Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-15T00:27:54.928Z Has data issue: false hasContentIssue false
  • English
  • Français

Towards amino acid recommendations for specific physiological and patho-physiological states in pigs

Published online by Cambridge University Press:  21 May 2012

Nathalie Le Floc'h ,
Florence Gondret ,
J. Jacques Matte  and
Hélène Quesnel
Nathalie Le Floc'h*
Affiliation:
INRA, UMR1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage (PEGASE), F-35590 Saint-Gilles, France Agrocampus Ouest, UMR1348 PEGASE, F-35000 Rennes, France
Florence Gondret
Affiliation:
INRA, UMR1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage (PEGASE), F-35590 Saint-Gilles, France Agrocampus Ouest, UMR1348 PEGASE, F-35000 Rennes, France
J. Jacques Matte
Affiliation:
Dairy and Swine R & D Centre, Agriculture and Agri-Food Canada, Canada
Hélène Quesnel
Affiliation:
INRA, UMR1348 Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage (PEGASE), F-35590 Saint-Gilles, France Agrocampus Ouest, UMR1348 PEGASE, F-35000 Rennes, France
*
*Corresponding author: Dr Nathalie Le Floc'h, email nathalie.lefloch@rennes.inra.fr
Rights & Permissions [Opens in a new window]

Abstract

The objective of this review is to provide an overview of the implication of amino acids (AA) in important physiological functions. This is done in the context of pig production where the competition for AA utilisation is exacerbated by constraints to maximise productive responses and the necessity to reduce dietary protein input for environmental, economic and sanitary issues. Therefore, there is an opportunity to refine the nutritional recommendations by exploring the physiological roles of AA. For example, methionine and cysteine, either in selenised or sulfur forms, are directly involved in the regulation of the glutathione antioxidative system. In sows, glutathione antioxidative system may contribute to improving ovulation conditions through control of oxidative pressure. Supplementation of sow diets with l-arginine, a precursor of NO and polyamines, may stimulate placental growth, promoting conceptus survival, growth and tissue development. The beneficial effect of arginine supplementation has been also suggested to improve lactation performance. Feed intake is usually the first response that is impacted by an inadequate AA supply. Valine and tryptophan imbalances may act as signals for decreasing feed intake. AA are also important nutrients for maintaining the animal's defence systems. Threonine, one of the main constituents of mucin protein, is important for gut development during the postnatal period. It may exert a protective effect that reduces the impact of weaning on gut morphology and associated disturbances. Finally, tryptophan is involved in the regulation of the defence system through its action as a precursor of antioxidants and its effect on the inflammatory response.

Keywords

Amino acidPigBody defenceReproductionDevelopmentGrowth
Type
Symposium on ‘Metabolic flexibility in animal and human nutrition’
Information
Proceedings of the Nutrition Society , Volume 71 , Issue 3 , August 2012 , pp. 425 - 432
Copyright
Copyright © The Authors 2012

Abbreviations:
AA

amino acid

GSH-Px

glutathione peroxidase

IDO

indoleamine 2,3-dioxygenase

There is a growing interest in considering the non-proteinogenic functions of some amino acids (AA) in physiological roles such as health, stress response and tissue development( Reference Massey, Blakeslee and Pitkow 1 ), and livestock species are concerned by these questions( Reference Kim, Mateo and Yin 2 ). The pig is an interesting model species to refine our knowledge on the roles of AA, because decades of selection on productive traits such as prolificacy, body fatness and growth rate may have modified nutrient partitioning and exacerbated the competition between physiological functions for AA utilisation. At present, nutritional recommendations for pigs are mainly established to maximise performance traits. These traits are mainly associated with maximising protein deposition during pre- and post-natal growth or exportation of protein in milk( 3 ). This is due to the fact that AA are used in large quantities for the synthesis of peptides and proteins, and that large amounts of AA are implicated in body protein turnover( Reference Lobley 4 ). However, this is true only for the twenty AA constituting body protein. At present, the revision of recommendations is necessary because of increasing constraints on pig production. The necessity to reduce the dietary crude protein content to cope with environmental issues may increase the risk that several AA are supplied in inadequate or sub-limiting amounts for physiological functions, some of which may not directly be associated with productive traits. There is also an increasing demand to reduce the utilisation of medication, mainly antibiotics, while preserving health and welfare. In fact, along with some micronutrients as cofactors, some AA act as precursors for neurotransmitters, signal molecules and as modulators of the immune system. Nutrition and recommendations should therefore include knowledge of the involvement of AA in metabolic pathways, AA metabolism and animal physiology. The objectives of this review are to identify AA involved in important physiological functions and to provide experimental evidence showing that the dietary AA supply may influence the response of the animal. In some cases, the AA profile can be modulated within the range of current nutritional recommendations. Other AA may need to be supplied in much larger amounts to induce a substantial effect. In this review, we will focus on the critical periods of pig production during which the opportunities to modulate the response of the pig by nutrition are clearly questioned.

Effects of amino acids on reproductive performance of the sows

Amino acids, antioxidative status and reproduction: methionine and cysteine

In reproducing animals, the hormonal regulation of the ovarian metabolism generates reactive oxygen species and free radicals( Reference Agarwal, Gupta and Sharma 5 ) that must be neutralised locally by antioxidants such as vitamin E, vitamin C and by the Se-dependent glutathione peroxidase (GSH-Px) system. A constant and adequate antioxidant status is critical for optimal ovulation both in terms of quantity and quality. This is particularly important in hyperprolific lines of sows, because of the poor quality of oocytes shed by the supplemental follicles( Reference Driancourt, Martinat-Botté and Terqui 6 ).

The metabolism of oxidised and reduced glutathione, as well as the enzymes GSH-Px and glutathione reductase, are closely related to cysteine and methionine via the key metabolite homocysteine. Homocysteine is an intermediate AA that can be metabolised by transmethylation (towards methionine) or transsulfuration (towards cysteine and glutathione, the precursor of GSH-Px). In fact, reactive oxygen species and peroxides up-regulate transsulfuration and down-regulate transmethylation( Reference Mosharov, Cranford and Banerjee 7 ). Therefore, the presence (or the production) of oxidative metabolites stimulates the transsulfuration pathway, which will in turn neutralise these metabolites.

