Swine nutrition and immunology

INTRODUCTION

Animals live surrounded by microorganisms (e.g., bacteria, viruses, parasites, etc.) and other antigens (e.g., allergens) that can activate the immune system, which is constantly challenged and must contend with subclinical infections on a daily basis. However, animals show clinical signs of disease quite infrequently because they are equipped with a highly-specialized immune system that affords protection against pathogens. This is a costly protection because several studies have demonstrated that animals reared in unsanitary environments with high level of host-pathogen interactions grow slower and consume less feed than animals reared in more sanitary environments (Coates et al., 1963; Roura et al., 1992; Williams et al., 1997b). The general notion is that nutrients that will be allocated to support skeletal muscle protein accretion and animal growth are reassigned to metabolic processes that support the immune system, which during infection is of higher biological priority (Klasing, 1988). This places the immune system at the interface of environmental pathogens and animal growth (Broussard et al., 2001). Infections can be generally classified as localized or systemic. Localized infections may or may not affect the growth performance of animals depending on the severity, organs, and tissues involved. To the contrary, systemic infections are very likely to negatively impact animal productivity of the physical location of the infection.

Inflammatory cytokines secreted by activated cells of the immune system are the critical molecules that orchestrate the immune response against pathogens. In addition, they act on several physiological systems, tissues and organs to induce necessary changes intended to assist in the immunological response. Pathogens stimulate the immune system, and the immune system in turn, via inflammatory cytokines, reduces feed intake, alters the amount of growth hormone (GH), decreases insulin-like growth factor-I (IGF-I) available to skeletal muscle, reduces the sensitivity of receptors for GH and IGF-I, inhibits muscle protein synthesis, enhances muscle protein degradation, and reduce apparent amino acid digestibility in pigs.

THE IMMUNE SYSTEM

The first line of defense against pathogens is the mechanical, chemical and microbiological barriers found throughout the epithelia surfaces. The response of the immune system to non-cognitive stimuli (e.g., bacteria, viruses, parasites, and antigens) is both complex and well organized. In general, an immune response can be divided into two main categories: innate and acquired, each one with its own cellular (white blood cells or leukocytes) and non-cellular (humoral) components. Innate immunity is inherent to the individual and is comprised of cellular (e.g., macrophages, natural killer cells, neutrophils and monocytes) and humoral components (e.g., alternative complement system activation) that do not distinguish one pathogen from another. Also, its capacity to respond does not improve from the first encounter to subsequent encounters. The receptors used by macrophages to recognize pathogens are invariant but highly specific against their antigen (i.e., any substance capable to induce an immune response) but unable to distinguish between two pathogens. For example, the macrophage lipopolysaccharide (LPS) receptor recognizes LPS, a component of the cell wall of Gram-negative bacteria but cannot distinguish Escherichia coli from Salmonella enterica.

Activated macrophages secrete cytokines that cause inflammation, which attract other phagocytic cells (e.g., neutrophils and monocytes) among many other functions. Some of these inflammatory cytokines include interleukin (IL)-1α/β, IL-6, and tumor necrosis factor-α (TNF-α). In addition, virus-infected cells produce interferon (IFN) α and γ. These interferons flag virally-infected cells for killing by cytotoxic T cells. They also activate natural killer cells that recognize and kill virally infected cells. If the infection cannot be contained at this level, it will spread to the lymphatic system where macrophages and dendritic cells will present antigens to lymphocytes so they can initiate an adaptive immune response, which includes additional cellular and humoral resources.

Acquired or adaptive immunity is a highly specific response against a particular pathogen. It is acquired over time due to previous exposure to a pathogen or pathogen-derived antigen(s) via infection, vaccination, or passive transfer of antibodies. An adaptive immune response is exerted via cells, antibodies, or both. Fully differentiated and activated cytotoxic T lymphocytes use discrete receptors to identify and kill cells infected with intracellular pathogens such as viruses, certain bacteria, and parasites. Fully differentiated and activated B lymphocytes produced and secreted antigen-specific antibodies. The adherence of antibodies to a pathogen causes its neutralization and preparation for uptake and destruction by phagocytes or classical complement system activation. Acquired immune responses take several days to develop after the initial encounter with a specific antigen. However, once the response has been mounted, a population of cells with immunological memory is produced. Thus, the second time the host encounters the same antigen a rapid and robust immune response will be initiated and the pathogen will be eliminated, perhaps even before clinical signs of disease can appear.

