addition of 500 mg/kg of Zn or Fe to diets containing 750 mg/kg of Cu prevented clinical signs of copper toxicity and resulted in normal serum concentration of AST [78].

High concentrations of Cu in the diet could also promote lipid peroxidation in cell membranes by inducing oxidative stress in diets as well as in the body [80]. Lipid peroxidation causes degradation of unsaturated fatty acids, which results in a reduction of energy in diets, and as a consequence, could negatively affect growth performance and health of pigs [81]. One method to determine the degree of peroxidation in the animal’s body is through the use of malondialdehyde [82]. Malondialdehyde is commonly used as a biomarker of oxidative stress, and the thiobarbitoric acid assay is a method frequently used to determine malondialdehyde in biological fluids and tissues [83]. The degree of oxidative stress varies and is influenced by diet type and source of Cu. Dietary factors that act as antagonists for Cu absorption, such as high concentrations of Zn and phytate, alleviate the pro-oxidant effects of excess Cu [39]. The major sources of Cu fed to pigs include CuSO4 and Cu hydroxychloride, and these sources vary greatly in their chemical characteristics [84]. Pigs fed diets with 225 mg/kg Cu hydroxychloride had reduced duodenal malondialdehyde concentrations compared with pigs fed CuSO4 at the same concentration, which resulted in less oxidative stress in the intestine [39].

Assessment methods for copper bioavailability

One way to evaluate efficacy of sources of Cu is to measure relative bioavailability or digestibility. Relative bioavailability of dietary Cu is defined as the proportion of the ingested dietary Cu that has been chemically absorbed and can be utilized by the animal for maintenance and growth [85]. Bioavailability is also defined as the proportion of an ingested nutrient that is absorbed, transported to its site of action, and utilized to synthesize a physiologically active metabolite [86]. Estimates for relative bioavailability of different Cu sources is commonly obtained through slope-ratio assays [87]. In this assay, diets with graded levels of Cu are formulated, and responses indicative of Cu status of the animals are evaluated [88]. Responses include tissue concentrations of Cu, concentrations of metalloproteins, or enzymatic activity of animals fed the test diets. The slope of the regression line obtained from animals fed the test source of Cu is compared with that from animals fed a reference Cu source [89, 90].

Cupric sulfate pentahydrate is the most commonly used reference standard for estimating bioavailability of Cu from different sources [91]. The relative bioavailability of Cu is evaluated in vivo using Cu radioisotopes and plethoric dietary supplementation [85]. Liver, bile, and gall bladder are usually harvested and Cu concentrations are measured to assess relative Cu bioavailability [92,93,94]. Plasma Cu concentrations, metalloproteins, and metalloenzymatic activities (ceruloplasmin, cytochrome C oxidase, and Cu-superoxide dismutase) can also be used as indicators of Cu status [95]. In pigs, Cu-Lys and Cu-Met are more bioavailable than CuSO4, whereas cupric carbonate and Cu citrate are less bioavailable than CuSO4 (Table 1). In general, plant feed ingredients are variable in the bioavailability of Cu and have lower bioavailability of Cu than animal and sources of Cu [85] because the majority of Cu in plant feed ingredients is bound to phytate [88]. However, Cu from pork liver has low bioavailability compared with other sources due to high concentration of Zn in the liver, which may inhibit Cu availability [88]. Copper oxide also has low bioavailability when fed to ruminants, poultry, and pigs [93, 96] due to the inability of copper oxide to solubilize in acidic conditions with relatively high passage rate in the gastrointestinal tract [95].

Table 1 Relative bioavailability of Cu sources for pigsa

Enzyme efficacy, digestibility, and in vitro bioavailability of Cu in feed ingredients have been studied [97]. Results of an in vitro digestibility assay indicated that CuSO4 and Cu hydroxychloride were completely dissolved during stomach digestion simulation, but the solubility of Cu from Cu hydroxychloride was more influenced by the pH of the digesta than Cu from CuSO4 if fed to poultry [98, 99]. Copper from CuSO4 was completely dissolved at pH 6.8, 4.8, 3.0, and 2.0. In contrast, Cu from Cu hydroxychloride was not soluble at pH 6.8, but solubility gradually increased as pH decreased [100]. The concentration of Cu in diets may also affect its solubility in the stomach. Solubility of Cu during simulated stomach digestion in pigs increased if 250 mg/kg of CuSO4 or Cu hydoxychloride was included in a control diet that contained 15 mg/kg of Cu [99]. Due to the low concentration of Cu in the control diet, other feed ingredients inhibit dissolution of Cu. Therefore, supplementation of CuSO4 or Cu hydoxychloride to the control diet may have increased the proportion of Cu available for stomach dissolution in pigs [99].

Copper sources and requirements for pigs

The Cu that is included in pig diets usually originates from plant or animal-based feed ingredients or from mineral supplements. Most commonly used cereal grains and their co-products in swine diets contain 4.4 to 38.4 mg/kg of Cu on an as-fed basis (Table 2), but the amount of Cu in each plant feed ingredient vary depending on the variety, type of soil on which plants grow, maturity stage, and climatic conditions during growth [18]. Oilseed meals including soybean meal, cottonseed meal, and linseed meal usually have greater Cu concentration compared with cereal grains [101]. Fermentation of plant feed ingredients increases concentration of crude protein and ash because soluble carbohydrates are fermented, and therefore, the concentration of Cu may also increase [102]. Animal protein sources commonly used in pig diets include fish meal, poultry meal, and blood meal and these ingredients are generally comparable in Cu concentration to plant feed ingredients ranging from 8 to 36 mg/kg [76]. Copper in milk products such as skim milk powder, lactose, casein, and whey powder ranges from 0.10 to 6 mg/kg [76].