The animal metabolism does not distinguish between sulfur forms of methionine and cysteine and their Se analogues( Reference Daniels 8 ). Under oxidative pressure, both seleno-cysteine and seleno-homocysteine are thus key factors just like their sulfur forms. Seleno-cysteine is either supplied directly by the diet or is derived from seleno-methionine after transsulfuration, a metabolic reaction that is up-regulated by redox changes( Reference Mosharov, Cranford and Banerjee 7 ). Then, it is mineralised to selenide and Se phosphate( Reference Johansson, Gafvelin and Arner 9 – Reference Yasumoto, Iwami and Yoshida 11 ) and resynthesised into a seleno-cysteinyl moiety that modulates gene expression and activates Se-dependent enzyme, GSH-Px( Reference Johansson, Gafvelin and Arner 9 , Reference Flohé, Wingender, Brigelus-Flohé, Forman and Cadenas 12 ). This metabolic control was observed recently in pigs( Reference Fortier, Audet and Giguère 13 ) by studying homoeostasis of Se-dependent GSH-Px during the peri-estral period under oxidative pressure (Fig. 1). The Se-dependent GSH-Px activity dropped shortly after ovulation in control gilts, while the synthesis of GSH-Px was maintained and enhanced by dietary supplementation of respectively inorganic and organic Se. This drop in GSH-Px activity of the control gilts is in agreement with the earlier-mentioned transient and local demand for antioxidants at ovulation. In contrast, there was an up-regulation of GSH-Px in gilts supplemented with organic Se in synchrony with the pro-oxidative conditions brought by ovulation. The inorganic source of Se (selenite, the dietary form routinely used in animal nutrition) is rapidly transformed to selenide and Se-phosphate( Reference Johansson, Gafvelin and Arner 9 – Reference Yasumoto, Iwami and Yoshida 11 ) and short-circuits the transsulfuration and the regulation of GSH-Px by redox changes. Therefore, it appears that inorganic Se produces a readily and persistent response to GSH-Px, independent of the need for this enzyme, while the response to seleno-AA directs the Se flow through a succession of metabolic steps in response to redox changes.

Fig. 1. Blood Se-dependent glutathione peroxidase (GSH-Px) activity during the peri-estrus period in gilts according to the level and source of dietary Se. Gilts were offered a control diet containing a basal level of 0·2 mg/kg Se, or a diet supplemented with 0·3 mg/kg of either inorganic selenite (MSe) or organic Se (OSe). Day 0=third estrus. One unit (U) of GSH-Px activity equals 1 μmol of NADPH oxidised per minute. Values are Least Squares means and maxima se were 206·5, 123·9, 147·5, 146·8, 129·7, 155·8, 165·1 and 195·6 for days −4, −3, −2, −1, 0, 1, 2 and 3 (adapted from( Reference Fortier, Audet and Giguère 13 )).

Several reactions of the transsulfuration pathway, which is involved in the fate of organic Se for the control of the GSH-Px system, are pyridoxine (vitamin B6)-dependent( Reference Yasumoto, Iwami and Yoshida 11 ). In a recent experiment, the importance of pyridoxine for an adequate flow of organic Se (Se-cysteine) towards the GSH-Px system was demonstrated in response to oxidative pressure induced by the peri-estrus period in sows( Reference Roy, Audet and Palin 14 ). Indeed, gene expressions of GSH-Px and Se-cysteine oxidase (control of the flow of Se-cysteine to the GSH-Px system) in the cytosol of both liver and kidney cells were 50–70% greater in gilts supplemented with an organic source of Se and vitamin B6 as compared with the other groups, either unsupplemented, supplemented with inorganic Se (with or without vitamin B6), or with organic Se without vitamin B6. In terms of reproductive performance, ovulation rate was approximately 23% greater in gilts supplemented with organic Se and vitamin B6 ( Reference Roy, Audet and Palin 14 ). These last two effects highlight the crucial role of micronutrients modulating the metabolic pathways of AA, such as seleno-analogues of methionine and cysteine, towards regulation of antioxidation and eventually optimal ovulation conditions.

Fetus development and lactation: l-arginine

A moderate to extensive dietary supplementation with specific AA can have important physiological effects on reproduction. l-Arginine is the common precursor for NO and polyamines, which are key regulators of angiogenesis, embryogenesis, and placental and fetal growth. Arginine is particularly abundant in porcine allantoic fluid, and associated with high rates of synthesis of NO and polyamines in the placenta during the first half of pregnancy( Reference Wu, Bazer and Wallace 15 ). This led to the hypothesis that dietary supplementation with l-arginine to sows may stimulate placental growth to promote conceptus survival, growth and development of some tissues (Fig. 2). Studies have consistently shown an effect of l-arginine supplementation during gestation on reproductive performance; however, the effects vary according to treatment period and dose. When given during early gestation (0–25 d of gestation)( Reference Li, Bazer and Johnson 16 ), l-arginine improved placental vascularity regardless of the dose. However, it had no effect on survival and weight of the embryos at a dose of 8 g/d supplemented arginine but had an adverse effect on these traits at a dose of 16 g/d. When supplementation started during embryonic implantation and lasted for 2 weeks (from 14 to 28 d of gestation) at a dose of 25 g/d supplemented arginine, a positive effect was observed on placental vascularity( Reference Hazeleger, Ramaekers, Smits, Wiseman, Varley, McOrist and Kemp 17 ). Additionally, it resulted in an increased number of fetuses (+1 to +3 fetuses)( Reference Hazeleger, Ramaekers, Smits, Wiseman, Varley, McOrist and Kemp 17 , Reference Berard and Bee 18 ) or in an increased number of piglets born alive (+1 piglet)( Reference Ramaekers, Kemp and van der Lende 19 ). Importantly, this treatment did not reduce within-litter birth weight( Reference Ramaekers, Kemp and van der Lende 19 ). When given from 30 d of gestation to term at the dose of 20 g/d supplemented arginine, a positive effect on litter size was still observed (+2 piglets born alive) without detrimental effects on within-litter birth weight and variation in birth weight( Reference Mateo, Wu and Bazer 20 ).

