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Dietary tryptophan helps to preserve tryptophan homeostasis in pigs suffering from lung inflammation¹

N. Le Floc’h^*,,2, D. Melchior and B. Sève^*,

^* Institut National de la Recherche Agronomique, UMR 1079 SENAH, F-35000 Rennes, France; and Agrocampus Rennes, UMR 1079, F-35000 Rennes, France; and Ajinomoto-Eurolysine S.A.S., 153 rue de Courcelles, 75817 Paris, France

	Abstract

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In pigs, inflammation modifies Trp metabolism and consequently could impact on Trp requirement for growth. In this study, the effects of lung inflammation, induced by the intravenous injection of complete Freund’s adjuvant, and dietary Trp content on Trp metabolism and availability were investigated. Two dietary Trp contents, one corresponding to a low-Trp diet (1.5 g of Trp/kg of diet, Basal diet) and the second to an adequate-Trp diet (2 g of Trp/kg of diet, TRP diet), were used. Ten blocks of 4 littermate piglets were selected at 40 d of age. Within each block, piglets were randomly assigned to 1 of the 4 experimental treatments: (1) healthy control and Basal diet, (2) inflammation and Basal diet, (3) inflammation and Basal diet + antioxidant, and (4) inflammation and TRP diet. Inflammation induced an increase in indoleam-ine 2,3 dioxygenase (IDO) activity, an enzyme involved in Trp catabolism, in lung, lymph nodes, heart, and spleen (P < 0.01). Contrary to piglets fed the TRP diet, pigs suffering from inflammation did not maintain their plasma Trp concentrations when they were fed the Basal diet. Furthermore, pigs fed the TRP diet had decreased plasma haptoglobin concentrations, IDO activity, and lung weight than those fed the Basal diet, indicating that the inflammatory response was moderated with the greater Trp supply. Antioxidant addition in the Basal diet decreased the effects of inflammation on plasma Trp concentrations and IDO activity. These results indicated that inflammation increases Trp catabolism and thus may decrease Trp availability for growth.

Key Words: inflammation • metabolism • pig • tryptophan

	INTRODUCTION

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In pig farms, unsanitary conditions and moderate infectious diseases are situations that may induce an inflammatory status that can limit growth performance by affecting feed intake and nutrient metabolism. For instance, AA are shifted from body protein accretion associated with growth toward tissues and functions involved in body defenses (Klasing, 1988). If an AA is supplied in limiting amounts, redirection of AA into metabolic pathways associated with body defenses is not necessary fully compensated by endogenous supplies. Additionally, this will lead to a decreased availability for growth. The knowledge of metabolic disturbances induced by inflammatory and immune responses should help in adapting feeding strategies to preserve AA for both growth and body defenses.

In a previous study, we showed that the inflammatory response induced a dramatic decrease in plasma Trp concentrations compared with healthy, pair-fed pigs (Melchior et al., 2004). Two metabolic pathways could explain the decrease in plasma Trp: the first one is the incorporation of Trp into proteins with a high Trp content such as acute phase proteins (Reeds et al., 1994), and the second pathway is the catabolism of Trp into kynurenine through the enzyme indoleam-ine 2,3 dioxygenase (IDO; E.C. 1.13.11.52). Accordingly, inflammation increased haptoglobin synthesis, a major acute phase protein in pig and IDO activity in the lungs and associated lymph nodes (Melchior et al., 2004, 2005).

In the present experiment, we compared the effect of a lung inflammation on some aspects of Trp metabolism in pigs fed a diet either marginally deficient or adequate in Trp. The first objective was to investigate the effect of dietary Trp content on metabolism and availability of Trp. In addition, in the inflammatory state, we hypothesized that Trp metabolism through IDO pathway contributes to meet the requirement for anti-oxidant defenses (Thomas and Stocker, 1999). Therefore, our second objective was to investigate whether the addition of antioxidants could mimic the effects of Trp during an inflammatory challenge.