Table 2 Copper concentration in feed ingredientsa

Supplemental Cu is provided by fortifying complete diets and premixes with Cu from CuSO4, copper chloride, Cu amino acid complexes, or Cu hydroxychloride. Copper sulfate pentahydrate (CuSO4·5H2O) is a blue crystalline Cu salt commonly used as a pesticide, fungicide, soil additive, and feed supplement [103]. Copper sulfate is soluble in water with decreased solubility upon subjection to increased acid conditions [104]. Copper sulfate is the most common form of supplemental Cu in animal feeding due to its availability, and its relatively low cost compared with other sources of Cu [105]. Results of a number of experiments have documented the effects of CuSO4 in enhancing growth performance and gut health in weanling pigs [106,107,108,109]. However, using pharmacological concentrations of CuSO4 in pig diets have resulted in antagonisms with other dietary constituents [110] and environmental concerns due to high excretion of Cu in feces [111]. Due to potential negative effects on the external environment, the European Union, China, and other countries recently reduced the authorized maximum concentration of Cu in animal feed [112]. Excessive use of Cu in diets fed to pigs resulted in acquired copper resistance in gram-negative bacteria (e.g., Escherichia coli, Pseudomonas syringae) and gram-positive bacteria (e.g., Bacillus subtilis, Lactococcus lactis), which may lead to antibiotic resistance and negatively influence antibiotic treatments for diseases [113,114,115,116]. Therefore, other forms of supplemented Cu, which are generally included in diets at a lower inclusion rate and are less reactive with other nutrients, have been introduced to the feed industry. Examples of other sources of Cu include chelated Cu and Cu hydroxychloride. Chelation involves binding of Cu to a ligand (i.e., ethylenediaminetetraacetic acid, hydrolyzed soy protein, amino acids, or polysaccharides), and it is possible that Cu from these sources is absorbed more efficiently and have higher retentions compared with Cu from CuSO4 [16, 112, 117]. Indeed, inclusion of chelated Cu in diets for weanling pigs is as effective as use of CuSO4 in improving growth performance [117,118,119]. Addition of 100 to 200 mg of Cu per kg complexed with amino acids such as CuLys is also as effective, and in some cases more effective, than Cu from CuSO4 in increasing average daily gain (ADG) and average daily feed intake (ADFI) in weanling pigs [120, 121]. In an experiment conducted by Ma et al. [122], treatments included 2 supplemental levels of Cu (50 or 250 mg/kg) and Cu from either Cu(2-hydroxy-4-methylthio butanoic acid)2 or CuSO4. Results indicated that Cu(2-hydroxy-4-methylthio butanoic acid)2 was more efficient than CuSO4 in improving feed efficiency [122]. Another source of inorganic Cu is Cu hydroxychloride, and several experiments demonstrate that this source of Cu, when included at 150 mg/kg, enhances growth rate and feed efficiency in pigs (Table 3). Copper hydroxychloride is insoluble in water due to covalent binding of Cu to hydroxyl groups, but it is highly soluble in acidic conditions, which makes it less reactive in vitamin-mineral premixes, less toxic, and it has less pro-oxidant activity than CuSO4 [84, 129, 130].

Table 3 Growth performance of pigs fed diets containing 0 or 150 mg Cu per kg from Cu hydroxychloride. Average of 7 experimentsa

The requirement for Cu by pigs is influenced by dietary factors and age of the animal. Neonatal pigs usually require 5 to 10 mg of Cu per kg of diet for normal metabolism [76, 131, 132] and as pigs get older, the requirement for Cu decreases. A requirement of 5 to 6 mg of Cu per kg of diet has been suggested for growing pigs [73, 76]. Both primiparous and multiparous sows require supplementation of 10 mg of Cu per kg of diet during gestation [49]. Limited information is available about feeding high levels of Cu for gestating and lactating sows, but including 60 mg of Cu per kg of diet for sows improve reproductive performance compared with sows fed a diet containing 6 mg/kg of Cu [76]. Sows fed diets containing 250 mg/kg of Cu from CuSO4 had reduced culling rate, farrowed larger litters of pigs, and had heavier pigs at birth and at weaning compared with sows fed diets without added Cu [133].

Dietary factors that interfere with Cu absorption, and therefore may influence the need for Cu, include dietary Zn, Fe, S, Mo, and phytate. Zinc is closely related to Cu, chemically and physiologically [134]. Zinc is an essential component and activator of several metalloenzymes, and some of these metalloenzymes, such as superoxide dismutase, has both Cu and Zn as one of its components [135]. High concentrations of dietary Zn increase the requirement for Cu [131] by inducing high concentrations of intestinal metallothionein, which binds Cu, and decreases Cu absorption [36]. High Zn intake, therefore, induces clinical signs of Cu deficiency [136,137,138]. High dietary concentrations of Fe decrease Cu absorption, which lead to Cu deficiency [139]. It is believed that Fe and Cu have antagonistic effects due to competition for absorption sites in intestinal mucosa [139], and the interference of Fe in Cu absorption involve formation of ferrous sulfide complexes [140]. The sulfide part in the complex forms insoluble complexes with Cu [141]. The presence of phytate in the diet can also affect Cu absorption because phytic acid binds dietary cations including Cu, rendering them unavailable for digestion and absorption [142]. Phytase supplementation, therefore, increases Cu absorption by releasing Cu from phytic acid [143], but microbial phytase may decrease Cu availability by releasing significant amounts of Zn bound to phytate [92].

Growth promoting levels of copper

Supplementing Cu to diets fed to weanling pigs at 100 to 250 mg/kg improve ADG and ADFI [108, 144, 145]. Reduction in diarrhea frequency and increased feed efficiency were also observed when high concentration of Cu was included in diets for weanling and growing pigs [123, 146]. Addition of 60 to 250 mg of Cu per kg in sow diets during late gestation and lactation reduce pre-weaning mortality [147] and increase pig weaning weights [148], presumably because of increased milk production. The greater ADFI reported for pigs fed diets supplemented with Cu is possibly due to the role of Cu in upregulating the mRNA expression of neuropeptide Y [149], a neuropeptide considered a feed intake inducer [150]. Copper also stimulates the secretion of growth hormone releasing hormone [151, 152] and is important for post-translational modification of regulatory peptides [153]. One of the hypothesized mechanism of Cu in improving growth performance is that Cu may stimulate activities of enzymes involved in nutrient digestion [154]. Addition of high concentrations of Cu increased lipase and phospholipase A activities in the small intestine [155], which may result in increased absorption of fatty acids and improved growth performance. However, supplementation of Cu at 150 mg/kg in diets for growing pigs did not improve apparent total tract digestibility of energy or true total tract digestibility of fat [124, 125]. Inclusion of 45 mg of Cu per kg of diet improved body weight gain of rabbits by upregulating the mRNA transcription of fatty acid transport protein and fatty acid-binding protein (FABP), and carnitine palmitoyl transferase 1 [156]. Supplementation of Cu to diets increased lipogenesis and fatty acid uptake in fish, indicating that dietary Cu influences post-absorptive metabolism of lipids [157]. Copper supplementation in diets for finishing pigs did not affect mRNA transcription of intestinal CTR1 and FABP [158]. However, supplementation of Cu at 150 mg/kg in diets for growing pigs increased the abundance of lipoprotein lipase and FABP1 in the subcutaneous adipose tissue and liver, respectively [126]. Therefore, the observed improvement in growth performance of pigs fed the Cu-supplemented diets may be a result of improved lipid metabolism with a subsequent improvement in energy utilization [126].

The growth-promoting effects of dietary Cu have also been attributed to its bacteriostatic and bactericidal properties [109] because Cu may alter the bacterial populations in the intestine, and thereby affect the growth and community structure of microorganisms in the cecum and colon [159]. Copper alters the 3-dimensional structure of bacterial proteins, which prevents bacteria from performing their normal functions [160]. Copper may disrupt enzyme structures and functions of bacteria by binding to S or carboxylate-containing groups and amino groups of proteins [161]. A high-Cu diet did not improve growth performance of germ-free pigs, but the high-Cu diet increased ADG and ADFI in conventionally reared pigs [162]. Clostridium, Escherichia coli, and Salmonella viable counts were reduced in the small intestine, and the numbers of coliforms were reduced as well in the cecum and colon of pigs upon Cu supplementation [106, 107, 163]. Copper supplementation in weanling pig diets reduced the counts of enterococci in the stomach and increased the lactobacilli population in the cecum of young pigs [159, 164]. Reduction in concentration of lactate, short chain fatty acids, biogenic amines (histamine, cadaverine, and putrescine), ammonia absorption, and urease activity in the gastrointestinal content of pigs were observed if 175 to 250 mg of CuSO4 per kg was supplemented to diets for weanling pigs [159, 163, 165, 166]. Supplementation of 150 mg/kg Cu as Cu hydroxychloride in diets for growing pigs also resulted in a reduction in microbial protein concentration, which is likely due to the ability of Cu to inhibit growth of microbes in the intestinal tract of pigs [167].