Fig. 2. Schematic involvement of arginine, NO and polyamines in fetal development (adapted from( Reference Wu, Bazer and Wallace 15 )).

Dietary supplementation with l-arginine may also benefit piglets, irrespective of the l-arginine given to the lactation sow( Reference Mateo, Wu and Moon 21 ) or directly to the piglet( Reference Kim, McPherson and Wu 22 , Reference Yao, Yin and Chu 23 ). Supplementing the lactation diet with 1% l-arginine has been shown to increase the concentration of most AA in milk compared with the control group( Reference Mateo, Wu and Moon 21 ). This greater transfer of AA in the milk could be related to the positive effects of l-arginine on vascularity and blood flow to the mammary gland( Reference Kim and Wu 24 ). In support of this hypothesis, a short-term infusion of a NO donor has been shown to increase the blood flow to the mammary gland in goats( Reference Lacasse and Prosser 25 ). Supplementing l-arginine to the diets of primiparous sows may also increase milk production( Reference Mateo, Wu and Moon 21 ). Moreover, piglets receiving milk-based diet supplemented with 0·4% l-arginine had greater plasma concentrations of insulin and growth hormone( Reference Kim, McPherson and Wu 22 , Reference Yao, Yin and Chu 23 ). All these studies reported an increase in weight gain of the piglets during the treatment period that may be due, at least partly, to an increase in protein synthesis and the signalling activity of the mammalian target of rapamycin in skeletal muscle( Reference Kim and Wu 24 ). Direct effects of l-arginine on tissue development have been reported in vivo and in vitro. In growing–finishing pigs, dietary l-arginine supplementation increased muscle gain by enhancing muscle protein, glycogen and fat content, while decreasing carcass fat content( Reference Tan, Yin and Liu 26 ). This is consistent with the finding that l-arginine supplementation favoured lipogenesis in muscle and lipolysis in adipose tissue( Reference Tan, Yin and Liu 27 ). Less consistent effects of arginine and NO have been reported in vitro. Arginine-induced pre-adipocyte differentiation in rats( Reference Yan, Aziz and Shillabeer 28 ), whereas NO suppressed some markers of differentiation in 3T3-L1 murine cell line through suppressing the transcriptional activity of the key regulator PPARγ( Reference Kawachi, Moriya and Korai 29 ). These results suggest that the l-arginine supply may affect the balance between fat and muscle development in pigs, but specific studies are required to identify the most critical periods.

Amino acids are involved in the control of body protein deposition

In growing pigs, formulation of low protein diets is associated with a reduction of nitrogen output and energy losses. Moreover, it is one of the best strategies to reduce digestive disorders( Reference Heo, Kim and Hansen 30 ). However, the supply of several AA could then be limiting for protein deposition and growth. These effects can be attributed to a direct effect on protein synthesis and deposition because one or several AA will be supplied in insufficient amounts to fulfill the potential for protein synthesis. Moreover, some AA are now known to act as signal molecules in the control of feed intake, appetite, or protein synthesis. Therefore, a better knowledge of the roles of AA in the control of feed intake and protein synthesis is needed to formulate diets for optimal feed efficiency and growth rate.

Control of feed intake by amino acids: tryptophan and valine

An inadequate or imbalanced AA supply implies that one (or more) AA is provided in disproportionate amount compared with the others. Many species are able to detect a dietary AA imbalance( Reference Harper and Rogers 31 ) and react by reducing feed intake. This is particularly the case for two essential AA, tryptophan and valine. In pigs, the effect of tryptophan and valine deficiencies on growth are mainly associated with a reduction in appetite and feed intake( Reference Ettle and Roth 32 – Reference Wiltafsky, Pfaffl and Roth 35 ). In growing pigs, the depressive effect of a tryptophan deficiency on feed intake was enhanced by increasing the level of protein and thus the level of large neutral AA (valine, isoleucine, leucine, tyrosine, phenylalanine and methionine). These AA compete with tryptophan for transport across the blood–brain barrier( Reference Henry, Sève and Mounier 34 , Reference Leathwood 36 ) because they share the same transport system. The depressive effect of valine deficiency on feed intake was enhanced by an excess supply of leucine known to stimulate the activity of the branched-chain keto acid dehydrogenase complex, thereby increasing the catabolism of valine in rats and pigs( Reference Wiltafsky, Pfaffl and Roth 35 , Reference May, Piepenbrock and Kelly 37 ). Recent data showed that pigs rejected a valine-imbalanced diet within 2 d of exposure to the diet by reducing the daily number of meals( Reference Gloaguen, Le Floc'h and Corrent 38 ). This behavioural response suggests that the response to a valine imbalance results from post-absorptive feedback signals.

The physiological mechanisms involved in the rejection of an AA imbalanced diet are probably different among AA and have not been clearly identified in pigs. In rats, an AA imbalance is detected by the brain in the cortex piriform anterior( Reference Hao, Sharp and Ross-Inta 39 ). An AA deficiency results in an accumulation of its uncharged tRNA, which activates the general control of non-depressible-2 kinase in the cortex piriform anterior. A valine deficiency increased the expression of somatostatin mRNA in the hypothalamus in the anorectic mice, and intracerebroventricular administration of somatostatin reduced the feed intake of mice( Reference Nakahara, Takata and Ishii 40 ). Moreover, because tryptophan is a precursor of serotonin, a brain neuromediator involved in the control of feed intake in pigs, this pathway might be involved in the rejection effect of a tryptophan-deficient diet. Serotonin manipulation is known to affect meal size( Reference Henry, Sève and Mounier 34 , Reference Blundell 41 ). Tryptophan could be also involved in the peripheric control of appetite through a modulation of the rate of gastric emptying( Reference Ponter, Cortamira and Sève 42 ), insulin secretion and sensitivity( Reference Ponter, Cortamira and Sève 42 , Reference Ponter, Cortamira and Sève 43 ). Tryptophan effect on appetite could be mediated by ghrelin( Reference Zhang, Yin and Defa 44 ), a gut hormone involved in the regulation of feed intake. Indeed, tryptophan supplementation to low-tryptophan diets induced ghrelin secretion, expression of ghrelin mRNA in the stomach and duodenum of piglets, and increased feed intake. Tryptophan also stimulates the release of cholecystokinin, a hormone that decreases meal size( Reference Wang, Chandra and Samsa 45 ).