INFECTION REDUCES ANIMAL GROWTH

Animals with infections have reduced appetites, lower growth rates, and are inefficient at the conversion of food to product. In fact, food intake and growth performance are inversely related to the level of interaction between the host and environmental pathogens. This is the reason of the poor performance of animals kept in "dirty" environments, which provide a high degree of host-pathogen interactions, compare to animals kept in cleaner environments. This indicates that the immune system "senses" the pathogenic environment and interacts with the brain and other physiological systems to regulate food intake and growth (Blalock, 1984). Initial studies showed that activation of the hypothalamic-pituitary-adrenal axis, fever, and behavioral signs of illness (e.g., hypersomnia) could be induced by injecting animals with cell-free supernatants collected from activated leukocytes (Hart, 1988). The immune system conveys its message to other physiological systems via inflammatory cytokines. Inflammatory stimuli (e.g., allergens, vaccination, infection) increase circulating levels of cytokines, which can reduce skeletal muscle protein accretion by reducing appetite, lowering the amount of GH and IGF-I available to skeletal muscle, reducing the sensitivity of receptors for GH and IGF-I, muscle protein synthesis and nutrient digestibility, and enhancing muscle protein degradation.

Appetite

Immune-induced anorexia is poorly understood but of high biological importance. For example, the mortality rate of mice experimentally infected mice with Listeria monocytogenes (LD50)-a Gram-positive intracellular pathogen-significantly increased when anorectic mice were tube-fed to levels comparable to healthy mice (Murray and Murray, 1979). During an inflammatory challenge, the reduction in food intake is due to a decrease in meal frequency and size (Langhans et al., 1993). In an experimental challenge with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), pigs reduce the amount of feeding time and feed intake after the viral challenge (Escobar et al., 2007). Broken-line regression analysis indicated that feed intake reached plateau one day earlier than feeding time. This suggests that feed intake is a better early indicator of sickness than feeding activity. During experimental infection of nursery pigs with PRRSV, covariant analysis indicated that the majority of the reduction in weight gain was explained by the reduction in feed intake (Escobar et al., 2004). Thus, several studies have investigated the effect of increasing the nutrient density of the diet to compensate for the reduction in feed consumption. However, increasing the diet concentration of limiting amino acids to account for decreased appetite of chicks and pigs under immunological stress did not increase whole-body protein accretion of infected animals compared to non-infected controls (Webel et al., 1998; Williams et al., 1997a,b,c). Therefore, inflammatory cytokines apparently reduce the animal's capacity to accrete protein and feed intake is adjusted accordingly.

GH-IGF-I Axis

Inflammatory cytokines can inhibit skeletal muscle protein accretion by thwarting the somatotropic axis. Under normal circumstances, GH induces IGF-I secretion-a potent growth factor that stimulates protein synthesis in skeletal muscle and other tissues. IGF-I increases skeletal muscle mass by binding the Type I IGF-I receptor and initiating a cascade of intracellular signaling events that ultimately initiate protein synthesis. Pigs infected with Salmonella Typhimurium or injected with LPS had reduced circulating levels of IGF-I with little or no change in circulating GH (Balaji et al., 2000; Wright et al., 2000). Finally, inflammatory cytokines can also act directly on skeletal muscle to induce IGF-I receptor resistance because skeletal muscle expresses receptors for IL-1, IL-6, TNF-α, and IFN-γ (Alvarez et al., 2002; Zhang et al., 2000).

Protein Accretion

Protein accretion is the net balance between protein synthesis and protein degradation. Thus, changes is protein accretion can be obtained be altering the rate of protein synthesis, protein degradation, or both. In growing animals, the increase in protein accretion is normally achieved by increases in the rate of protein synthesis with little or no changes in the rate of protein degradation. Protein accretion is most profoundly affected when there is an increase in muscle protein degradation accompanied by a decrease in muscle protein synthesis. If the rate of degradation exceeds that of synthesis, then muscle will be wasted and animals will likely start losing weight. Inflammatory cytokines have the ability to independently influence both protein synthesis and protein at the same time. In general, inflammatory cytokines reduce protein synthesis and increase protein degradation in muscle. The liver; however, markedly increases protein synthesis-especially of acute-phase proteins-and size (Flores et al., 1989; Fong et al., 1989; Ling et al., 1997). When pigs were challenged with LPS there was a marked increase in circulating TNF-α and IL-6 that preceded a 3-fold increase in plasma urea nitrogen (PUN). Because pigs were fasted, the increase in PUN was interpreted to suggest an increase in skeletal muscle protein degradation (Webel et al., 1997).