	MATERIALS AND METHODS

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The experiment was conducted under the guidelines of the French Ministry of Agriculture for animal care.

Animals and Experimental Diets

Forty Piétrain x (French Landrace x Large White) piglets were used in this experiment. They were selected from litter weaned at 4 wk of age. Ten days after weaning, 10 blocks of 4 littermate piglets, female and castrated males, were selected on the basis of their BW. Under general anesthesia (Fluothane, Belamont, France), they were fitted with an indwelling catheter in a jugular vein as described previously (Melchior et al., 2004). Then, piglets from the same block were kept in individual cages where they had free access to water in a room maintained at 26°C. They were fed a prestarter diet for 1 wk and then randomly assigned to the experimental treatments and the corresponding diets, which were fed until the end of the experiment.

Three experimental diets were formulated. They were based on corn, pea, and soybean meal (Table 1). The basal low-Trp diet (Basal diet) was formulated to meet the requirement of weaned piglets (9.62 MJ/ kg of NE and 10.2 g of digestible Lys/kg) except for Trp, which was 20% less than the recommendations made by Sève at al. (1994). Total Trp content was 1.9 g/kg, which corresponded to 1.5 g of digestible Trp/ kg of diet. Crystalline L-Trp (0.55 g/kg) was added in the second diet (TRP diet). Total Trp content was 2.4 g/kg, which corresponds to 2 g of digestible Trp/kg of diet. The digestible Trp:digestible Lys ratio was 0.15 and 0.20 for Basal and TRP diets, respectively. A third diet was prepared from the Basal diet in which 5 g/kg of an antioxidant premix was added (Basal/Aox diet). The antioxidant premix supplied 1,200 mg of betaine, 91 mg of iron, 60 mg vitamin E, and 0.175 mg of organic selenium per kilogram of diet.

One week after surgery, which corresponds to 2 d before the induction of the inflammation, pigs received the experimental diets twice daily. The amount of allocated feed was limited to 100 g per pig on the day they were challenged with complete Freund’s adjuvant (CFA). Then, it was increased to 40 g of fresh feed/(kg of BW·d), which corresponds to 80% of ad libitum feeding. This rationing allowed avoiding feed refusals within block. Within each block, 2 piglets received the Basal diet, 1 the Basal/Aox diet, and the fourth pig received the TRP diet. Ten days after surgery, an emulsion composed of 3 mL of CFA and 7 mL of saline was intravenously injected to one of the 2 piglets fed the Basal diet (Infl Basal treatment), the TRP piglet (Infl TRP treatment), and the pig receiving the Basal/Aox diet (Infl Basal/Aox treatment). As described by Edwards and Slauson (1983), CFA injection in the jugular vein induces an interstitial pneumonia. The fourth piglet received 10 mL of saline and was fed the Basal diet. Piglets assigned to this treatment constituted the healthy control group (Control Basal treatment). Piglets were weighed before being challenged with CFA, then twice a week for the 2 wk of the experimental period.

Blood and Tissue Sampling

Blood samples (5 mL) were taken from the jugular catheter after an overnight fast. A basal sample was taken before the challenge at d 0 and d 2, 5, 7, and 9 after the injection of CFA or saline. Blood was put in a tube with 10 µ L of heparin and centrifuged (4,000 x g for 15 min at 4°C), and plasma was retained frozen at -20°C until analyses. Nine days after the challenge, pigs were killed by electronarcose and exsanguination. The lungs and their associated lymph nodes, heart, thymus, small intestine, and semitendinosus muscle were quickly removed and weighed. The small intestine was emptied and rinsed with saline. Approximately 2 to 5 g of each tissue and organ were frozen in liquid nitrogen. Tissues were kept at -80°C until IDO activity determination.