Control of protein synthesis by amino acids: leucine

The role of leucine, one of the three branched-chain AA, has been known for a long time for its ability to stimulate muscle protein synthesis and inhibit protein degradation in rodents( Reference Dardevet, Sornet and Balage 46 , Reference Dardevet, Sornet and Bayle 47 ) and young piglets( Reference Escobar, Frank and Suryawan 48 – Reference Torrazza, Suryawan and Gazzaneo 50 ). The role of leucine as a signal molecule for the intracellular pathway leading to activation of the first step of protein synthesis has been widely explored. Leucine is known to activate mammalian target of rapamycin leading to activation of the translation initiation factor and then to the aggregation of ribosome and mRNA translation( Reference Stipanuk 51 ). Recently, this effect has been reported in young growing pigs fed a low-protein diet supplemented with leucine up to 30% higher than the recommendations for maximum growth rate( Reference Yin, Yao and Liu 52 ). After 2 weeks of treatment, growth rate and tissue protein synthesis were increased in pigs fed the leucine-supplemented diet and this effect was independent of feed intake. This result opens new ways to improve feed efficiency and growth rate through nutrition.

Amino acids are involved in health preservation

Preservation of gut homoeostasis: threonine

In young piglets, threonine has been shown to be indispensable for gut development and physiology. Threonine is extracted from the small intestine in greater proportion than the other essential AA( Reference Le Floc'h and Sève 53 ). In orally fed piglets, the threonine requirement, evaluated by the indicator AA oxidation technique, is twice that of parenterally fed piglets( Reference Bertolo, Chen and Law 54 ). The high rate of intestinal threonine extraction is not explained by threonine catabolism( Reference Le Floc'h and Sève 53 , Reference Le Floc'h, Thibault and Sève 55 ) but is associated with intestinal protein synthesis, especially for the synthesis of mucins( Reference Law, Bertolo and Adjiri-Awere 56 , Reference Wang, Qiao and Yin 57 ). The threonine content in mucin ranges from 13 to 26% of total constituting AA( Reference Lien, Sauer and Fenton 58 , Reference Mantle and Allen 59 ). Mucins are excreted in the lumen, and their constituting AA are poorly re-absorbed. Therefore threonine is found in high concentrations in ileal endogenous protein losses( Reference Hess and Sève 60 ). This questions the impact of dietary threonine supply on gut homoeostasis. In piglets, a threonine deficiency impaired total protein and mucin synthesis( Reference Wang, Qiao and Yin 61 , Reference Wang, Zeng and Mao 62 ) and also had an impact on other functions of the small intestine. In piglets, a low threonine supply (70% of recommendations) for 2 weeks induced atrophy of the villi associated with a reduction in aminopeptidase N activity in the ileum( Reference Hamard, Sève and Le Floc'h 63 ). It also increased paracellular permeability and glucose absorption capacity( Reference Hamard, Mazurais and Boudry 64 ), and modified ileal gene expression profiles. Notably, the increase in the expression of genes involved in immune and defence functions associated with the increased paracellular permeability suggests that threonine is essential to preserve intestinal integrity. These morphological and functional disturbances are also observed during starvation or malnutrition (e.g. after weaning) and are frequently associated with an increased risk of gut disorders( Reference Boza, Möennoz and Vuichoud 65 – Reference Boudry, Péron and Le Huërou-Luron 67 ). The impact of dietary threonine on weaning diet as a strategy to minimise gut disorders deserves further attention( Reference de Lange, Pluske and Gong 68 ).

Control of inflammatory response: tryptophan

In pig farms, permanent exposure to antigens, unfavourable sanitary conditions and moderate infectious diseases induce an inflammatory status that limits growth by reducing feed intake( Reference Sandberg, Emmans and Kyriazakis 69 ) and affecting nutrient metabolism( Reference Le Floc'h, Jondreville and Matte 70 , Reference Pastorelli, van Milgen and Lovatto 71 ). Indeed, AA are partitioned from body protein deposition towards tissues and functions involved in the animal's defence system( Reference Klasing 72 ). If an AA is supplied in limited amount, this partition is not necessary fully compensated by endogenous supplies. The consequence could be a reduction of AA available for protein deposition, the defence system, or for both. The impact of an inflammatory challenge on AA metabolism has been demonstrated in several species for dispensable AA such as cysteine involved in glutathione synthesis( Reference Malmezat, Breuillé and Pouyet 73 ), glutamine used as a fuel for rapidly dividing cells such as enterocytes and lymphocytes( Reference Yoo, Field and McBurney 74 ), and tryptophan and its metabolites implied in the inflammatory response.

Tryptophan is one of the indispensable AA that is found in low concentration in body proteins and plasma. This relatively low amount of tryptophan is singular considering that this AA is involved in several physiological functions such as the regulation of growth, mood, behaviour and immune responses( Reference Le Floc'h, Otten and Merlot 75 ). Depletion of plasma tryptophan has been reported during experimentally induced inflammation in pigs( Reference Lindberg and Clowes 76 , Reference Melchior, Sève and Le Floc'h 77 ), mice( Reference Saito, Markey and Heyes 78 ) and human subjects( Reference Brown, Ozaki and Datta 79 , Reference Pfefferkorn 80 ). This decrease can be attributed to the synthesis of acute phase proteins, which have a high tryptophan content( Reference Reeds, Fjeld and Jahoor 81 ), and/or to an increase in tryptophan catabolism. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme for the catabolism of tryptophan to kynurenine, is induced by interferon-γ( Reference Pfefferkorn 80 , Reference MacKenzie and Hadding 82 ) and by inflammation in pigs( Reference Melchior, Mézière and Sève 83 , Reference Le Floc'h, Melchior and Sève 84 ).

