Impact of health decline on protein and amino acid metabolism: what's the implication on amino acid requirements in swine?

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Impact of health decline on protein and amino acid metabolism: what’s the implication on amino acid

requirements in swine?

Nathalie Le Floc’H

To cite this version:

Nathalie Le Floc’H. Impact of health decline on protein and amino acid metabolism: what’s the implication on amino acid requirements in swine?. ANAC, Animal Nutrition Association of Canada (ANAC)., May 2012, Kitchener, Canada. 13 p. �hal-01210301�

Impact of health decline on protein and amino acid metabolism: what's the implication on amino acid requirements in swine?

Nathalie Le Floc’h

INRA, UMR1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage, F-35590 Saint-Gilles, France et Agrocampus Ouest, UMR1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage, F-35000 Rennes, France

Introduction

Health preservation is one of the main priorities and a constant challenge for swine production. Indeed, health decline and diseases are responsible for an increase in production costs due to mortality and reduced performance and feed efficiency. A wide range of health problems can be described. Some of them are caused by major specific pathogens acting alone or in combination with other pathogens. Other kinds of pig diseases, also named “production diseases”, are caused by more or less opportunistic microbes that can become pathogenic when associated with social and climatic conditions⁽¹⁾, degree of hygiene of the environment^(2,3) and practices such as diet changing, pig mixing, transfer from a building to another or weaning⁽⁴⁾. Production diseases are thus clearly multifactorial, and this makes their management very complex.

Medication based on antibiotics are still used systematically and preventively to limit the negative consequences of production diseases. The reduction of their utilization is a challenge for the development of sustainable pig production systems preserving health, high performance and with reduced environmental impact. The role of nutrition is clearly questioned because it may be one of the solutions that contribute to limit medication through preserving health and performance. Indeed, health and nutrition are strongly connected. First, because health disturbances impact on the different components of nutrition function, i.e. feed intake, digestion, and metabolism; and second, because nutrition determines the organism’s ability to maintain or to restore homeostasis in response to health disturbances. In this review, we will examine how and to what extent health impacts on performance and nutrition of swine, with a special focus on amino acids (AA). Indeed, AA metabolism is modified by health disturbances, as a consequence that AA are repartitioned between growth and body defences. If all AA constituting proteins are impacted by re-partitioning, some AA deserve a specific attention because of their role in pathways connected to immune responses and health preservation.

1/ How and how much health decline reduces performance?

Growth performances in commercial farms are usually lower compared to what is determined by the genetic potential of the animals. If environmental and housing conditions are responsible for these differences, the effect on performance are partly associated to the stimulation of the immune system that impacts on health status of pigs⁽⁵⁾ inducing reduction in feed intake, digestive disturbances, and metabolic changes such as increased energy expenditure, body temperature, and body protein turnover⁽⁶⁾.

The reduction in feed intake induced by health decline is the response that is the most frequently reported. The amplitude of feed intake reduction varies from complete anorexia in case of clinical disease to much more moderate feed intake reduction for subclinical infection⁽⁷⁾. For instance, a moderate inflammatory response caused by poor hygiene reduces feed intake by 5 to 10% compared to control pigs^(2,3). Different mechanisms can be responsible for the reduction in feed intake, including a direct effect of inflammatory cytokines synthesized by the activated immune cells. The interleukin IL-1β is one of the main factor involved in the feed intake regulation⁽⁸⁾. Injected in the brain or in the peripheral blood, IL-1β induced anorexia and sickness behavior ⁽⁹⁾. TNF-α, another pro inflammatory cytokine, synergizes with IL-1β to suppress feeding. Cytokines may also reduce feed intake through their action on the digestive tract motility. Alternatively, feed intake may be lowered as a consequence of the reduced growth rate.

Pigs with a lower growth rate have indeed lower requirement and appetite than pigs growing faster. This explanation is probably relevant for explaining the long lasting reduction in feed intake and growth rate reported during chronic subclinical diseases.

Impaired digestion and absorption capacity is the second mechanism responsible for decreased growth performance⁽¹⁰⁾. Bacterial and parasitic infections targeting the gut epithelia cause intestinal cell damage and increase endogenous secretions^(11,12). This in turn affects feed digestion and nutrient absorption thereby reducing the availability of AA and energy for growth. Such gut disturbances may also contribute to reduce feed intake because of associated pain and discomfort.

At least, diarrheas also contribute to the reduction in growth rate because of induced malabsorption and water loss.