The PRRSV preferentially infects and replicates within mononuclear phagocytic cells (i.e., macrophages). Mononuclear phagocytic cells infected by PRRSV produce copious amounts of inflammatory cytokines (van Reeth et al., 1999; van Reeth and Nauwynck, 2000). Growth and whole-body protein accretion was markedly reduced in nursery pigs infected with the PRRSV for 14 days (Escobar et al., 2004). In this study, pigs infected with PRRSV accrued less protein during the first (59.1%) and second (32.9%) week of the experiment compared to PRRSV-negative pigs. Multiple-linear regression analysis indicated that PRRSV-negative pigs accrued 110.3 g/d DM basis while PRRSV-infected pigs accrued 49.0 g/d throughout the 14-day trial. This means that in average, PRRSV-infected pigs accrued 55.6% less whole-body protein each day than PRRSV-negative pigs. Pigs infected with PRRSV grew slower and ate less than PRRSV-negative pigs. A covariance analysis was performed to correct growth and protein accretion by food intake. The results indicated that the reduction in food intake accounted for the majority of the reduction in body weight gain. This finding was not surprising given the fact that gain:feed ratio was not affected by PRRSV infection. However, the reduction in protein accretion for the entire 14-day trial was not entirely explained by the reduction in food intake. Thus, after correction for feed intake, it was calculated the PRRSV-negative pigs accrued in average 105.9 g/d DM basis compared to 76.8 g/d DM basis for PRRSV-infected pigs. In other words, if PRRSV-negative and PRRSV-infected pigs would have eaten the same daily ration and had a comparable weight gain, protein accretion would have been lower in virally infected pigs. This latest finding is a clear indication that PRRSV-infected pigs experience profound metabolic changes. Furthermore, there was a high negative correlation between protein accretion and circulating IL-1β and IL-6. Infection with PRRSV also caused a reduction in whole-body accretion of water and ash but completely inhibited the accretion of lipids.

Protein Synthesis

The synthesis of new protein starts with the initiation of mRNA translation (i.e., translation initiation). In eukaryotic cells, translation initiation involves several proteins called eukaryotic initiation factors (eIF) as well as other structural proteins. For detail information about this process, the reader is referred to excellent reviews elsewhere (Kimball, 2002; Shah et al., 2000). Inflammatory cytokines responsible for inducing a systemic immune response are capable of differential effects protein synthesis in various muscles of mammals (e.g., rodents, pigs, and humans). Skeletal muscles are comprise of two major fiber types: 1) slow-twitch, or Type I muscle fibers are designed to work repetitively and generally use oxygen to fuel metabolic processes; and 2) fast-twitch, or Type II muscle fibers contract at a high rate of speed and work well in the absence of oxygen. Research in rodents (Vary and Kimball, 1992) and, more recently in pigs, (Orellana et al., 2004; Orellana et al., 2007) have indicated that cytokine-mediated systemic responses reduce protein synthesis in muscles containing mainly fast-twitch muscles fibers (e.g., longissimus dorsi and gastrocnemius) to a greater extent than muscles containing mainly slow-twitch muscle fibers (e.g., soleus and masseter). This differential effect of inflammatory cytokines on skeletal muscle fiber type is important in food producing animals. In domestic pigs, the longissimus dorsi contains more fast-twitch fibers and fewer slow-twitch fibers compared to wild boars of the same age (Essen-Gustavsson and Lindholm, 1984). The effects of cytokines on muscle tissue growth are potentially more deleterious in leaner, more modern genotypes because pigs selected for maximal lean growth rate have a greater proportion of muscles containing fast-twitch than slow-twitch muscles (Rahelic and Puac, 1981).

Protein Degradation

There are 3 major pathways to degrade proteins in tissues: 1) the ATP-ubiquitin (Ub)-dependent pathway consumes energy and the cofactors Ub and 26S proteasome complex, and degrades the majority of short-lived and long-lived myofibrillar proteins in muscle; 2) the Ca2+-dependent pathway degrades sarcomeric proteins, which may facilitate the degradation of myofilaments; and 3) the lysosomal pathway degrades long-lived, soluble and integral membrane proteins. Lysosomal and calcium-dependent contributions to the overall degradation of muscle proteins are small compared to the ATP-Ub-dependent pathway. However, it has been proposed that the Ca2+-dependent release of myofilaments from the sarcomere is the rate-limiting event for ATP-Ub-dependent proteasome degradation of the myofilaments (Hasselgren et al., 2002). Publications during the last two decades have reported increased proteolytic activity for these systems in response inflammatory cytokines or experimental infection in both cultured muscle cells and rodents. Contrary to protein synthesis, protein degradation is enhanced in both fast-twitch and slow-twitch muscles.

DISEASE AND NUTRITION NEEDS

When animals become sick in commercial facilities is normally difficult to precisely identify all the factors contributing to the malady. Diagnostic and pathological evaluations will normally indicate the biggest(s) or most obvious culprit(s) but will miss those contributors lacking physical pathology in the body; for example, wind drafts. Often these findings will identify medical conditions and pathogens causing present conditions but unlikely mentioned the sum of predisposing or contributing factors that resulted in disease. Thus, we can define natural illness as a sum of combined deficiencies in environmental, management, productive, sanitary, and nutritional practices among others, and hence, is a multifaceted problem. Consequently, experimental models are unlikely to encompass the totality of factors contributing to illness. These models are simplified versions of very complex systems and they are used to assist in the elucidation of biological processes and responses to specific nutritional interventions.