Increased tryptophan catabolism and IDO activation during inflammation are considered as mechanisms involved in the defence system. Three hypotheses have been proposed (Fig. 3). The first one is that local tryptophan depletion resulting from IDO activation in macrophages would be a mechanism controlling proliferation of bacteria, virus and parasite( Reference Pfefferkorn 80 , Reference MacKenzie and Hadding 82 , Reference MacKenzie, Heseler and Müller 85 ). The second one is that IDO regulates T-cell activity. Such a mechanism has been shown during gestation where IDO exerts a protective role by preventing the fetal allograft rejection by maternal T-lymphocytes( Reference Munn, Zhou and Attwood 86 ). Finally, IDO induction during immune activation may protect cells from oxidative damage( Reference Hayaishi 87 ). Indeed, 3-hydroxyanthranilic acid and 3-hydroxykynurenine, produced from tryptophan through the IDO–kynurenine pathway, have antioxidant properties( Reference Christen, Peterhans and Stocker 88 ). This suggests that dietary tryptophan could influence the inflammatory response and the animal health. In support of this hypothesis, pigs suffering from an experimentally induced lung inflammation and offered a diet with tryptophan concentration slightly higher than the recommendations had lower acute phase protein concentration and were healthier compared with pigs offered a diet moderately deficient in tryptophan( Reference Le Floc'h, Melchior and Sève 84 ). In a porcine model of induced colitis, tryptophan supplementation loading down-regulated inflammation, restored local immune response and reduced colitis symptoms( Reference Kim, Kovacs-Nolan and Yang 89 ).

Fig. 3. Roles of tryptophan catabolism by the enzyme indoleamine 2,3-dioxygenase (IDO) on the animal's defence system. , , increase and decrease respectively.

The consequences of inflammation on tryptophan metabolism probably impaired the availability of tryptophan for body protein deposition and growth( Reference Le Floc'h, LeBellego and Matte 90 ). However, additional crystalline tryptophan did not totally prevent growth retardation caused by inflammation. Nevertheless, an improvement in growth rate by additional tryptophan was observed in pigs suffering from a moderate inflammation compared with control pigs( Reference Le Floc'h, Matte and Melchior 91 ). Additional tryptophan allowed pigs to partially compensate for the effects of an Escherichia coli infection by increasing feed intake and maintaining growth( Reference Trevisi, Melchior and Mazzoni 92 ). These results suggest that dietary tryptophan should be maintained at an adequate level to preserve health during critical phases of pig rearing.

Conclusion

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 revise nutritional requirements and recommendations. Moreover, ranges for safety and efficiency of AA utilisation should be clearly established, especially when AA are supplied in large amounts. The interactions between AA and other nutrients also merit further consideration. Despite the increasing availability of synthetic AA or AA precursors, their utilisation could be still limited by their cost and specific regulation.

Acknowledgements

The authors are grateful to the Oskar Kellner Symposium committee. We acknowledge our colleagues from INRA PEGASE, France and Dairy and Swine R & D Centre, Agriculture and Agri-Food Canada, Canada for their contributions. The authors have no conflict of interest. All the authors contributed significantly to the preparation of this manuscript.