Weanling pigs are susceptible to infections, diseases, and villous atrophy in the gut, which result in physiological and pathological changes and altered intestinal tight junction barrier resulting in increased intestinal permeability [168, 169]. Tight junctions are made up of integral membrane proteins, mainly occludin and zonula occludens protein-1, and the integrity of the tight junctions is one of the important components of the intestinal mucosal barrier function [170]. Intestinal permeability increases upon diarrhea, which allows entry of toxins and pathogenic microorganism through the epithelial cells [171]. Inclusion of Cu at 100 to 200 mg/kg in diets fed to weanling pigs increases villus height and reduces crypt depth, thus improving intestinal health [172]. A reduction in concentrations of plasma diamine oxidase and D-lactate was observed when diets were supplemented with Cu-exchanged montmorillonites at 1500 mg/kg [163]. Diamine oxidase is located exclusively in intestinal villus and its preference in blood plasma serves as a marker for mucosal injury [173]. When pigs undergo stress and intestinal mucosal barrier is damaged, intestinal mucosal cells are being sloughed into the lumen, which leads to increased concentration of diamine oxidase [163]. Plasma D-lactate is a byproduct of intestinal bacteria, and excessive production of this metabolite pass through the damaged mucosa [173]. Therefore, the observed reduction in plasma diamine oxidase and D-lactate upon supplementation of dietary of Cu to diets indicates reduction in intestinal permeability and improvement of intestinal health. However, this is in contrast with data indicating that supplementation of Cu hydroxychloride did not affect the lactulose:mannitol ratio in pigs [127] indicating that high concentration of dietary Cu did not impact intestinal permeability of pigs.

Copper plays an important role in improving the innate and acquired immune function of animals [174], but improvements in the immune status of pigs fed high-Cu diets may be indirect because of the bacteriostatic property of Cu, which may reduce inflammation caused by pathogens [123, 174]. Exposure of pigs to pathogenic or nonpathogenic antigens results in an activated immune system and subsequent release of cytokines such as tumor necrosis factor α, interleukin-1, and interleukin-6 [168]. Pigs fed diets containing 3000 mg of Zn per kg and 250 mg of Cu per kg had reduced plasma cytokine circulation after a coliform lipopolysaccharide challenge, which likely indicates that both Cu and Zn can reduce infection and alleviate stress responses induced by bacterial endotoxin [175]. Likewise, pigs fed diets containing nanoCu had greater ADG and feed efficiency, and greater concentrations of γ-globulin, total globulin protein, and IgG compared with pigs fed the control diet [176]. Supplementation of dietary Cu to diets also resulted in reduced tumor necrosis factor α concentration and increased activity of superoxide dismutase in blood serum of weanling pigs [123, 176]. This indicates that the observed improvement in growth performance in pigs fed the Cu-supplemented diets was possibly due to improved antioxidant capacity and humoral immune response, which can prevent susceptibility of pigs to infections and diseases.


Copper is an important micronutrient needed for maintenance, growth, and optimum health. Inclusion of 75 to 250 mg/kg of Cu in diets for pigs improve feed intake and feed efficiency. Results of several experiments demonstrated that the consistent improvement in growth performance upon Cu supplementation to diets is likely a result of the ability of dietary Cu to modulate intestinal microbial populations, increase lipase activity, stimulate secretion of neuropeptide Y and growth hormone, regulate antioxidant system, indirectly improve the immune response, and increase mRNA abundance of genes involved in post-absorptive metabolism of lipids in pigs. Dietary factors that interfere with Cu absorption was discussed, but further research needs to focus on determining potential interactions of Cu with non-nutritive feed additives (e.g., enzymes, probiotics). The optimum amount and duration of feeding supplemental Cu in diets fed to pigs also need to be further investigated. By addressing these gaps in the knowledge about Cu, the use of Cu in the feeding of pigs can be optimized.

Availability of data and materials

Not applicable.



Average daily feed intake


Average daily gain


Antioxidant protein 1


Copper transporting ATPase 1 protein


Copper transporting ATPase 2 protein


Aspartate transaminase


Copper transport protein 1


Copper transport protein 2


Cytochrome C oxidase Cu chaperone


Divalent metal transporter


Gain to feed ratio


Cytosolic Cu-Zn superoxide dismutase


Extracellular Cu-Zn superoxide dismutase 3


  1. 1.

    Suttle NF. Mineral nutrition of livestock. 4th ed. Oxfordshire: CABI Publishing; 2010.

    Book  Google Scholar 

  2. 2.

    Ammerman CB, Goodrich RD. Advances in mineral nutrition in ruminants. J Anim Sci. 1983;57:519–33.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    McCollum EV. A history of nutrition. Boston: Houghton Mifflin Co.; 1957.

    Google Scholar 

  4. 4.

    Mateos GG, Lazaro R, Astillero JR, Perez-Serrano M. Trace minerals: what text books don’t tell you. In: Taylor-Pickard JA, Tucker LA, editors. Re-defining mineral nutrition. Nottingham: Nottingham Univ. Press; 2005. p. 21–61.

    Google Scholar 

  5. 5.

    Goff JP. Minerals, bones, and joints. In: Reece WO, editor. Duke’s physiology of domestic animals. Oxford: Wiley; 2015. p. 581–3.

    Google Scholar 

  6. 6.

    McDowell LR. Copper and molybdenum. In: Cunha TJ, editor. Minerals in animal and human nutrition. San Diego: Academic; 1992. p. 176–202.

    Google Scholar 

  7. 7.

    Crapo JD, Oury T, Rabouille C, Slot JW, Chang LY. Copper-zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci U S A. 1992;89:10405–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Manto M. Abnormal copper homeostasis: mechanisms and roles in neurodegeneration. Toxics. 2014;2:327–45.

    CAS  Article  Google Scholar 

  9. 9.

    Hill GM. Minerals and mineral utilization in swine. In: Chiba LI, editor. Sustainable swine nutrition. Oxford: Blackwell Publishing Ltd; 2013. p. 186–9.

    Google Scholar 

  10. 10.

    Turnlund JR. Human whole-body copper metabolism. Am J Clin Nutr. 1998;67:960S–4S.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Gaetke LM, Chow CK. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology. 2003;189:147–63.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Hart EB, Steenbock H, Waddell J, Elvehjem CA. Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem. 1928;77:797–812.

    CAS  Article  Google Scholar 

  13. 13.

    Elvehjem CA. The biological significance of copper and its relation to iron metabolism. Physiol Rev. 1935;15:471–507.