Because preserving the body alive is of highest biological importance, animals must use dietary nutrients first to fulfill their maintenance requirements. Excess nutrients not used for maintenance can be used for productive functions like body growth, milk, eggs, etc. Proportionally, nutrients needed for maintenance are considerably less than those needed to maximize animal performance. The nutritional needs for maintenance markedly increase when animals become sick, but this occurs with concomitant reductions in feed intake. We briefly mentioned that the anorectic response is part of a series of complex but coordinated physiological and behavioral adaptations to recover from illness. Thus, it is not surprising that sick animals appear to have a physiological preference for using endogenous nutrients over dietary nutrients, especially during acute immune activation. Although limited in quantity, endogenous nutrients are more readily available and have higher bioavailability indices than oral nutrients. Because survival and recovery have utmost nutritional and physiological priorities, sick animals usually exhibit reduced productive performance (e.g., growth, milk, and egg) nutritionists usually need to rely on non-productive outcomes to determine the benefits of nutritional interventions. There are several experimental procedures to stimulate the innate, acquired, or both branches of the immune system using from purified chemical compounds (e.g., LPS and toxins) to vaccines, allergens, and live pathogens. The dose, duration, and severity (i.e., degree of immune activation) of each experimental immune stimulating procedure will directly influence results, interpretation, and applicability to commercial facilities. For example, a piglet does not reduce growth performance to a vaccination to the same degree as infection with E. coli. Nonetheless, both insults are causing systemic activation of the innate and acquired branches of the immune system. The effects of supplementing diets with nutrients and feed additives on intestinal health and immunological parameters have been evaluated in a plethora of animal models using a wide variety of controlled single or multiple immunological challenges. Therefore, it is extremely important to become acquainted with strengths and constrains of experimental nutrition×immunology models in order to understand the branch(es) and depth of immune system activation but more importantly how to apply experimental results to commercial animal production.

Nutrient Digestibility and Utilization

Currently, our laboratory is using both Salmonella enterica- and LPS-challenge approaches in pigs to determine how immune activation alters nutrient digestibility and utilization. Recent results from our laboratory indicate that apparent amino acid digestibility (AID) of Arg, Ile, Met, Phe, Thr, and Val was greatly reduced in nursery pigs, with free access to feed, 24 h after experimental infection with Salmonella enterica compared to healthy controls (Escobar et al., 2010). During the same period of time, Salmonella infection did not affected AID coefficients for His, Leu, and Lys. Infection with Salmonella markedly increased endogenous nitrogen losses (ENL). Thus, a likely overcorrection or overestimation of standardized amino acid digestibility (SID) coefficients was made because they were statistically similar or higher in Salmonella pigs compared to healthy non-infected controls. Three days after Salmonella infection, AID remains significantly lower for most essential amino acids but a reduction in ENL makes SID not different from non-infected control pigs. Because of vast variations in ENL during an enteric challenge, AID appears to be a better biological indicator of amino acid digestibility than SID, which is opposite to current knowledge and practices in healthy animals. A recent study in restricted-fed pigs, however, found no differences in nitrogen, energy, Lys, Thr, Ile, Met, Cys, and Leu AID at the end of a 7-day treatment with LPS or sterile saline (Rakhshandeh et al., 2009). Combined result from these studies can be interpreted to suggest that nutrient digestibility is reduced soon after the initiation of an immune stimulation and then slowly returns to normal levels. Furthermore, results from chicks inoculated with Eimeria acervulina not only support this interpretation but also indicates that diet feedstuff composition greatly impacts amino acid and energy digestibility during infection (Persia et al., 2006).

After proteins are digested and amino acids are absorbed, they must be used for metabolic functions or the excess nitrogen and sulfur will be excreted in urine. Over a decade ago, it was proposed that the profile of amino acids needed to maintain the high levels of hepatic protein synthesis using amino acids derived from muscle catabolism was vastly different from those needed for growth (Reeds et al., 1994). Since then, several studies in pigs have reported elevated levels of urea nitrogen in plasma and urine, as an indication of muscle protein and whole body nitrogen catabolism (e.g., Webel et al., 1997). Reduced urinary sulfur excretion in pigs treated for 7 days with LPS indicates that sulfur-containing amino acids were preferentially conservation or repartitioned, thus, suggesting a higher requirement during immune activation compared to other amino acids (Rakhshandeh et al., 2009). Results from our laboratory indicate great variations in plasma amino acid concentration during acute immune activation, which also suggest differential requirements during this period compared to growth (Price et al., 2010b). For example, from 6 to 12 h after an acute LPS challenge in nursery pigs, plasma concentrations of urea nitrogen and Phe linearly increased to fed levels but Tyr concentrations drop below fasting levels. These results indicate at least 3 distinct metabolic conditions: 1) massive amounts of Phe are being catabolized from bodily tissues with muscle and intestine being the most likely candidates; 2) despite high levels in plasma, Phe is not being converted to Tyr at a speed commensurate with metabolic demands, and hence, Tyr could be classified as an essential amino acid during this time; and 3) the increase in plasma urea nitrogen is an unequivocal sign of enhanced whole body amino acid catabolism because were not eating during this period. In summary, immune activation reduces appetite and nutrient digestibility, increases catabolism of certain tissues and amino acids, preservation or repartitioning of other amino acids, and apparent essentialities of amino acids normally considered as dietary non-essential. Therefore, collective results from these studies suggest using highly digestible feedstuffs during immune activation.