Finally, part of the reduction in growth rate result from the nutritional cost associated with the stimulation of the immune system⁽¹¹⁾. Indeed, immune system stimulation requires energy, AA and trace elements for the proliferation of immune cells, synthesis of cytokines, antibodies, and acute phase proteins⁽¹³⁾. This is supported by changes in metabolism and nutrient fluxes leading to changes in nutrient partitioning⁽¹⁴⁾ caused by cytokines and hormones. During immune and inflammatory responses, metabolic changes are associated with an increase in basal metabolic rate, increased energy utilization and a switch from glucose to fatty acids and AA as a preferred energy source by many tissues, redistribution of iron, zinc, and copper within the body for the hepatic synthesis of metallothionein, ferritin, and ceruloplasmin and release of hormones such as insulin, glucagon, and glucocorticoids⁽¹⁵⁾. Hyperinsulinaemia and hyperglycaemia are commonly observed during inflammation and are a characteristic of reduced muscle insulin sensitivity⁽¹⁶⁾.

A recent paper⁽¹⁷⁾ reported a meta-analysis carried out to quantify the feed intake and growth responses of growing pigs after different sanitary challenges that reproduced production diseases.

A database was constructed using 122 published experiments reporting the average daily feed intake (ADFI) and average daily gain (ADG) of pigs submitted to six sanitary challenges:

digestive bacterial infections, poor hygiene conditions, lipopolysaccharide (LPS) challenges, contaminations with mycotoxins, parasitic infections and respiratory diseases. All challenges resulted in a reduction in feed intake and ADG but the amplitude of the reduction differed between challenges. The figure 1 represents the relationship between the change in growth and feed intake of the challenged pigs relative to that of a control group. The strongest responses were reported for mycotoxins, respiratory diseases, and digestive bacterial infections (8 to 23%

reduction in ADFI and 16 to 29% reduction in ADG). As discussed above, the growth reduction is partly caused by a reduction in feed intake but also to changes in digestion and metabolism.

Indeed, a 10% reduction in ADFI resulted in a 10 to 43% reduction in ADG for mycotoxins and digestive bacterial infections, respectively. More than 70% of the reduction in ADG could be explained by the reduction in ADFI for mycotoxins, LPS challenge and respiratory diseases, while for digestive infections and poor hygiene, a large proportion of the reduction in ADG was due to an increase in maintenance requirements, i.e. requirement not associated with a reduction in feed intake, suggesting digestive and metabolic changes. Indeed, for poor housing conditions, conditions that reproduce a chronic immune challenge (figure 1b), the quadratic regression between ADG and ADFI indicates that the difference in ADG increased with the difference in ADFI between challenged and control pigs. Consequently, the more the ADFI decreased in challenged pigs, the more the feed efficiency, i.e. associated with a reduction in feed intake, was reduced compared with that of the control group indicating that a greater proportion of feed intake is used to meet maintenance requirements.

(a) digestive bacterial infections (d) mycotoxins

(b) poor housing conditions (e) parasitic infections

(c) LPS challenge (f) respiratory diseases

Figure 1. Relationship between the change in growth (∆ADG) and feed intake (∆ADFI) of pigs challenged with digestive bacterial infections (a), poor housing conditions (b), LPS challenge (c), contaminations with mycotoxins (d), parasitic infections (e) and respiratory diseases (f). Responses are expressed as results of the challenged pigs relative to that of a control group. The lines represent the linear or the quadratic model adjustments. Estimated parameters differed from zero (P< 0.05), except for the intercept in LPS challenge From⁽¹⁷⁾.

2/ Consequences of health decline on protein and amino acid metabolism Tissue protein metabolism

Changes in protein metabolism occurring during infection and inflammation have been extensively documented in many species. Protein accretion in the skeletal muscle is impaired during immune challenge because of simultaneous increased protein breakdown and decreased

protein synthesis^(18-20). Inflammatory cytokines like TNF-α acts directly on skeletal muscle to inhibit muscle protein synthesis⁽²¹⁾. Moreover, TNF-α reduces the efficacy of hormones such as IGF-I and insulin to stimulate protein synthesis⁽²²⁾. Additionally, cytokines enhance the rate of skeletal muscle protein degradation^(23,24) and the efficacy of insulin to decrease muscle protein breakdown is reduced during infection^(25,26). Increased myostatin mRNA, a negative regulator of muscle mass, in skeletal muscle was reported in pigs with a respiratory infection⁽²⁷⁾. Amino acids released from muscle protein breakdown are partly degraded and converted into urea. However, AA are also used to support body defences.