References

1. Massey, KA, Blakeslee, CH & Pitkow, HS (1998) A review of physiological and metabolic effects of essential amino acids. Amino Acids 14, 271–300.CrossRefGoogle ScholarPubMed
2. Kim, SW, Mateo, RD, Yin, Y-L et al. (2007) Functional amino acids and fatty acids for enhancing production performance of sows and piglets. Asian-Aust J Anim Sci 20, 295–306.CrossRefGoogle Scholar
3. National Research Council (1998) Nutrient Requirements of Swine, 10th revised edition. Washington, DC: National Academy Press.Google Scholar
4. Lobley, GE (2003) Protein turnover – what does it mean for animal production? Can J Anim Sci 83, 327–340.CrossRefGoogle Scholar
5. Agarwal, A, Gupta, S & Sharma, RK (2005) Role of oxidative in stress in female reproduction. Reprod Biol Endocrinol 3, 1–28.CrossRefGoogle ScholarPubMed
6. Driancourt, MA, Martinat-Botté, F & Terqui, M (1998) Contrôle du taux d'ovulation chez la truie: l'apport des modèles hyperprolifiques. INRA Prod Anim 11, 221–226.CrossRefGoogle Scholar
7. Mosharov, E, Cranford, MR & Banerjee, R (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39, 13005–13011.CrossRefGoogle ScholarPubMed
8. Daniels, LA (1996) Selenium metabolism and bioavailability. Biol Trace Element Res 54, 185–199.CrossRefGoogle ScholarPubMed
9. Johansson, LG, Gafvelin, G & Arner, ESJ (2005) Selenocysteine in proteins – properties and biotechnological use. Biochim Biophys Acta Gen Subj 1726, 1–13.CrossRefGoogle ScholarPubMed
10. Suzuki, KT & Orga, Y (2002) Metabolic pathway for selenium in the body: speciation by HPLC-ICP MS with enriched Se. Food Addit Contam 19, 974–983.CrossRefGoogle ScholarPubMed
11. Yasumoto, K, Iwami, K & Yoshida, M (1979) Vitamin B6 dependence of selenomethionine and selenite utilization for glutathione peroxidase in the rat. J Nutr 109, 760–766.CrossRefGoogle ScholarPubMed
12. Flohé, L, Wingender, E & Brigelus-Flohé, R (1997) Regulation of glutathione peroxidase. In Oxidative Stress and Signal Transduction, pp. 415–440 [Forman, HJ and Cadenas, H, editors]. New York: Chapman and Hall.CrossRefGoogle Scholar
13. Fortier, ME, Audet, I, Giguère, A et al. (2012) Effect of dietary organic and inorganic selenium on antioxidant status, embryo development and reproductive performance in hyperovulatory first-parity gilts. J Anim Sci 90, 231–240.CrossRefGoogle ScholarPubMed
14. Roy, M, Audet, I, Palin, MF et al. (2011) Dietary sources of selenium in nulliparous sows: the importance of vitamin B6 status for some aspects of antioxidant status and ovulation during the peri-estrus period. J Anim Sci 89, E-Suppl. 1, S584.Google Scholar
15. Wu, G, Bazer, FW, Wallace, JM et al. (2006) Intrauterine growth retardation: implications for the animal sciences. J Anim Sci 84, 2316–2337.CrossRefGoogle ScholarPubMed
16. Li, X, Bazer, FW, Johnson, GA et al. (2010) Dietary supplementation with 0·8% L-arginine between days 0 and 25 of gestation reduces litter size in gilts. J Nutr 140, 1111–1116.CrossRefGoogle Scholar
17. Hazeleger, W, Ramaekers, P, Smits, C et al. (2007) Influence of nutritional factors on placenta growth and piglet imprinting. In Paradigms in Pig Science, pp. 309–327 [Wiseman, J, Varley, MA, McOrist, S and Kemp, B, editors]. Nottingham, UK: Nottingham University Press.Google Scholar
18. Berard, J & Bee, G (2010) Effects of dietary l-arginine supplementation to gilts during early gestation on foetal survival, growth and myofiber formation. Animal 4, 1680–1687.CrossRefGoogle ScholarPubMed
19. Ramaekers, P, Kemp, B & van der Lende, T (2006) Progenos in sows increases number of piglets born. J Anim Sci 84, Suppl. 1/J Dairy Sci 89, Suppl. 1, S394.Google Scholar
20. Mateo, RD, Wu, G, Bazer, FW et al. (2007) Dietary L-arginine supplementation enhances the reproductive performance of gilts. J Nutr 137, 652–656.CrossRefGoogle ScholarPubMed
21. Mateo, RD, Wu, G, Moon, HK et al. (2008) Effects of dietary arginine supplementation during gestation and lactation on the performance of lactating primiparous sows and nursing piglets. J Anim Sci 86, 827–835.CrossRefGoogle ScholarPubMed
22. Kim, SW, McPherson, R & Wu, G (2004) Dietary arginine supplementation enhances the growth of milk-fed young pigs. J Nutr 134, 625–630.CrossRefGoogle ScholarPubMed
23. Yao, K, Yin, YL, Chu, W et al. (2008) Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs. J Nutr 138, 867–872.CrossRefGoogle ScholarPubMed
24. Kim, SW & Wu, G (2009) Regulatory role for amino acids in mammary gland growth and milk synthesis. Amino Acids 37, 89–95.CrossRefGoogle ScholarPubMed
25. Lacasse, P & Prosser, CG (2003) Mammary blood flow does not limit milk yield in lactating goats. J Dairy Sci 86, 2094–2097.CrossRefGoogle Scholar
26. Tan, B, Yin, Y, Liu, Z et al. (2009) Dietary L-arginine supplementation increases muscle gain and reduces body fat mass in growing-finishing pigs. Amino Acids 37, 169–175.CrossRefGoogle ScholarPubMed
27. Tan, B, Yin, Y, Liu, Z et al. (2011) Dietary L-arginine supplementation differentially regulates expression of lipid-metabolic genes in porcine adipose tissue and skeletal muscle. J Nutr Biochem 22, 441–445.CrossRefGoogle ScholarPubMed
28. Yan, H, Aziz, E, Shillabeer, G et al. (2002) Nitric oxide promotes differentiation of rat white preadipocytes in culture. J Lipid Res 43, 2123–2129.CrossRefGoogle ScholarPubMed
29. Kawachi, H, Moriya, NH, Korai, T et al. (2007) Nitric oxide suppresses preadipocyte differentiation in 3T3-L1 culture. Mol Cell Biochem 300, 61–67.CrossRefGoogle ScholarPubMed
30. Heo, JM, Kim, JC, Hansen, CF et al. (2008) Effects of feeding low protein diets to piglets on plasma urea nitrogen, faecal ammonia nitrogen, the incidence of diarrhoea and performance after weaning. Arch Anim Nutr 62, 343–358.CrossRefGoogle ScholarPubMed
31. Harper, AE & Rogers, QR (1965) Amino acid imbalance. Proc Nutr Soc 24, 173–190.CrossRefGoogle ScholarPubMed
32. Ettle, T & Roth, FX (2004) Specific dietary selection for tryptophan by the piglet. J Anim Sci 82, 1115–1121.CrossRefGoogle ScholarPubMed
33. Gloaguen, M, Le Floc'h, N, Brossard, L et al. (2011) Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids. Animal 5, 1734–1742.CrossRefGoogle Scholar