Plasma and Tissue Analyses

For plasma Trp and kynurenine determination, 200 µ L of plasma was mixed with the same volume of potassium phosphate buffer (0.05 M, pH 6.0) and 50 µ L of 2 M trichloroacetic acid. After centrifugation (3,000 x g for 10 min at 4°C), supernatant was analyzed by HPLC on a reverse phase C 18 column (Alliance system, Waters, Northwich, UK). The 3-nitro-L-Tyr was used as an internal standard. Tryptophan and kynure-nine were detected by fluorometry and UV absorbance, respectively, as described by Widner et al. (1997). The plasma concentration of haptoglobin, a major acute phase protein in pig, was measured by a colorimetric assay (Phase Haptoglobin Assay, Tridelta Development Limited, Kildare, UK). Tissue IDO-specific activity was measured as described by Melchior et al. (2005) and expressed as the rate of kynurenine production per milligram of protein. Kynurenine production by tissue homogenates was measured following the same procedure as that described for plasma.

Statistical Analysis

For all data, the experimental unit was the piglet. The 4 experimental treatments were compared within litter using the MIXED procedure (SAS Inst. Inc., Cary, NC). For data that did not include repeated measures (growth rate, IDO activity, and tissue weights), the model included the treatment, and litter was included in the model as a random effect. The preplanned contrasts were used to test the effects of inflammation (Control vs. Infl Basal), dietary Trp (Control Basal vs. Infl TRP), and antioxidant addition (Infl Basal vs. Infl Basal/Aox). The contrasts were declared significant at P < 0.05. The results are expressed as least squares (LS) means.

Plasma Trp, kynurenine, and haptoglobin concentrations were analyzed as repeated measures. The model included the treatment, day, and the day x treatment interaction. The results are expressed as LS means calculated at each time and for each experimental treatment. At each time, LS means were compared using the test of Scheffe, and differences between treatments were considered significant at P < 0.05.

	RESULTS

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Clinical Observations and Growth

The day before the induction of inflammation, pigs had an average BW of 11.8 ± 0.4 kg (Table 2). They weighed 15.4 ± 0.6 kg the day they were slaughtered. Daily BW gain did not differ among experimental groups (328 ± 25 g/d). Immediately after the injection of CFA, all pigs exhibited the same clinical signs (Melchior et al., 2004, 2005). They became lethargic, had increased respiration rate, and a febrile response (38.3 vs. 39.1°C on the day after the CFA injection for Control and Infl, respectively). After 2 d, these clinical signs decreased, and piglets seemed to recover.

Activity of IDO

Compared with Control Basal pigs, CFA induced an increase in IDO-specific activity (Table 3) measured in the lungs, tracheo-bronchial lymph nodes, heart, and spleen in Infl Basal pigs (P < 0.001 for the lungs and lymph nodes, and P = 0.009 and 0.02 for the heart and spleen, respectively). For groups suffering from lung inflammation, IDO activity was greater in the lungs and the heart (P = 0.02 and P < 0.001, respectively) of pigs fed with the Basal diet than in those fed the TRP diet. For the lymph nodes, that contrast did not reach a statistically significant value (P = 0.09). For pigs suffering from inflammation and fed the Basal diet, antioxidant supplementation tended to decrease IDO activity measured in the lungs (P = 0.1) and decreased IDO activity in the heart (P = 0.02).

The overall effects of treatments, day, and the day x treatments interaction were statistically significant for haptoglobin (Figure 1). In Control Basal pigs, hap-toglobin plasma concentrations remained low and constant for the 7-d postinjection period (P = 0.50). In each day, haptoglobin measured for each treatment was compared with the value measured in Control Basal pigs. At d 0, haptoglobin plasma concentrations were not different among the experimental groups. During the first week of experiment (i.e., d 2 and 5 after the induction of the inflammation), plasma haptoglobin concentrations were greater in all pigs suffering from lung inflammation compared with healthy Control Basal pigs (P < 0.001). During the second week of experiment (i.e., d 7 and 9), plasma haptoglobin concentrations were still greater in pigs suffering from inflammation and fed the Basal diet without antioxidant compared with the Control Basal (P < 0.05). The average values of haptoglobin measured in piglets suffering from inflammation and fed the TRP and the Basal/Aox diets were not different from those of Control Basal at d 7 and 9. However, in pigs suffering from inflammation, despite important numerical differences observed at d 9, neither additional Trp and the antioxidant did not decrease plasma haptoglobin.