In contrast to what is described in muscle, protein synthesis is increased in the liver mainly because of the increased acute-phase protein (APP) synthesis. These proteins serve important functions in restoring homeostasis after infection or inflammation⁽²⁸⁾. These include haemostatic functions, microbicidal and phagocytic functions, antithrombotic properties, and antiproteolytic actions. During inflammation, APP plasma concentrations increase 2- to 100-fold depending on the protein, the animal species and the challenge, while their synthesis increases in greater proportion. For example, in pigs injected with turpentine, fibrinogen plasma concentrations increase by 30% and fibrinogen synthesis increases by 140%⁽²⁹⁾. Therefore, the increase in APP synthesis may require large amount of AA. The pro inflammatory cytokine IL-6 acts in synergy with IL-1 on the liver, but IL-6 is considered as the primary initiator of the liver acute-phase response⁽³⁰⁾. Glucocorticoids are known to exert an anabolic effect on the liver⁽³¹⁾ and glucocorticoids alone are able to induce the secretion of some APP such as α1 glycoprotein acid, but generally, they act as a permissive or synergetic factor to the action of cytokines⁽³⁰⁾. This explains that increases in APP concentrations have been reported in response to both physical and psychological stressors in pigs^(32-34) and not only to immune challenges.

Amino acid partitioning during immune challenges and inflammation

The modifications of tissue protein metabolism described when health is challenged lead to changes in AA partitioning between growth and tissues and cells involved in health maintenance like the immune responses. The term nutrient partitioning refers to the process by which nutrients are channelled in various proportions to different metabolic functions⁽³⁵⁾. This concept is notably relevant when it addresses the competition between productive functions and immune and defence functions, that are traditionally regarded as part of maintenance requirements. Some experimental data indicate that there may be competition for nutrient resources between the immune system and the reproductive functions⁽³⁶⁾ but few data are available for young growing animals. Coop & Kyriazakis⁽³⁷⁾ proposed a nutrient partitioning framework to describe the concept of prioritization for the allocation of scarce nutrients between different functions, including immune functions during parasitic diseases. Nutrient scarcity refers to situations where dietary nutrient supplies were not sufficient to meet maintenance and productive requirements.

Briefly, for growing animals (Table 1), once immunity has been acquired, nutrients are allocated firstly to meet the maintenance functions, then the growth functions and finally the expression of acquired immunity. This means that growth could have the priority over immunity for nutrient

utilization and that nutrient supplementation may improve the expression of immunity and body defences. For younger “naïve” animals, it can be expected that nutrient supplementation may be useful to improve growth once requirements for acquisition of immunity have been met.

Table 1. Proposed order of partitioning of scarce resources to body functions in a growing animal. The acquisition (naïve animals) and expression (immune animals) phase of immunity are considered separately. Adapted from⁽³⁷⁾.

Acquisition phase

“Naïve animals” Expression phase

“Immune animals”

1. Maintenance of body protein 1. Maintenance of body protein 2. Acquisition of immunity 2. Protein gain

3. Protein gain 3. Expression of immunity

4. Maintenance and gain of body lipid

4. Maintenance and gain of body lipid

Analysis of plasma AA responses to different challenges provides some indications for evaluating the changes in AA partitioning when health is challenged. Lower plasma AA concentrations have been reported in pigs with enterotoxigenic Escherichia coli peritonitis or with chronic lung inflammation, respectively, compared to healthy pigs^(38,39). The decrease in AA concentrations following inflammatory diseases could reflect a decrease in feed consumption and in absorption for the first study⁽³⁸⁾. In the second experiment⁽³⁹⁾, because healthy and sick pigs were pair fed, this means they ate the same amount of feed, decrease in plasma AA concentrations can be explained by a greater AA utilisation, including AA catabolism, AA incorporation into proteins other than muscle protein, and AA conversion into specific molecules.

For instance, the decrease in plasma tryptophan can be attributed to the synthesis of APP which are tryptophan rich proteins⁽⁴⁰⁾. This is further supported by results obtained in humans showing negative correlations between plasma tryptophan concentrations and the plasma concentrations of APP, transferrin, haptoglobin⁽⁴¹⁾ and fibrinogen⁽⁴²⁾. Moreover, indoleamine 2,3 dioxygenase (IDO), a rate limiting enzyme for the catabolism of tryptophan into kynurenine, was also found to be induced by the cytokine interferon-γ⁽⁴³⁾ and by inflammation in pigs^(44,45). Thus, the low plasma tryptophan concentrations can also be caused by an increase in tryptophan catabolism.