    CAS  Article  Google Scholar 

  14. 14.

    Hambridge KM, Casey CE, Krebs NF. Zinc. In: Mertz W, editor. Trace elements in human and animal nutrition. New York: Academic; 1986. p. 1–138.

    Google Scholar 

  15. 15.

    Lebel A, Matte JJ, Guay F. Effect of mineral source and mannan oligosaccharide supplements on zinc and copper digestibility in growing pigs. Arch Anim Nutr. 2014;68:370–84.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Liu Y, Ma YL, Zhao JM, Vazquez-Añón M, Stein HH. Digestibility and retention of zinc, copper, manganese, iron, calcium, and phosphorus in pigs fed diets containing inorganic or organic minerals. J Anim Sci. 2014;92:3407–15.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Richards JD, Zhao J, Harrell RJ, Atwell CA, Dibner JJ. Trace mineral nutrition in poultry and swine. Asian-Australas J Anim Sci. 2010;23:1527–34.

    CAS  Article  Google Scholar 

  18. 18.

    Underwood EJ, Suttle NF. The mineral nutrition of livestock. 3rd ed. Oxfordshire: CABI Publishing; 1999.

    Book  Google Scholar 

  19. 19.

    Powell JJ, Whitehead MW, Ainley CC, Kendall MD, Nicholson JK, Thompson RPH. Dietary minerals in the gastrointestinal tract: hydroxypolymerisation of aluminium is regulated by luminal mucins. J Inorg Biochem. 1999;75:167–80.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Mullan BP, D'Souza DN. The role of organic minerals in modern pig production. In: Taylor JA, Tucker LA, editors. Re-defining mineral nutrition. Nottingham: Nottingham Univ. Press; 2005. p. 89–106.

    Google Scholar 

  21. 21.

    van Campen DR, Mitchell EA. Absorption of Cu-64, Zn-65, Mo-99, and Fe-59 from ligated segments of the rat gastrointestinal tract. J Nutr. 1965;86:120–4.

    Article  Google Scholar 

  22. 22.

    van den Berghe PVE, Klomp LWJ. New developments in the regulation of intestinal copper absorption. Nutr Rev. 2009;67:658–72.

    PubMed  Article  Google Scholar 

  23. 23.

    Pappenheimer JR, Reiss KZ. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J Membr Biol. 1987;100:123–36.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Georgatsou E, Mavrogiannis LA, Fragiadakis GS, Alexandraki D. The yeast fre1p/fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated mac1p activator. J Biol Chem. 1997;272:13786–92.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood. 2006;108:1388.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter identification of a Ctr1-independent copper transport system. J Biol Chem. 2002;277:40253–9.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Hill GM, Link JE. Transporters in the absorption and utilization of zinc and copper. J Anim Sci. 2009;87:E85–9.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Zhou B, Gitschier J. hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci. 1997;94:7481–6.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Cater MA, Mercer JFB. Copper in mammals: mechanisms of homeostasis and pathophysiology. In: Tamas MJ, Martinoia E, editors. Molecular biology of metal homeostasis and detoxification: from microbes to man. Berlin, Heidelberg: Springer Berlin Heidelberg; 2006. p. 101–29.

    Google Scholar 

  30. 30.

    Vonk WI, Wijmenga C, van de Sluis B. Relevance of animal models for understanding mammalian copper homeostasis. Am J Clin Nutr. 2008;88:840S–5S.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev. 2007;87:1011–46.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Kim H, Son H-Y, Bailey SM, Lee J. Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis. Am J Physiol Gastrointest Liver Physiol. 2009;296:G356–G64.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Axelsen KB, Palmgren MG. Evolution of substrate specificities in the P-type ATPase superfamily. J Mol Evol. 1998;46:84–101.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Peña MM, Jaekwon OL, Thiele DJ. A delicate balance: homeostatic control of copper uptake and distribution. J Nutr. 1999;129:1251–60.

    PubMed  Article  Google Scholar 

  35. 35.

    Davis GK, Mertz W. Copper. In: Mertz W, editor. Trace elements in human and animal nutrition. San Diego: Academic; 1987. p. 301–64.

    Chapter  Google Scholar 

  36. 36.

    Cousins RJ. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev. 1985;65:238–309.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Carlson MS, Hill GM, Link JE. Early- and traditionally weaned nursery pigs benefit from phase-feeding pharmacological concentrations of zinc oxide: effect on metallothionein and mineral concentrations. J Anim Sci. 1999;77:1199–207.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Toriumi S, Saito T, Hosokawa T, Takahashi Y, Numata T, Kurasaki M. Metal binding ability of metallothionein-3 expressed in Escherichia coli. Basic Clin Pharmacol Toxicol. 2005;96:295–301.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Huang Y, Ashwell M, Fry R, Lloyd K, Flowers W, Spears J. Effect of dietary copper amount and source on copper metabolism and oxidative stress of weanling pigs in short-term feeding. J Anim Sci. 2015;93:2948–55.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Goff JP. Invited review: mineral absorption mechanisms, mineral interactions that affect acid-base and antioxidant status, and diet considerations to improve mineral status. J Dairy Sci. 2018;101:2763–813.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Linder MC. Biochemistry of copper. New York: New York Plenum Press; 1991.

    Book  Google Scholar 

  42. 42.

    Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Clin Invest. 1970;49:2408–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem. 1966;241:2746–51.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Ragan HA, Nacht S, Lee GR, Bishop CR, Cartwright GE. Effect of ceruloplasmin on plasma iron in copper-deficient swine. Am J Phys. 1969;217:1320–3.

    CAS  Article  Google Scholar 

  45. 45.

    Milne DB, Matrone G. Forms of ceruloplasmin in developing piglets. Biochim Biophys Acta. 1970;212:43–9.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Gubler CJ, Brown H, Markowitz H, Cartwright GE, Wintrobe MM. Studies on copper metabolism. XXIII: portal (Laennec’s) cirrhosis of the liver. J Clin Invest. 1957;36:1208–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Gubler CJ, Lahey ME, Cartwright GE, Wintrobe MM. Studies on copper metabolism. X: factors influencing the plasma copper level of the albino rat. Am J Phys. 1952;171:652–8.

    CAS  Article  Google Scholar 

  48. 48.

    Lahey ME, Gubler CJ, Chase MS, Cartwright GE, Wintrobe MM. Studies on copper metabolism. II: hematologic manifestations of copper deficiency in swine. Blood. 1952;7:1053–74.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Lorenzen EJ, Smith SE. Copper and manganese storage in the rat, rabbit, and guinea pig. J Nutr. 1947;33:143–54.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Hart EB, Steenbock H, Waddell J, Elvehjem CA. Iron in nutrition VII. Copper as a supplement to iron for hemoglobin building in the rat. Nutr Rev. 1987;45:181–3.

    Article  Google Scholar 

  51. 51.

    Suttle NF, Angus KW. Effects of experimental copper deficiency on the skeleton of the calf. J Comp Pathol. 1978;88:137–48.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Carla LGG. Copper levels in livers of turkeys with naturally occurring aortic rupture. Avian Dis. 1977;21:113–6.