View larger version (21K): [in this window] [in a new window]   Figure 1. Plasma haptoglobin concentrations in healthy pigs (Control) and pigs suffering from lung inflammation (Infl) and fed either an adequate-Trp diet (TRP) or a low-Trp diet (Basal) without or with an antioxidant premix (Aox). Values are least squares (LS) means calculated for 10 piglets per experimental group (SEM = 0.14, 0.14, 0.20, 0.27, and 0.34 at d 0, 2, 5, 7, and 9, respectively). CFA = complete Freund’s adjuvant. a,bWithin a day, LS means with different letters differ (P < 0.05).

There was no effect of the experimental treatments on plasma kynurenine concentrations (average concentration, 0.96 µ M). Plasma Trp concentrations over time in the different experimental groups are presented in Figure 2. The overall effects of treatments, day, and the interaction, treatments x day, were statistically significant. From d 0 to 7, pigs fed the TRP diet had greater plasma Trp concentrations compared with pigs assigned to the 3 other experimental treatments. For an unknown reason, at d 0, Control Basal piglets had less (P < 0.05) plasma Trp concentrations than piglets assigned to the 2 other experimental groups fed the Basal diet. On d 2 and 5, plasma Trp concentration in Control Basal pigs increased and was no longer different from concentrations in the 2 other groups fed the Basal diet. During wk 2 of the experiment, plasma Trp concentrations were less in piglets suffering from inflammation and fed the Basal diet (P = 0.07 and P < 0.05 at d 7 and 9, respectively) than those in the other groups. The last day of the experiment, at d 9, there was no statistical difference in concentrations between the Control Basal pigs and piglets suffering from inflammation and fed either the TRP or the Basal/Aox diet.

View larger version (22K): [in this window] [in a new window]   Figure 2. Plasma Trp concentrations in healthy pigs (Control) and pigs suffering from lung inflammation (Infl) and fed either an adequate-Trp diet (TRP) or a low-Trp diet (Basal) without or with an antioxidant premix (Aox). Values are least squares (LS) means calculated for 10 piglets per experimental group (SEM = 3.52 for each day). CFA = complete Freund’s adjuvant. a–cWithin a day, LS means with different letters differ (P < 0.05).

	DISCUSSION

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In the present study, comparison of 2 dietary Trp contents, 1 limiting (Basal) and the second adequate (TRP), showed that decrease in plasma Trp with inflammation occurred only with the low Trp supply. This provides evidence that the increase in Trp utilization associated with the inflammatory challenge worsened the inadequacy of the basal Trp supply. The consequence could be that an inadequate Trp dietary supply did not compensate for the increased Trp utilization because of the inflammatory challenge. The consequence could be a reduction of Trp available for protein accretion, increasing Trp requirement for growth. Such an effect of an inflammatory challenge on AA metabolism and requirement has been already suggested for dispensable AA such as Cys involved in glutathione synthesis (Malmezat et al., 1998) or Gln required to sustain immune cell proliferation (Kew et al., 1999). In the present study, because the inflammation and the Trp deficiency did not affect BW growth rate, this did not allow us to conclude that Trp requirement for growth was increased. As previously shown (Cortamira et al., 1991), the lack of effect of Trp deficiency on growth rate is partly explained by the technique of equal feeding used to control dietary Trp intake. Likewise, decreased feed intake is a major factor explaining the reduction of protein deposition and growth observed in animals suffering from inflammation (Sandberg et al., 2006).

The last 20 yr, Trp degradation along the IDO-kynurenine pathway has been a focus of interest in medical research. Indeed, this metabolic pathway seems to be involved in defenses against pathogens (Pfeffer-korn, 1984). At the tissue level, local Trp depletion resulting from IDO activation would be a mechanism controlling bacteria (MacKenzie and Hadding, 1998), virus (Burudi et al., 2002), and parasite (Pfefferkorn, 1984) proliferation. The Trp depletion is likely not a specific mechanism of control for pathogen proliferation, because it has been suggested for many other nutrients.