34. Henry, Y, Sève, B, Mounier, A et al. (1996) Growth performance and brain neurotransmitters in pigs as affected by tryptophan, protein, and sex. J Anim Sci 74, 2700–2710.CrossRefGoogle ScholarPubMed
35. Wiltafsky, MK, Pfaffl, MW & Roth, FX (2010) The effects of branched-chain amino acid interactions on growth performance, blood metabolites, enzyme kinetics and transcriptomics in weaned pigs. Br J Nutr 103, 964–976.CrossRefGoogle ScholarPubMed
36. Leathwood, PD (1987) Tryptophan availability and serotonin synthesis. Proc Nutr Soc 25, 143–156.CrossRefGoogle Scholar
37. May, RC, Piepenbrock, N, Kelly, RA et al. (1991) Leucine-induced amino acid antagonism in rats: muscle valine metabolism and growth impairment. J Nutr 121, 293–301.CrossRefGoogle ScholarPubMed
38. Gloaguen, M, Le Floc'h, N, Corrent, E et al. (2012) Providing a diet deficient in valine but with excess leucine results in a rapid decrease in feed intake and modifies the postprandial plasma amino acid and α-keto acid concentrations in pigs. J Anim Sci (In the Press).CrossRefGoogle Scholar
39. Hao, SZ, Sharp, JW, Ross-Inta, CM et al. (2005) Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307, 1776–1778.CrossRefGoogle ScholarPubMed
40. Nakahara, K, Takata, S, Ishii, A et al. (2012) Somatostatin is involved in anorexia in mice fed a valine-deficient diet. Amino Acids 42, 1397–1404.CrossRefGoogle ScholarPubMed
41. Blundell, JE (1986) Serotonin manipulations and the structure of feeding-behavior. Appetite 7, 39–56.CrossRefGoogle Scholar
42. Ponter, AA, Cortamira, NO, Sève, B et al. (1994) Intragastric tryptophan reduces glycemia after glucose, possibly via glucose-mediated insulinotropic polypeptide (GIP) in early weaned piglets. J Nutr 124, 259–267.CrossRefGoogle Scholar
43. Ponter, AA, Cortamira, NO, Sève, B et al. (1994) The effects of energy source and tryptophan on the rate of protein synthesis and on hormones of the entero-insular axis in the piglet. Br J Nutr 71, 661–674.CrossRefGoogle ScholarPubMed
44. Zhang, H, Yin, J, Defa, L et al. (2007) Tryptophan enhances ghrelin expression and secretion associated with increased food intake and weight gain in weanling pigs. Domest Anim Endocrinol 33, 47–61.CrossRefGoogle ScholarPubMed
45. Wang, Y, Chandra, R, Samsa, LA et al. (2011) Amino acids stimulate cholecystokinin release through the ca(2+)-sensing receptor. Am J Physiol Gastrointest Liver Physiol 300, G528–G537.CrossRefGoogle Scholar
46. Dardevet, D, Sornet, C, Balage, M et al. (2000) Stimulation of in vitro rat muscle protein synthesis by leucine decreases with age. J Nutr 130, 2630–2635.CrossRefGoogle ScholarPubMed
47. Dardevet, D, Sornet, C, Bayle, G et al. (2002) Postprandial stimulation of muscle protein synthesis in old rats can be restored by a leucine-supplemented meal. J Nutr 132, 95–100.CrossRefGoogle ScholarPubMed
48. Escobar, J, Frank, JW, Suryawan, A et al. (2005) Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation. Am J Physiol 288, E914–E921.Google ScholarPubMed
49. Escobar, J, Frank, JW, Suryawan, A et al. (2009) Regulation of muscle growth in neonates. Curr Opin Nutr Metab Care 12, 78–85.Google Scholar
50. Torrazza, RM, Suryawan, A, Gazzaneo, MC et al. (2010) Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation. J Nutr 140, 2145–2152.CrossRefGoogle Scholar
51. Stipanuk, MH (2007) Leucine and protein synthesis: mTOR and beyond. Nutr Rev 65, 122–129.CrossRefGoogle ScholarPubMed
52. Yin, Y, Yao, K, Liu, Z et al. (2010) Supplementing L-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids 39, 1477–1486.CrossRefGoogle ScholarPubMed
53. Le Floc'h, N & Sève, B (2005) Catabolism through the threonine dehydrogenase pathway does not account for the high first-pass extraction rate of dietary threonine by the portal drained viscera in pigs. Br J Nutr 93, 447–456.CrossRefGoogle Scholar
54. Bertolo, RFP, Chen, CZL, Law, G et al. (1998) Threonine requirement of neonatal piglets receiving total parenteral nutrition is considerably lower than that of piglets receiving an identical diet intragastrically. J Nutr 128, 1752–1759.CrossRefGoogle ScholarPubMed
55. Le Floc'h, N, Thibault, JN & Sève, B (1997) Tissue localization of threonine oxidation in pigs. Br J Nut 77, 593–603.Google ScholarPubMed
56. Law, GK, Bertolo, RF, Adjiri-Awere, A et al. (2007) Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. Am J Physiol Gastrointest Liver Physiol 292, 1293–1301.CrossRefGoogle ScholarPubMed
57. Wang, X, Qiao, S, Yin, Y et al. (2007) A deficiency or excess of dietary threonine reduces protein synthesis in jejunum and skeletal muscle of young pigs. J Nutr 137, 1442–1446.CrossRefGoogle ScholarPubMed
58. Lien, KA, Sauer, WC & Fenton, M (1997) Mucin output in ileal digesta of pigs fed a protein free diet. Z Ernährungswiss 36, 182–190.CrossRefGoogle ScholarPubMed
59. Mantle, M & Allen, A (1981) Isolation and characterization of the native glycoprotein from pig small-intestinal mucus. Biochem J 195, 267–275.CrossRefGoogle ScholarPubMed
60. Hess, V & Sève, B (1999) Effects of body weight and feed intake level on basal ileal endogenous losses in growing pigs. J Anim Sci 77, 3281–3288.CrossRefGoogle ScholarPubMed
61. Wang, X, Qiao, SY, Yin, YL et al. (2007) A deficiency or excess of dietary threonine reduces protein synthesis in jejunum and skeletal muscle of young pigs. J Nutr 137, 1442–1446.CrossRefGoogle ScholarPubMed
62. Wang, W, Zeng, X, Mao, X et al. (2010) Optimal dietary true ileal digestible threonine for supporting the mucosal barrier in small intestine of weanling pigs. J Nutr 140, 981–986.CrossRefGoogle ScholarPubMed
63. Hamard, A, Sève, B & Le Floc'h, N (2007) Intestinal development and growth performance of early-weaned piglets fed a low-threonine diet. Animal 1, 1134–1142.CrossRefGoogle ScholarPubMed
64. Hamard, A, Mazurais, D, Boudry, G et al. (2010) A moderate threonine deficiency affects gene expression profile, paracellular permeability and glucose absorption capacity in the ileum of piglets. J Nutr Biochem 21, 914–921.CrossRefGoogle ScholarPubMed
65. Boza, JJ, Möennoz, D, Vuichoud, J et al. (1999) Food deprivation and refeeding influence growth, nutrient retention and functional recovery of rats. J Nutr 129, 1340–1346.CrossRefGoogle ScholarPubMed