    Article  Google Scholar 

  53. 53.

    Savage JE, Bird DW, Reynolds G, O'Dell BL. Comparison of copper deficiency and lathyrism in turkey poults. J Nutr. 1966;88:15–25.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Coulson WF, Carnes WH. Cardiovascular studies on copper-deficient swine. v. the histogenesis of the coronary artery lesions. Am J Pathol. 1963;43:945–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Carnes WH, Coulson WF, Albino AM. Intimal lesions in muscular arteries of young copper-deficient swine. Ann N Y Acad Sci. 1965;127:800–10.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Buffoni F, Blaschko HKF. Benzylamine oxidase and histaminase: purification and crystallization of an enzyme from pig plasma. Proc R Soc Lond B Biol Sci. 1964;161:153–67.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Prohaska JR. Changes in tissue growth, concentrations of copper, iron, cytochrome oxidase and superoxide dismutase subsequent to dietary or genetic copper deficiency in mice. J Nutr. 1983;113:2048–58.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Miller ER, Stowe HD, Ku PK, Hill GM. Copper and zinc in animal nutrition. Literature Review Committee. West Des Moines: National Feed Ingredients Association; 1979.

    Google Scholar 

  59. 59.

    Sorenson JRJ. Copper complexes offer a physiological approach to treatment of chronic diseases. In: Ellis GP, West GB, editors. Progress in medicinal chemistry: Elsevier; 1989. p. 437–568..

  60. 60.

    Segal AW, Meshulam T. Production of superoxide by neutrophils: a reappraisal. FEBS Lett. 1979;100:27–32.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Teague HS, Carpenter LE. The demonstration of a copper deficiency in young growing pigs: five figures. J Nutr. 1951;43:389–99.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Pletcher JM, Banting LF. Copper deficiency in piglets characterized by spongy myelopathy and degenerative lesions in the great blood vessels. J S Afr Vet Assoc. 1983;54:43–6.

    CAS  PubMed  Google Scholar 

  63. 63.

    Johnson LR, Engle TE. The effects of copper source and concentration on lipid metabolism in growing and finishing angus steers. Asian-Australas J Anim Sci. 2003;16:1131–6.

    CAS  Article  Google Scholar 

  64. 64.

    Kaya A, Altiner A, Ozpinar A. Effect of copper deficiency on blood lipid profile and haematological parameters in broilers. J Vet Med. 2006;53:399–404.

    CAS  Article  Google Scholar 

  65. 65.

    Dove CR. The effect of adding copper and various fat sources to the diets of weanling swine on growth performance and serum fatty acid profiles. J Anim Sci. 1993;71:2187–92.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Elliot JI, Bowland JP. Effects of dietary copper sulfate on the fatty acid composition of porcine depot fats. J Anim Sci. 1968;27:956–60.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Wu F, Woodworth JC, DeRouchey JM, Coble KF, Tokach MD, Goodband RD, et al. Effect of standardized ileal digestible lysine and added copper on growth performance, carcass characteristics, and fat quality of finishing pigs. J Anim Sci. 2018;96:3249–63.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Carr TP, Lei KY. In vivo apoprotein catabolism of high density lipoproteins in copper-deficient, hypercholesterolemic rats. Proc Soc Exp Biol Med. 1989;191:370–6.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Burkhead JL, Lutsenko S. The role of copper as a modifier of lipid metabolism. In: Baez RV, editor. Lipid metabolism. Rijeka: InTech; 2013. p. Ch. 03.

    Google Scholar 

  70. 70.

    Meagher EA, FitzGerald GA. Indices of lipid peroxidation in vivo: strengths and limitations. Free Radic Biol Med. 2000;28:1745–50.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Abdel-Mageed AB, Oehme FW. A review of the biochemical roles, toxicity and interactions of zinc, copper and iron: II. Copper. Vet Hum Toxicol. 1990;32:230–4.

    CAS  PubMed  Google Scholar 

  72. 72.

    Lamand M. Copper toxicity in sheep. In: L'hermite P, Dehandtschutter J, editors. Copper in animal wastes and sewage sludge. London: D. Reidel Publishing Co.; 1981. p. 261–72.

    Chapter  Google Scholar 

  73. 73.

    ARC. The nutrient requirements of pigs. Slough: Commonwealth; 1981.

    Google Scholar 

  74. 74.

    Suttle NF, Alloway BJ, Thornton I. Effect of soil ingestion on the utilization of dietary copper by sheep. J Agric Sci. 1975;84:249–54.

    Article  Google Scholar 

  75. 75.

    Thompson LJ. Copper. In: Gupta RC, editor. Veterinary toxicology (third edition): Academic; 2018. p. 425–7.

  76. 76.

    NRC. Nutrient requirements of swine. 11th rev. ed. Washington, D.C.: Natl. Acad. Press; 2012.

    Google Scholar 

  77. 77.

    Jacela JY, DeRouchey JM, Tokach MD, Goodband RD, Nelssen JL, Renter DG, et al. Feed additives for swine: fact sheets – high dietary levels of copper and zinc for young pigs, and phytase. J Swine Health Prod. 2010;18:87–91.

    Google Scholar 

  78. 78.

    Suttle NF, Mills CF. Studies of the toxicity of copper to pigs: 1. Effects of oral supplements of zinc and iron salts on the development of copper toxicosis. Br J Nutr. 2007;20:135–48.

    Article  Google Scholar 

  79. 79.

    Ellingsen DG, Horn N, Aaseth JAN. Copper. In: Nordberg GF, Fowler BA, Nordberg M, Friberg LT, editors. Handbook on the toxicology of metals. Burlington: Academic; 2007. p. 529–46.

    Chapter  Google Scholar 

  80. 80.

    Bremner I. Manifestations of copper excess. Am J Clin Nutr. 1998;67:1069–73.

    Article  Google Scholar 

  81. 81.

    Lykkesfeldt J, Svendsen O. Oxidants and antioxidants in disease: oxidative stress in farm animals. Vet J. 2007;173:502–11.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Fry RS, Ashwell MS, Lloyd KE, O’Nan AT, Flowers WL, Stewart KR, et al. Amount and source of dietary copper affects small intestine morphology, duodenal lipid peroxidation, hepatic oxidative stress, and mRNA expression of hepatic copper regulatory proteins in weanling pigs. J Anim Sci. 2012;90:3112–9.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Khoubnasabjafari M, Ansarin K, Jouyban A. Reliability of malondialdehyde as a biomarker of oxidative stress in psychological disorders. Bioimpacts. 2015;5:123–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Miles RD, O'Keefe SF, Henry PR, Ammerman CB, Luo XG. The effect of dietary supplementation with copper sulfate or tribasic copper chloride on broiler performance, relative copper bioavailability, and dietary prooxidant activity. Poult Sci. 1998;77:416–25.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Baker DH, Ammerman CB. Copper bioavailability. In: Ammerman CB, Baker DH, Lewis AJ, editors. Bioavailability of nutrients for animals. San Diego: Academic; 1995. p. 127–56.