Functional Feedstuffs

We can define feedstuff as a substance fed to animals that contains one or more of the main nutritive elements (i.e., energy, carbohydrates, water, amino acids, fatty acids, vitamins, and minerals), which are essential for the maintenance, growth, and productive functions of animals. The term "functional feedstuff" is being used for feedstuffs with purported or proven beneficial health effects. The problem with this definition is that deficiency of any essential nutrient will result in deleterious health consequences for an animal. Consequently, it is hard to imagine a feedstuff that is not functional. To date, the term "functional" is mainly used to indicate feedstuffs containing health-promoting compounds, disease-preventing, or immune-enhancing compounds like fatty acids, carotenoids, fibers, prebiotics, probiotics, as well as certain proteins and minerals among many others. Research findings are indicating that the majority of these functional feedstuffs exert their beneficial effects at the level of the gastrointestinal tract (GIT), and more specifically via alterations of its microbiota. This is not surprising if we consider that GIT is the biggest immunological organ of the body that must live in harmony with more prokaryotic microorganisms than the totality of eukaryotic cells in the body. Furthermore, this ever-changing microbiota is of paramount importance for the health of the host and can be commensal or pathogenic; they occupy different niches within the GIT; they can be resident or transient occupants; and most of them coat or aggregate along the GIT surface, a phenomenon known as biofilm formation (Anderson, 2003; Probert and Gibson, 2002). Resident bacteria refer to species that are usually present under normal conditions. Transient occupants are bacteria occupying other than their normal niche or microorganisms that are acquired through the diet. An example of transient bacteria is a probiotic supplement. Prebiotic supplements will encourage the proliferation of select resident bacteria. Diet-induced changes to the microbiota are transient and generally will regress when the supplement is not longer consumed. If some of these functional dietary compounds are needed to maintain normal physiological functions of the body, especially in the GI tract, and their effects impact the physiology of the animal, then, they could be consider a new generation of nutrients.

Results from our group indicate that inclusion of a yeast-derived prebiotic in the diet of Salmonella-challenged nursery pigs improved fecal beneficial bacteria (e.g., Bacteroides, Bacteroidetes, and Lactobacillus) and intestinal morphology, which were associated with enhanced compensatory growth performance during the recovery phase (Price et al., 2010a). The mode of action of prebiotics is still under investigation, however, several hypothesis include enhanced vitamin and energy production from fermentation processes, enhanced intestinal mobility and mineral absorption, elimination of ammonium, direct stimulation of the immune system, toxin and pathogen binding activities, increased growth and activity of specific beneficial resident bacterial species, and production of short-chain fatty acids (Branner and Roth-Maier, 2006; Macfarlane et al., 2008; Rhoades et al., 2008). Additional consideration must be taken with prebiotics and ENL. For example, insoluble kernel fibers in barley increase ENL but soluble β-glucans and barley hulls appear not to affect ENL and amino acid digestibility (Leterme et al., 2000). Given the wide and complex variety of prebiotic compounds it is impossible to generalize their effects on ENL, amino acid digestibility, fermentability, and growth stimulation of bacterial species in GIT. It is important to understand that GIT microbiota will slowly adjust to the inclusion of prebiotic compounds in the diet and that this adaptation will be also gradually is lost upon removal of the product.

Direct-fed microbials (DFM) is the official name for probiotics since 1989 in the U.S., they are a source of live (i.e., viable) and naturally occurring microorganisms, and are generally categorized as: Bacillus, lactic acid bacteria, and yeasts. Some DFM have been shown to reduce pathogenic bacterial adherence and inflammation in both tissue cultures and in animal models. For example, fecal shedding in neonatal pigs treated with a cecal-derived bacterial culture from a healthy 6-week-old pig and experimentally infected with Salmonella enterica serotype Cholerasusis or E. coli was lower compared to pathogen-infected piglets not treated with the probiotic (Genovese et al., 2000; Genovese et al., 2003; Kim et al., 2005). Like these, there are many more examples of reduced pathogenic activity, increased immunological parameters, and reduced disease severity in the literature. Like prebiotics, DFM will take some time to establish transient colonization of the GIT, which will slowly decrease upon cessation of supplementation.