However, such a decline in tryptophan concentration was not reported when pigs were fed a tryptophan supplemented diet⁽⁴⁵⁾. Plasma AA concentrations are thus not necessarily indicative of metabolic changes because concentrations result from dynamic metabolic fluxes, which are influenced by many factors. Few studies have examined the consequences of health challenge on AA fluxes between tissues or metabolic pathways. Severe illness is associated with a depletion of plasma and muscle glutamine pool and increased plasma glutamine flux, suggesting that the requirement for glutamine would increase in a catabolic state⁽⁴⁶⁾. In pigs, surgery and LPS injection increased glutamine release from the hindquarter and intestine, while glutamine uptake by the liver and spleen increased^(47,48). In septic rats, plasma cysteine flux measured during the

constant infusion of labelled cysteine is increased compared to that in pair-fed control rats. This is explained by a concomitant increase in cysteine incorporation into the tripeptide glutathione and APP⁽⁴⁹⁾. Moreover, a reduction of cysteine catabolism and an increase in cysteine transsulfuration from methionine were also reported, mechanisms that probably preserve the availability of cysteine for glutathione synthesis by the liver^(50,51). Recently, very similar results have been reported in growing pigs, for which repeated injections of LPS increased the conversion of cysteine into non protein compounds, namely glutathione and taurine, while cysteine catabolism into sulfate decreased^(52,53). Intestinal disorders also induce changes in AA fluxes. Experimental ileitis induced in minipigs increased liver and ileal GSH fractional synthesis rate from cysteine⁽⁵⁴⁾ and arterial threonine uptake by the gastrointestinal tract⁽⁵⁵⁾. Moreover, during its intestinal absorption, more than one half of orally supplied threonine is extracted in first-pass by the small intestine of young pigs^(56,57). Consequently, the small intestine would have the priority over other tissues (liver, carcass and colon) when threonine is not adequately supplied by the feed and/or during digestive inflammation. The high threonine extraction by the small intestine is an important nutritional question, notably because it determines threonine availability for tissues depending on threonine supplied by the blood only⁽⁵⁸⁾.

Amino acid utilization and functions during immune challenges and inflammation

Health decline modifies AA partitioning between growth and metabolic responses that support immune functions and body defences. If they are not catabolized, AA provided by feed and accelerated muscle protein catabolism are used as substrates for gluconeogenesis and immune cell proliferation. As indicated above, they can serve as substrates for the synthesis of APP in the liver and also immunoglobulin and mucins in the intestine. Moreover, some AA play specific roles closely related to immune response regulation or in other processes associated with body defences⁽⁵⁹⁾.

Whereas many papers described the relationships between AA and immunity or body defenses, very few showed a clear relationship between AA dietary supplies and pig health.

Glutamine is not considered as an essential amino acid for growth. However, many data indicate that this AA is essential for rapidly dividing cells like lymphocytes and enterocytes^(60,61). In vitro, glutamine modulates immune functions of cultured lymphocytes and enterocytes^(62,63). In pigs, dietary supplementation with 1% glutamine prevented jejunal atrophy occurring during the first week postweaning⁽⁶⁴⁾. In the same species, glutamine supplementation was also efficient to preserve an optimal immune function during an infection⁽³⁹⁾. Cysteine, a sulphur AA derived from methionine, is the main limiting factor for the synthesis of glutathione^(65,66), a tripeptide (L- glutamyl-L-cysteinyl-glycine) involved in the intracellular antioxidant defences. Depletion of glutathione pool has been reported in pigs suffering from inflammation, this phenomenon being clearly aggravated for low protein intake⁽⁶⁷⁾. In neonatal pigs, cysteine and methionine deficiencies reduced cellular cysteine and GSH concentrations and increased oxidant stress in the small intestine which is associated with reduced small intestinal growth⁽⁶⁸⁾. Threonine is the most abundant essential AA in glycoproteins like immunoglobulins and intestinal mucins⁽⁶⁹⁾. Growing

pigs⁽⁷⁰⁾ and gestating sows⁽⁷¹⁾ fed threonine-deficient diets have significant lower plasma concentrations of total or specific IgG titre following bovine serum albumin injection and swine fever vaccination. In piglets, threonine deficiency impaired total protein and mucin synthesis⁽⁷²⁾ and impacted also on other functions of the small intestine⁽⁷³⁾. Increased tryptophan catabolism and IDO activation during inflammation are considered as mechanisms involved in the regulation of immune and inflammatory response⁽⁷⁴⁾. Pigs suffering from an experimentally induced lung inflammation and fed a diet with tryptophan concentration slightly above recommendations had lower APP concentration, indicating that inflammation was reduced, and were healthier compared to pigs fed a diet moderately deficient in tryptophan⁽⁴⁵⁾. In a porcine model of induced colitis, tryptophan supplementation down-regulated inflammation, restored local immune response and reduced colitis symptoms⁽⁷⁵⁾.