66. Gupta, PD & Waheed, AA (1992) Effect of starvation on glucose transport and membrane fluidity in rat intestinal epithelial cells. FEBS Lett 300, 263–267.CrossRefGoogle ScholarPubMed
67. Boudry, G, Péron, V, Le Huërou-Luron, I et al. (2004) Weaning induces both transient and long-lasting modifications of absorptive, secretory, and barrier properties of piglet intestine. J Nutr 134, 2256–2262.CrossRefGoogle ScholarPubMed
68. de Lange, CFM, Pluske, J, Gong, J et al. (2010) Strategic use of feed ingredients and feed additives to stimulate gut health and development in young pigs. Livest Sci 134, 124–134.CrossRefGoogle Scholar
69. Sandberg, FB, Emmans, GC & Kyriazakis, I (2006) A model for predicting feed intake of growing animals during exposure to pathogens. J Anim Sci 84, 1552–1566.CrossRefGoogle Scholar
70. Le Floc'h, N, Jondreville, C, Matte, JJ et al. (2006) Importance of sanitary environment for growth performance and plasma nutrient homeostasis during the post-weaning period in piglets. Arch Anim Nutr, 60, 23–34.CrossRefGoogle Scholar
71. Pastorelli, H, van Milgen, J, Lovatto, P et al. (2012) Meta-analysis of feed intake and growth responses of growing pig after a sanitary challenge. Animal 6, 952–961.CrossRefGoogle ScholarPubMed
72. Klasing, KC (1988) Nutritional aspects of leukocytic cytokines. J Nutr 118, 1436–1446.CrossRefGoogle ScholarPubMed
73. Malmezat, T, Breuillé, D, Pouyet, C et al. (2000) Methionine transsulfuration is increased during sepsis in rats. Am J Physiol Endocrinol Metab 279, 1391–1397.CrossRefGoogle ScholarPubMed
74. Yoo, SS, Field, CJ & McBurney, MI (1997) Glutamine supplementation maintains intramuscular glutamine concentrations and normalizes lymphocyte function in infected early weaned pigs. J Nutr 127, 2253–2259.CrossRefGoogle ScholarPubMed
75. Le Floc'h, N, Otten, W & Merlot, E (2011) Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41, 1195–1205.CrossRefGoogle ScholarPubMed
76. Lindberg, BO & Clowes, GH (1981) The effects of hyperalimentation and infused leucine on the amino acid metabolism in sepsis: an experimental study in vivo . Surgery 90, 278–290.Google ScholarPubMed
77. Melchior, D, Sève, B & Le Floc'h, N (2004) Chronic lung inflammation affects plasma amino acid concentrations in pigs. J Anim Sci 82, 1091–1099.CrossRefGoogle ScholarPubMed
78. Saito, K, Markey, SP & Heyes, MP (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neurosciences 51, 25–39.CrossRefGoogle ScholarPubMed
79. Brown, RR, Ozaki, YS, Datta, P et al. (1991) Implications of interferon-induced tryptophan catabolism in auto-immune diseases and AIDS. Adv Exp Med Biol 294, 425–435.CrossRefGoogle ScholarPubMed
80. Pfefferkorn, ER (1984) Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc Natl Acad Sci USA 81, 908–912.CrossRefGoogle ScholarPubMed
81. Reeds, PJ, Fjeld, CR & Jahoor, F (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.CrossRefGoogle ScholarPubMed
82. MacKenzie, CR & Hadding, U (1998) Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocytederived macrophages inhibits the growth of group B streptococci. J Infect Dis 178, 875–878.CrossRefGoogle ScholarPubMed
83. Melchior, D, Mézière, N, Sève, B et al. (2005) Is tryptophan catabolism increased through indoleamine 2,3 dioxygenase activity during chronic lung inflammation in pigs? Reprod Nutr Dev 45, 175–183.CrossRefGoogle ScholarPubMed
84. Le Floc'h, N, Melchior, D & Sève, B (2008) Dietary tryptophan helps to preserve tryptophan homeostasis in pigs suffering from lung inflammation. J Anim Sci 86, 3473–3479.CrossRefGoogle ScholarPubMed
85. MacKenzie, CR, Heseler, K, Müller, A et al. (2007) Role of indoleamine 2,3-dioxygenase in antimicrobial defense and immuno-regulation: tryptophan depletion versus production of toxic kynurenines. Curr Drug Metab 8, 237–244.CrossRefGoogle ScholarPubMed
86. Munn, DH, Zhou, M, Attwood, JT et al. (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193.CrossRefGoogle ScholarPubMed
87. Hayaishi, O (1996) Utilization of superoxide anion by indoleamine oxygenase-catalyzed tryptophan and indoleamine oxidation. Adv Exp Med Biol 398, 285–289.CrossRefGoogle ScholarPubMed
88. Christen, S, Peterhans, E & Stocker, R (1990) Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci USA 87, 2506–2510.CrossRefGoogle ScholarPubMed
89. Kim, CJ, Kovacs-Nolan, JA, Yang, C et al. (2010) L-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. J Nutr Biochem 21, 468–475.CrossRefGoogle Scholar
90. Le Floc'h, N, LeBellego, L, Matte, JJ et al. (2009) The effect of sanitary status degradation and dietary tryptophan level on growth rate and tryptophan metabolism in weaning pigs. J Anim Sci 87, 1686–1694.CrossRefGoogle Scholar
91. Le Floc'h, N, Matte, JJ, Melchior, D et al. (2010) A moderate inflammation caused by the deterioration of housing conditions modifies Trp metabolism but not Trp requirement for growth of post-weaned piglets. Animal 4, 1891–1898.CrossRefGoogle Scholar
92. Trevisi, P, Melchior, D, Mazzoni, M et al. (2009) A tryptophan-enriched diet improves feed intake and growth performance of susceptible weanling pigs orally challenged with Escherichia coli K88. J Anim Sci 87, 148–156.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1. Blood Se-dependent glutathione peroxidase (GSH-Px) activity during the peri-estrus period in gilts according to the level and source of dietary Se. Gilts were offered a control diet containing a basal level of 0·2 mg/kg Se, or a diet supplemented with 0·3 mg/kg of either inorganic selenite (MSe) or organic Se (OSe). Day 0=third estrus. One unit (U) of GSH-Px activity equals 1 μmol of NADPH oxidised per minute. Values are Least Squares means and maxima se were 206·5, 123·9, 147·5, 146·8, 129·7, 155·8, 165·1 and 195·6 for days −4, −3, −2, −1, 0, 1, 2 and 3 (adapted from(13)).

Figure 1

Fig. 2. Schematic involvement of arginine, NO and polyamines in fetal development (adapted from(15)).

Figure 2

Fig. 3. Roles of tryptophan catabolism by the enzyme indoleamine 2,3-dioxygenase (IDO) on the animal's defence system. , , increase and decrease respectively.