Depending on processing methods, source, and nutrient composition certain feedstuffs appear to have microbiota-independent immunomodulating properties like spray-dry plasma proteins (SDPP) and omega-3 fatty acids. To date, we recognize that SDPP exert non-nutritional effects during pathogenic disease and other immune activation scenarios like "dirty" environments. Hence, the functionality of SDPP is among the most studied feedstuffs in monogastric animal nutrition. The effects feeding SDPP on intestinal barrier and immune functions have been recently review elsewhere (Moreto and Perez-Bosque, 2009). Briefly, SDPP maintain intestinal barrier function by enhancing the integrity and functionality of tight junctions; they reduce the over-stimulation of the immune system; and, prevent reductions in nutrient absorption. Thus, it appears that obtaining a positive effect of SDPP inclusion in the diets of food producing animal is highly dependent on environmental conditions and pathogen/antigen exposure. Polyunsaturated fatty acids belonging to the omega-6 family tend to be inflammatory in nature whereas the omega-3 family, particularly eicosapentaenoic (EPA) and docosahexenoic (DHA) acids tend to be anti-inflammatory (Calder, 2009). In growing pigs for example, supplementation of fish oil increased EPA and DHA content in both adipose and muscle tissues, reduced expression of the LPS receptor, reduced circulating levels of the inflammatory cytokine tumor necrosis factor-α, and reduced the febrile response to LPS administration (Gabler et al., 2008).

CONCLUSIONS

Most of the knowledge regarding in vivo effects of infection and inflammatory cytokines on skeletal muscle protein accretion has been derived from adult animal models of sepsis or cancer, diseases often characterized by severe muscle wasting. These models have contributed to elucidate the mechanisms involved during acute immune activation. In general, the economically important diseases in growing farm animals do not cause muscle wasting. Instead, these diseases cause significant and chronic reductions in the growth performance and whole-body protein accretion of food-producing animals. Nevertheless, it is reasonable to postulate that the mechanisms involved in muscle wasting are also involved in the reduction of muscle protein accretion in infected slow-growing animals. Animal production systems should work diligently to minimize the exposure to infectious pathogens. However, because many infectious pathogens are endemic it is necessary to understand how and why the immune system regulates protein accretion in growing animals. This is especially important because even animals with sub-clinical infections grow at lower rates. As with any other nutritional intervention strategy there may be potential negative or undesirable consequences when using prebiotics, DFM, and other functional feedstuffs. Like any other intervention strategy, economical and biological benefits should be carefully considered. Therefore, decisions regarding when to include functional feedstuffs in the diet and for how long should they be used deserves careful consideration, but remember that most of these functional feedstuffs are not meant to be use intermittently.