3/ Which consequences on swine nutrition

There is a growing interest in considering the specific AA requirement for preserving both health and performance. Basically, nutritional recommendations for growing pigs are still mainly established according to the maximization of performance criteria. All these criteria correspond to productive traits and are mainly associated to maximizing protein deposition during post-natal growth⁽⁷⁶⁾. This approach is consistent with the fact that AA are largely used for the synthesis of peptides and proteins, and that daily whole body protein turn-over requires huge amounts of AA⁽⁷⁷⁾; in fact, this is true only for the 20 AA constituting proteins. To determine AA requirement for health maintenance, indicators of health status are needed. Indeed, if good growth performance is usually associated to good health, this criterion does not reflect necessarily physiological or nutritional status that could predispose the animal to disease and make him less resilient.

The necessity to reduce the dietary crude protein content to cope with environmental issues should increase the risk that several AA are supplied in inadequate or sub-limiting amounts for their physiological functions, some of them being not directly associated with productive traits.

As previously underlined in the description of partitioning of scarce resources theory (see table 1), the question is which type of functions will have a priority for AA utilization. This is an important question considering that AA can be supplied at a suboptimal level for economic reasons. Another factor to take in account is the effect of health and sanitary conditions on feed intake. Indeed, depressed feed intake will limit the availability of AA for the body and this is probably the main limiting factor for developing nutritional strategies for preserving health and performance.

Few studies aimed to evaluate the impact of health status on the AA requirement for growth performance in pigs. All these studies clearly confirmed the negative impact of the health status on performance and feed intake. Pigs kept in an environment with a low sanitary status required less lysine for protein accretion because of their lower growth rate⁽⁷⁸⁾. This occurred without

change in efficiency of lysine utilization for protein deposition⁽⁷⁹⁾. Indeed, lysine has little physiological functions other than being incorporated in proteins. This explained that its requirement is mainly associated to growth and protein deposition. This result has been reported in poultry and confirmed for other AA such as threonine and arginine^(80,81). Health status has an impact on tryptophan metabolism and this probably impairs the availability of tryptophan for body protein deposition and growth. Additional crystalline tryptophan did not totally prevent growth retardation caused by low sanitary status. However, the improvement of growth rate by supplementary tryptophan added to a low tryptophan diet was greater than for pigs with a good sanitary status, but maximum growth rate was obtained for the same tryptophan level in both sanitary statuses⁽²⁾. Recently, a series of experiments examined the impact of immune system stimulation on sulfur AA, methionine and cysteine, metabolism and requirement for growth and protein deposition. Using a model of repeated injections of LPS in growing pigs, it was shown that LPS challenge did not influence nutrient digestibility and reduced the nitrogen balance.

However, sulfur retention increased indicating a partitioning of sulfur AA in favor of non-protein body stores, i.e. glutathione and taurine⁽⁸²⁾. This partitioning is probably the reason why pigs required more sulfur AA for maximizing protein accretion when submitted to repeated injection of LPS⁽⁸³⁾. Antimicrobial growth promoters (AGP) were classically incorporated in feed to enhance performance. They act in preventing the development of bacteria in the gastrointestinal tract and maintaining the sanitary status of the animals. A series of experiments evaluated the impact of AGP removal on performance and AA requirement in pigs. Withdrawal of AGP increased threonine requirement to reach a maximum growth rate⁽⁸⁴⁾. This could originate from an increased utilization threonine by the gut and/or the microflora.

Conclusion

The changes in protein and AA metabolism occurring when health status decline probably influence AA requirements. Additionally, specific AA can either enhance or inhibit body defenses. What is expected is that AA that have a direct effect on body defenses will have their requirement increased whereas decreased requirement is expected for AA involved in

“production functions”. The question is whether and how dietary AA supplies could be adapted to preserve both health and performance. Indeed, the physiological and metabolic status of an animal will be different if it is in good health or not. Moreover, health cannot be considered as a steady state but rather as a dynamic process resulting from the adaptation of the animal to their environment. As a consequence, the best strategy to adapt nutrition to health status is quite complex to define. A preventive strategy may lead to AA spoiling since additional AA will not be used by animals in good health. By contrast a curative solution may be inefficient since reduced feed intake caused by health deterioration will limit the availability of AA. The better strategy is likely to avoid situations of marginal AA deficiency. Marginal deficiencies may have no impact on productivity but may affect the animal ability to adapt to an immune challenge. Further investigations are required to improve our knowledge on AA metabolism and their implications in various physiological functions. One of the challenges in the future will be to identify novel

traits and indicators that are modulated by the AA supply and that could be used to refine nutritional requirements and recommendations.

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