    Chapter  Google Scholar 

  86. 86.

    O'Dell BL. Bioavailability of essential and toxic trace elements. Fed Proc. 1983;42:1714–8.

    CAS  PubMed  Google Scholar 

  87. 87.

    Littell RC, Lewis AJ, Henry PR. Statistical evaluation of bioavailability assays. In: Ammerman CB, Baker DH, Lewis AJ, editors. Bioavailabiltiy of nutrients for animals. San Diego: Academic; 1995. p. 5–33.

    Chapter  Google Scholar 

  88. 88.

    Aoyagi S, Baker DH, Wedekind KJ. Estimates of copper bioavailability from liver of different animal species and from feed ingredients derived from plants and animals. Poult Sci. 1993;72:1746–55.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    L'Abbé MR, Fischer PWF. The effects of high dietary zinc and copper deficiency on the activity of copper-requiring metalloenzymes in the growing rat. J Nutr. 1984;114:813–22.

    PubMed  Article  Google Scholar 

  90. 90.

    Suttle NF. A technique for measuring the biological availability of copper of sheep, sing hypocupraemic ewes. Br J Nutr. 2007;32:395–405.

    Article  Google Scholar 

  91. 91.

    Lönnerdal B, Bell J, Keen C. Copper absorption from human milk, cow’s milk, and infant formulas using a suckling rat model. Am J Clin Nutr. 1985;42:836–44.

    PubMed  Article  Google Scholar 

  92. 92.

    Aoyagi S, Baker DH. Effect of microbial phytase and 1,25-dihydroxycholecalciferol on dietary copper utilization in chicks. Poult Sci. 1995;74:121–6.

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Cromwell GL, Stahly TS, Monegue HJ. Effects of source and level of copper on performance and liver copper stores in weanling pigs. J Anim Sci. 1989;67:2996–3002.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Lo GS, Settle SL, Steinke FH. Bioavailability of copper in isolated soybean protein using the rat as an experimental model. J Nutr. 1984;114:332–40.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Kegley EB, Spears JW. Bioavailability of feed-grade copper sources (oxide, sulfate, or lysine) in growing cattle. J Anim Sci. 1994;72:2728–34.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Baker DH. Cupric oxide should not be used as a copper supplement for either animals or humans. J Nutr. 1999;129:2278–9.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Kong C, Park CS, Kim BG. Effects of an enzyme complex on in vitro dry matter digestibility of feed ingredients for pigs. Springerplus. 2015;4:261.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Pang Y, Applegate TJ. Effects of copper source and concentration on in vitro phytate phosphorus hydrolysis by phytase. J Agric Food Chem. 2006;54:1792–6.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Park CS, Kim BG. In vitro solubility of copper(II) sulfate and dicopper chloride trihydroxide for pigs. Asian-Austral J Anim. 2016;29:1608–15.

    CAS  Article  Google Scholar 

  100. 100.

    Pang Y, Applegate TJ. Effects of dietary copper supplementation and copper source on digesta pH, calcium, zinc, and copper complex size in the gastrointestinal tract of the broiler chicken. Poult Sci. 2007;86:531–7.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    O'Dell BL. Mineral availability and metal binding constituents of the diet. Ithaca: Proc. Cornell Nutr. Conf. Feed Manufact; 1962.

    Google Scholar 

  102. 102.

    Drew MD, Borgeson TL, Thiessen DL. A review of processing of feed ingredients to enhance diet digestibility in finfish. Anim Feed Sci Technol. 2007;138:118–36.

    CAS  Article  Google Scholar 

  103. 103.

    Milligan D, Moyer H. Crystallization in the copper sulphate- sulphuric acid- water system. Eng Min J. 1975;176:85–9.

    Google Scholar 

  104. 104.

    Justel FJ, Claros M, Taboada ME. Solubilities and properties of saturated solutions in the copper sulfate + sulfuric acid + seawater system at different temperatures. Braz J Chem Eng. 2015;32:629–35.

    CAS  Article  Google Scholar 

  105. 105.

    Shelton NW, Tokach MD, Nelssen JL, Goodband RD, Dritz SS, DeRouchey JM, et al., editors. Effects of copper sulfate and zinc oxide on weanling pig growth and plasma mineral levels. In: Swine Day: Kansas State University; 2009.

  106. 106.

    Ma YL, Guo T, Xu ZR. Effect of Cu (II)-exchange montmorillonite on diarrhea incidence, intestinal microflora and mucosa morphology of weaning pigs. Chin J Vet Sci. 2007;27:279–83.

    CAS  Google Scholar 

  107. 107.

    Ma YL, Xu ZR, Guo T. Effect of inorganic copper/montmorillonite nanomaterial on growth performance, intestinal microbial flora and bacterial enzyme activities in broilers. Chin J Anim Sci. 2006;42:28–31.

    CAS  Google Scholar 

  108. 108.

    Perez VG, Waguespack AM, Bidner TD, Southern LL, Fakler TM, Ward TL, et al. Additivity of effects from dietary copper and zinc on growth performance and fecal microbiota of pigs after weaning. J Anim Sci. 2011;89:414–25.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Stahly TS, Cromwell GL, Monegue HJ. Effects of the dietary inclusion of copper and(or) antibiotics on the performance of weanling pigs. J Anim Sci. 1980;51:1347–51.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Wang YZ, Shan TZ, Xu ZR, Feng J, Wang ZQ. Effects of the lactoferrin (LF) on the growth performance, intestinal microflora and morphology of weanling pigs. Anim Feed Sci Technol. 2007;135:263–72.

    CAS  Article  Google Scholar 

  111. 111.

    Zhao J, Allee G, Gerlemann G, Ma L, Gracia MI, Parker D, et al. Effects of a chelated copper as growth promoter on performance and carcass traits in pigs. Asian-Austral J Anim. 2014;27:965–73.

    CAS  Article  Google Scholar 

  112. 112.

    Lin G, Guo Y, Liu B, Wang R, Su X, Yu D, et al. Optimal dietary copper requirements and relative bioavailability for weanling pigs fed either copper proteinate or tribasic copper chloride. J Anim Sci Biotechnol. 2020;11:54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Hasman H, Aarestrup FM. Relationship between copper, glycopeptide, and macrolide resistance among Enterococcus faecium strains isolated from pigs in Denmark between 1997 and 2003. Antimicrob Agents Chemother. 2005;49:454–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Leelawatcharamas V, Chia LG, Charoenchai P, Kunajakr N, Liu CQ, Dunn NW. Plasmid-encoded copper resistance in Lactococcus lactis. Biotechnol Lett. 1997;19:639–43.

    CAS  Article  Google Scholar 

  115. 115.

    Solioz M, Abicht HK, Mermod M, Mancini S. Response of gram-positive bacteria to copper stress. J Biol Inorg Chem. 2009;15:3.

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    Brown NL, Barrett SR, Camakaris J, Lee BTO, Rouch DA. Molecular genetics and transport analysis of the copper-resistance determinant (pco) from Escherichia coli plasmid pRJ1004. Mol Microbiol. 1995;17:1153–66.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Fouad MT. The physiochemical role of chelated minerals in maintaining optimal body biological functions. J App Nutr. 1976;28:5.