CITED LITERATURE

Alvarez, B., L. S. Quinn, S. Busquets, F. J. Lopez-Soriano, and J. M. Argiles. 2002. TNF-alpha modulates cytokine and cytokine receptors in C2C12 myotubes. Cancer Lett. 175:181-185.
Anderson, K. L. 2003. The complex world of gastrointestinal bacteria. Can. J. Anim. Sci. 83:409-427.
Balaji, R., K. J. Wright, C. M. Hill, S. S. Dritz, E. L. Knoppel, and J. E. Minton. 2000. Acute phase responses of pigs challenged orally with Salmonella typhimurium. J. Anim. Sci. 78:1885-1891.
Blalock, J. E. 1984. The immune system as a sensory organ. J. Immunol. 132:1067-1070.
Branner, G. R. and D. A. Roth-Maier. 2006. Influence of pre-, pro-, and synbiotics on the intestinal availability of different B-vitamins. Arch. Anim. Nutr. 60:191-204.
Broussard, S., J. H. Zhou, H. D. Venters, R. M. Bluthe, R. W. Johnson, R. Dantzer, and K. Kelley. 2001. At the interface of environment-immune interactions: cytokines and growth factor receptors. J. Anim. Sci. 79:268-284.
Calder, P. C. 2009. Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale. Biochimie 91:791-795.
Coates, M. E., R. Fuller, G. F. Harrison, M. Lev, and S. F. Suffolk. 1963. A comparison of the growth of chicks in the Gustafsson germ-free apparatus and in a conventional environment, with and without dietary supplements of penicillin. Br. J. Nutr. 17:141-150.
Escobar, J., M. A. Ponder, K. L. Price, and H. B. Lee. 2010. Possible nutritional interventions to improve intestinal health. J.Anim.Sci. 88 (E-Suppl. 2):599.
Escobar, J., W. G. Van Alstine, D. H. Baker, and R. W. Johnson. 2004. Decreased protein accretion in pigs with viral and bacterial pneumonia is associated with increased myostatin expression in muscle. J. Nutr. 134:3047-3053.
Escobar, J., W. G. Van Alstine, D. H. Baker, and R. W. Johnson. 2007. Behaviour of pigs with viral and bacterial pneumonia. Appl. Anim. Behav. Sci. 105:42-50.
Essen-Gustavsson, B. and A. Lindholm. 1984. Fiber types and metabolic characteristics in muscles of wild boars, normal and halothane sensitive Swedish landrace pigs. Comp. Biochem. Physiol. A 78:67-71.
Flores, E. A., B. R. Bistrian, J. J. Pomposelli, C. A. Dinarello, G. L. Blackburn, and N. W. Istfan. 1989. Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J. Clin. Invest. 83:1614-1622.
Fong, Y., L. L. Moldawer, M. Marano, H. Wei, A. Barber, K. Manogue, K. J. Tracey, G. Kuo, D. A. Fischman, A. Cerami, and S. F. Lowry. 1989. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am. J. Physiol. 256:659-665.
Gabler, N. K., J. D. Spencer, D. M. Webel, and M. E. Spurlock. 2008. n-3 PUFA attenuate lipopolysaccharide-induced down-regulation of toll-like receptor 4 expression in porcine adipose tissue but does not alter the expression of other immune modulators. J. Nutr. Biochem. 19:8-15.
Genovese, K. J., R. C. Anderson, R. B. Harvey, T. R. Callaway, T. L. Poole, T. S. Edrington, P. J. Fedorka-Cray, and D. J. Nisbet. 2003. Competitive exclusion of Salmonella from the gut of neonatal and weaned pigs. J. Food Prot. 66:1353-1359.
Genovese, K. J., R. C. Anderson, R. B. Harvey, and D. J. Nisbet. 2000. Competitive exclusion treatment reduces the mortality and fecal shedding associated with enterotoxigenic Escherichia coli infection in nursery-raised neonatal pigs. Can. J. Vet. Res. 64:204-207.
Hart, B. L. 1988. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12:123-137.
Hasselgren, P. O., C. Wray, and J. Mammen. 2002. Molecular regulation of muscle cachexia: it may be more than the proteasome. Biochem. Biophys. Res. Commun. 290:1-10.
Kim, L. M., J. T. Gray, J. S. Bailey, R. D. Jones, and P. J. Fedorka-Cray. 2005. Effect of porcine-derived mucosal competitive exclusion culture on antimicrobial resistance in Escherichia coli from growing piglets. Foodborne Pathog. Dis. 2:317-329.
Kimball, S. R. 2002. Regulation of global and specific mRNA translation by amino acids. J. Nutr. 132:883-886.
Klasing, K. C. 1988. Nutritional aspects of leukocytic cytokines. J. Nutr. 118:1436-1446.
Langhans, W., D. Savoldelli, and S. Weingarten. 1993. Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-1 beta. Physiol. Behav. 53:643-649.
Leterme, P., W. B. Souffrant, and A. Thewis. 2000. Effect of barley fibres and barley intake on the ileal endogenous nitrogen losses in piglets. J. Cereal Sci. 31:229-239.
Ling, P. R., J. H. Schwartz, and B. R. Bistrian. 1997. Mechanisms of host wasting induced by administration of cytokines in rats. Am. J. Physiol. 272:E333-E339.
Macfarlane, G. T., H. Steed, and S. Macfarlane. 2008. Bacterial metabolism and health-related effects of galacto-oligosaccharides and other prebiotics. J. Appl. Microbiol. 104:305-344.
Moreto, M. and A. Perez-Bosque. 2009. Dietary plasma proteins, the intestinal immune system, and the barrier functions of the intestinal mucosa. J. Anim. Sci. 87:E92-E100.
Murray, M. J. and A. B. Murray. 1979. Anorexia of infection as a mechanism of host defense. Am. J. Clin. Nutr. 32:593-596.
Orellana, R. A., A. Jeyapalan, J. Escobar, J. W. Frank, H. V. Nguyen, A. Suryawan, and T. A. Davis. 2007. Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation. Am. J. Physiol. Endocrinol. Metab. 293:E1416-E1425.
Orellana, R. A., S. R. Kimball, H. V. Nguyen, J. A. Bush, A. Suryawan, M. C. Thivierge, L. S. Jefferson, and T. A. Davis. 2004. Regulation of muscle protein synthesis in neonatal pigs during prolonged endotoxemia. Pediatr. Res. 55:442-449.
Persia, M. E., E. L. Young, P. L. Utterback, and C. M. Parsons. 2006. Effects of dietary ingredients and Eimeria acervulina infection on chick performance, apparent metabolizable energy, and amino acid digestibility. Poult. Sci. 85:48-55.
Price, K. L., H. R. Totty, H. B. Lee, M. D. Utt, G. E. Fitzner, I. Yoon, M. A. Ponder, and J. Escobar. 2010a. Use of Saccharomyces cerevisiae fermentation product on growth performance and microbiota of weaned pigs during Salmonella infection. J. Anim. Sci. In press (Published online first on July 23, 2010 as doi:10.2527/jas.2009-2728).
Price, K. L., M. D. Utt, H. B. Lee, and J. Escobar. 2010b. Using routine blood chemistry results to estimate changes in plasma AA during experimental endotoxemia. FASEB J. 24:740.22.
Probert, H. M. and G. R. Gibson. 2002. Bacterial biofilms in the human gastrointestinal tract. Curr. Issues Intest. Microbiol. 3:23-27.
Rahelic, S. and S. Puac. 1981. Fiber types in longissimus dorsi from wild and highly selected pig breeds. Meat Sci. 5:439.
Rakhshandeh, A., J. K. Htoo, and C. F. de Lange. 2009. Immune system stimulation of growing pigs does not alter apparent ileal amino acid digestibility but reduces the ratio between whole body nitrogen and sulfur retention. XI International Symposium on Digestive Physiology of Pigs. Montbrió del Camp, Costa Daurada, Spain.
Reeds, P. J., C. R. Fjeld, and F. Jahoor. 1994. Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? J. Nutr. 124:906-910.
Rhoades, J., K. Manderson, A. Wells, A. T. Hotchkiss, Jr., G. R. Gibson, K. Formentin, M. Beer, and R. A. Rastall. 2008. Oligosaccharide-mediated inhibition of the adhesion of pathogenic Escherichia coli strains to human gut epithelial cells in vitro. J. Food Prot. 71:2272-2277.
Roura, E., J. Homedes, and K. C. Klasing. 1992. Prevention of immunologic stress contributes to the growth-permitting ability of dietary antibiotics in chicks. J. Nutr. 122:2383-2390. 
Shah, O. J., J. C. Anthony, S. R. Kimball, and L. S. Jefferson. 2000. 4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle. Am. J. Physiol. Endocrinol. Metab. 279:715-729.
van Reeth, K., G. Labarque, H. Nauwynck, and M. Pensaert. 1999. Differential production of proinflammatory cytokines in the pig lung during different respiratory virus infections: correlations with pathogenicity. Res. Vet. Sci. 67:47-52.
van Reeth, K. and H. Nauwynck. 2000. Proinflammatory cytokines and viral respiratory disease in pigs. Vet. Res. 31:187-213.
Vary, T. C. and S. R. Kimball. 1992. Sepsis-induced changes in protein synthesis: differential effects on fast- and slow-twitch muscles. Am. J. Physiol. 262:1513-1519.
Webel, D. M., B. N. Finck, D. H. Baker, and R. W. Johnson. 1997. Time course of increased plasma cytokines, cortisol, and urea nitrogen in pigs following intraperitoneal injection of lipopolysaccharide. J. Anim. Sci. 75:1514-1520.
Webel, D. M., R. W. Johnson, and D. H. Baker. 1998. Lipopolysaccharide-induced reductions in food intake do not decrease the efficiency of lysine and threonine utilization for protein accretion in chickens. J. Nutr. 128:1760-1766.
Williams, N. H., T. S. Stahly, and D. R. Zimmerman. 1997a. Effect of chronic immune system activation on body nitrogen retention, partial efficiency of lysine utilization, and lysine needs of pigs. J. Anim. Sci. 75:2472-2480.
Williams, N. H., T. S. Stahly, and D. R. Zimmerman. 1997b. Effect of chronic immune system activation on the rate, efficiency, and composition of growth and lysine needs of pigs fed from 6 to 27 kg. J. Anim. Sci. 75:2463-2471.
Williams, N. H., T. S. Stahly, and D. R. Zimmerman. 1997c. Effect of level of chronic immune system activation on the growth and dietary lysine needs of pigs fed from 6 to 112 kg. J. Anim. Sci. 75:2481-2496.
Wright, K. J., R. Balaji, C. M. Hill, S. S. Dritz, E. L. Knoppel, and J. E. Minton. 2000. Integrated adrenal, somatotropic, and immune responses of growing pigs to treatment with lipopolysaccharide. J. Anim. Sci. 78:1892-1899.
Zhang, Y., G. Pilon, A. Marette, and V. E. Baracos. 2000. Cytokines and endotoxin induce cytokine receptors in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 279:E196-E205.

This presentation was given at IV CLANA in November 2010, Sao Pedro, Sao Paulo, Brazil. Engormix.com thanks the author and the organizing committee for the contribution.