    CAS  Google Scholar 

  118. 118.

    Stansbury WF, Tribble LF, Orr DE. Effect of chelated copper sources on performance of nursery and growing pigs. J Anim Sci. 1990;68:1318–22.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    van Heugten E, Coffey MT. Efficacy of copper-lysine chelate as growth promotant in weanling swine. J Anim Sci. 1992;70(Suppl. 1):18 (Abstr.).

    Google Scholar 

  120. 120.

    Coffey RD, Cromwell GL, Monegue HJ. Efficacy of a copper-lysine complex as a growth promotant for weanling pigs. J Anim Sci. 1994;72:2880–6.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Windisch WM, Gotterbarm GG, Roth FX. Effect of potassium diformate in combination with different amounts and sources of excessive dietary copper on production performance in weaning piglets. Arch Anim Nutr. 2001;54:87–100.

    CAS  Google Scholar 

  122. 122.

    Ma YL, Zanton GI, Zhao J, Wedekind K, Escobar J, Vazquez-Añón M. Multitrial analysis of the effects of copper level and source on performance in nursery pigs. J Anim Sci. 2015;93:606–14.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Espinosa CD, Fry RS, Usry JL, Stein HH. Effects of copper hydroxychloride and choice white grease on growth performance and blood characteristics of weanling pigs kept at normal ambient temperature or under heat stress. Anim Feed Sci Technol. 2019;256:114257.

    CAS  Article  Google Scholar 

  124. 124.

    Espinosa CD, Fry RS, Usry JL, Stein HH. Copper hydroxychloride improves growth performance and reduces diarrhea frequency of weanling pigs fed a corn–soybean meal diet but does not change apparent total tract digestibility of energy and acid hydrolyzed ether extract. J Anim Sci. 2017;95:5447–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Espinosa CD, Fry RS, Kocher M, Stein HH. Effects of copper hydroxychloride and increasing concentrations of dietary fat on growth performance, total tract endogenous loss of fat, and apparent total tract digestibility of fat by growing pigs. J Anim Sci. 2019;97:68.

    PubMed Central  Article  PubMed  Google Scholar 

  126. 126.

    Espinosa CD, Fry RS, Kocher ME, Stein HH. Effects of copper hydroxychloride on growth performance and abundance of genes involved in lipid metabolism of growing pigs. J Anim Sci. 2020;98..

  127. 127.

    Espinosa CD, Fry RS, Kocher ME, Stein HH. Effects of copper hydroxychloride and dietary fiber on intestinal permeability, growth performance, and blood characteristics of nursery pigs. Anim Feed Sci Technol. 2020:114447..

  128. 128.

    Shelton NW, Nelssen JL, Hill GM, Tokach MD, Goodband RD, DeRouchey JM, et al., editors. Effects of copper sulfate, tri-basic copper chloride, and zinc oxide on weanling pig growth and plasma mineral concentrations. In: Swine Day: Kansas State University; 2008.

  129. 129.

    Fry RS, Hu W, Williams SB, Paton ND, Cook DR. Diet form and by-product level affect growth performance and carcass characteristics of grow-finish pigs. J Anim Sci. 2012;90(Suppl 3):380.

    Google Scholar 

  130. 130.

    Liu Z, Bryant MM, Roland SDA. Layer performance and phytase retention as influenced by copper sulfate pentahydrate and tribasic copper chloride. J Appl Poult Res. 2005;14:499–505.

    CAS  Article  Google Scholar 

  131. 131.

    Underwood EJ. Trace elements in human and animal nutrition. 4th ed. New York: Academic; 1977.

    Google Scholar 

  132. 132.

    Hill G, Ku P, Miller E, Ullrey D, Losty T, O'Dell B. A copper deficiency in neonatal pigs induced by a high zinc maternal diet. J Nutr. 1983;113:867–72.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Cromwell GL, Monegue HJ, Stahly TS. Long-term effects of feeding a high copper diet to sows during gestation and lactation. J Anim Sci. 1993;71:2996–3002.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Hill GM, Brewer GJ, Hogikyan ND, Stellini MA. The effect of depot parenteral zinc on copper metabolism in the rat. J Nutr. 1984;114:2283–91.

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    O'Dell BL. Role of zinc in plasma membrane function. J Nutr. 2000;5:1432S–6S.

    Article  Google Scholar 

  136. 136.

    Bird DW. Copper deficiency and its effect upon reproduction, growth and connective tissue synthesis in avian species. Columbia: PhD Diss. Univ. Missouri; 1966.

    Google Scholar 

  137. 137.

    Esparza Gonzalez BP, Fong RN, Gibson CJ, Fuentealba IC, Cherian MG. Zinc supplementation decreases hepatic copper accumulation in LEC rat. Biol Trace Elem Res. 2005;105:117–34.

    Article  Google Scholar 

  138. 138.

    Hill GM, Miller ER, Whetter PA, Ullrey DE. Concentration of minerals in tissues of pigs from dams fed different levels of dietary zinc. J Anim Sci. 1983;57:130–8.

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Hedges JD, Kornegay ET. Interrelationship of dietary copper and iron as measured by blood parameters, tissue stores and feedlot performance of swine. J Anim Sci. 1973;37:1147–54.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr Rev. 2010;68:133–47.

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Suttle NF, Abrahams P, Thornton I. The role of a soil × dietary sulphur interaction in the impairment of copper absorption by ingested soil in sheep. J Agric Sci. 2009;103:81–6.

    Article  Google Scholar 

  142. 142.

    Martin CJ, Evans WJ. Phytic acid: divalent cation interactions: III. A calorimetric and titrimetric study of the pH dependence of copper(II) binding. J Inorg Biochem. 1986;28:39–55.

    CAS  Article  Google Scholar 

  143. 143.

    Adeola O. Digestive utilization of minerals by weanling pigs fed copper- and phytase-supplemented diets. Can J Anim Sci. 1995;75:603–10.

    CAS  Article  Google Scholar 

  144. 144.

    Cromwell GL, Lindemann MD, Monegue HJ, Hall DD, Orr JDE. Tribasic copper chloride and copper sulfate as copper sources for weanling pigs. J Anim Sci. 1998;76:118–23.

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Hill GM, Cromwell GL, Crenshaw TD, Dove CR, Ewan RC, Knabe DA, et al. Growth promotion effects and plasma changes from feeding high dietary concentrations of zinc and copper to weanling pigs (regional study). J Anim Sci. 2000;78:1010–6.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Barber RS, Braude R, Mitchell KG. Antibiotics and copper supplements for fattening pigs. Br J Nutr. 1955;9:378–81.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Thacker PA. Effect of high levels of copper or dichlorvos during late gestation and lactation on sow productivity. Can J Anim Sci. 1991;71:227–32.

    CAS  Article  Google Scholar 

  148. 148.

    Wallace HD, Houser RH, Combos GE, editors. High level copper supplementation of the sow during the farrowing and early lactation period. Gainesville: Florida Anim. Sci. Mimeograph Series; 1966.

    Google Scholar 

  149. 149.

    Li J, Yan L, Zheng X, Liu G, Zhang N, Wang Z. Effect of high dietary copper on weight gain and neuropeptide Y level in the hypothalamus of pigs. J Trace Elem Med Biol. 2008;22:33–8.

    PubMed  Article  CAS  Google Scholar 

  150. 150.

    Gehlert DR. Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides. 1999;33:329–38.

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Yang W, Wang J, Liu L, Zhu X, Wang X, Liu Z, et al. Effect of high dietary copper on somatostatin and growth hormone-releasing hormone levels in the hypothalami of growing pigs. Biol Trace Elem Res. 2011;143:893–900.

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    LaBella F, Dular R, Vivian S, Queen G. Pituitary hormone releasing or inhibiting activity of metal ions present in hypothalamic extracts. Biochem Bioph Res Co. 1973;52:786–91.

    CAS  Article  Google Scholar 

  153. 153.

    Eipper BA, Mains RE. Peptide α-Amidation. Annu Rev Physiol. 1988;50:333–44.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Dove CR. The effect of copper level on nutrient utilization of weanling pigs. J Anim Sci. 1995;73:166–71.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Luo XG, Dove CR. Effect of dietary copper and fat on nutrient utilization, digestive enzyme activities, and tissue mineral levels in weanling pigs. J Anim Sci. 1996;74:1888–96.

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Lei L, Xiaoyi S, Fuchang L. Effect of dietary copper addition on lipid metabolism in rabbits. Food Nutr Res. 2017;61:1348866.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Chen F, Luo Z, Chen G-H, Shi X, Liu X, Song Y-F, et al. Effects of waterborne copper exposure on intestinal copper transport and lipid metabolism of Synechogobius hasta. Aquat Toxicol. 2016;178:171–81.

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Coble KF, Burnett DD, DeRouchey JM, Tokach MD, Gonzalez JM, Wu F, et al. Effect of diet type and added copper on growth performance, carcass characteristics, energy digestibility, gut morphology, and mucosal mRNA expression of finishing pigs. J Anim Sci. 2018;96:3288–301.

    PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Højberg O, Canibe N, Poulsen HD, Hedemann MS. Influence of dietary zinc oxide and copper sulfate on the gastrointestinal ecosystem in newly weaned pigs. Appl Environ Microbiol. 2005;71:2267–77.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. 160.

    Thurman RB, Gerba CP, Bitton G. The molecular mechanisms of copper and silver ion disinfection of bacteria and viruses. Crit Rev Environ Control. 1989;18:295–315.

    Article  Google Scholar 

  161. 161.

    Sterritt RM, Lester JN. Interactions of heavy metals with bacteria. Sci Total Environ. 1980;14:5–17.

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Shurson GC, Miller ER, Waxler GL, Yokoyama MT, Ku PK. Physiological relationships between microbiological status and dietary copper levels in the pig. J Anim Sci. 1990;68:1061–71.

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Song J, Li Y, Hu C. Effects of copper-exchanged montmorillonite, as alternative to antibiotic, on diarrhea, intestinal permeability and proinflammatory cytokine of weanling pigs. Appl Clay Sci. 2013;77–78:52–5.

    Article  CAS  Google Scholar 

  164. 164.

    Wang M-Q, Du Y-J, Wang C, Tao W-J, He Y-D, Li H. Effects of copper-loaded chitosan nanoparticles on intestinal microflora and morphology in weaned piglets. Biol Trace Elem Res. 2012;149:184–9.

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Dierick NA, Vervaeke IJ, Decuypere JA, Henderickx HK. Influence of the gut flora and of some growth-promoting feed additives on nitrogen metabolism in pigs. II. Studies in vivo. Livest Prod Sci. 1986;14:177–93.

    CAS  Article  Google Scholar 

  166. 166.

    Yen JT, Nienaber JA. Effects of high-copper feeding on portal ammonia absorption and on oxygen consumption by portal vein-drained organs and by the whole animal in growing pigs. J Anim Sci. 1993;71:2157–63.

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Espinosa CD, Fry RS, Kocher ME, Stein HH. Effects of copper hydroxychloride and distillers dried grains with solubles on intestinal microbial concentration and apparent ileal and total tract digestibility of energy and nutrients by growing pigs. J Anim Sci. 2019;97:4904–11.

    PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Al-Sadi R, Boivin M, Ma T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci. 2009;14:2765–78.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  169. 169.

    Wijtten PJA, Meulen J, Verstegen MWA. Intestinal barrier function and absorption in pigs after weaning: a review. Br J Nutr. 2011;105:967–81.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Ballard ST, Hunter JH, Taylor AE. Regulation of tight-junction permeability during nutrient absorption across the intestinal epithelium. Annu Rev Nutr. 1995;15:35–55.

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Zhang B, Guo Y. Supplemental zinc reduced intestinal permeability by enhancing occludin and zonula occludens protein-1 (ZO-1) expression in weaning piglets. Br J Nutr. 2009;102:687–93.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Zhao J, Harper AF, Estienne MJ, Webb KE, McElroy AP, Denbow DM. Growth performance and intestinal morphology responses in early weaned pigs to supplementation of antibiotic-free diets with an organic copper complex and spray-dried plasma protein in sanitary and nonsanitary environments. J Anim Sci. 2007;85:1302–10.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Hu CH, Gu LY, Luan ZS, Song J, Zhu K. Effects of montmorillonite–zinc oxide hybrid on performance, diarrhea, intestinal permeability and morphology of weanling pigs. Anim Feed Sci Technol. 2012;177:108–15.

    CAS  Article  Google Scholar 

  174. 174.

    Prohaska JR, Failla ML. Copper and immunity. In: Klurfeld DM, editor. Nutrition and immunology. Boston: Springer US; 1993. p. 309–32.

    Chapter  Google Scholar 

  175. 175.

    Namkung H, Gong J, Yu H, de Lange CFM. Effect of pharmacological intakes of zinc and copper on growth performance, circulating cytokines and gut microbiota of newly weaned piglets challenged with coliform lipopolysaccharides. Can J Anim Sci. 2006;86:511–22.

    CAS  Article  Google Scholar 

  176. 176.

    Gonzales-Eguia A, Fu C-M, Lu F-Y, Lien T-F. Effects of nanocopper on copper availability and nutrients digestibility, growth performance and serum traits of piglets. Livest Sci. 2009;126:122–9.

    Article  Google Scholar 

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HHS conceived the manuscript’s purpose and critically revised the manuscript. CDE wrote and revised the manuscript. Both authors read and approved the final manuscript.

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Espinosa, C.D., Stein, H.H. Digestibility and metabolism of copper in diets for pigs and influence of dietary copper on growth performance, intestinal health, and overall immune status: a review. J Animal Sci Biotechnol 12, 13 (2021).

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  • Copper
  • Copper nutrition
  • Intestinal health
  • Metabolism
  • Pharmacological concentrations
  • Pigs