Two other hypotheses should be mentioned here. First, decreased Trp concentration caused by IDO activation has been also shown to be involved in the regulation of cellular immune response (Mellor et al., 2002), because Trp is an indispensable AA for T cell proliferation (Munn et al., 1999; Fallarino et al., 2002). More specifically, some of the Trp metabolites produced along the IDO-kynurenine pathway can exert a strong inhibitory effect on T cell viability (Frumento et al., 2002). This regulation of T cell proliferation by IDO seems to be a mechanism that allows immune tolerance to prevent fetuses and graft rejection (Mellor and Munn, 2001; Liu et al., 2006). Such a mechanism could also be involved in the lack of control of inflammatory response by T cells leading to chronic inflammatory diseases (Murray, 2003). Second, IDO activation could be a mechanism protecting the cell against free radicals. Indeed, the enzyme IDO uses oxygen free radicals as cofactors in its catalytic process (Hayaishi, 1996). Moreover, 3-hydroxy-anthralinic acid and 3-hydroxy-kynurenine that are produced from Trp along the IDO-kynurenine pathway seem to have antioxidant properties (Christen et al., 1990). In piglets fed the low-Trp diet and suffering from lung inflammation, the addition of an antioxidant premix tended to decrease IDO activity measured in the lungs. The lack of difference could be due to the high variability of the response between piglets in this experimental group. In the heart, where IDO activity is much less, the antioxidant premix decreased IDO activity.

Our results agree with studies conducted in vitro and showed that some antioxidant molecules such as cou-maric acid and pyrrolidine dithiocarbamate were able to decrease IDO activity in murine dendritic cells (Kim et al., 2007) and human macrophages (Thomas et al., 2001). The mechanism whereby antioxidants could decrease IDO activity is not known. However, antioxi-dants are also known to have antiinflammatory effects and could exert an indirect control on IDO activity. Indeed, IDO activity is not regulated by its own substrate, Trp, but by the cytokine interferon (Taylor and Feng, 1991; Takikawa et al., 1998). This means that the degree of immune system activation would impact on IDO induction and thus on Trp catabolism and availability. For instance, in patients suffering from lung disease, the decrease in plasma Trp concentrations caused by the induction of IDO activity has been associated with the severity of the illness (Meyer et al., 1995).

In the present experiment, CFA injection induced an increase in IDO activity, lung weight, as well as hap-toglobin plasma concentrations. Haptoglobin is a major acute phase protein in pigs used as an indicator of the inflammatory response (Eckersall et al., 1996). All these effects were less important when piglets were fed the Trp-adequate diet or the Basal diet with the anti-oxidant premix compared with piglets fed the low-Trp diet. Our results indicate that Trp, when supplied at an adequate dietary concentration, could be involved in the control of inflammatory response through one of the previously discussed mechanisms (i.e., control of inflammatory response by T cell or antioxidant properties of Trp metabolites produced along the IDO-kynurenine pathway).

In conclusion, our study indicated that Trp catabolism is increased in pigs suffering from lung inflammation because of the induction of the enzyme IDO. In this situation, dietary Trp supplies cannot be sufficient to prevent the reduction in plasma Trp. Consequently, the decrease in plasma Trp observed with an inadequate Trp supply may induce decreased Trp availability for functions such as growth. In addition, we obtained data indicating that Trp is involved in the regulation of the inflammatory response in pigs. The present data indicated an antioxidant action of Trp or its metabolites through IDO action. However, this hypothesis requires further investigations.

	Footnotes

 
¹ We acknowledge Ajinomoto-Eurolysine for their financial support. We also acknowledge INZO (Saint Grégoire, France) for the gracious gift of antioxidant mixture. We gratefully acknowledge Y. Colléaux, P. Ganier, Y. Lebreton, M. Lefebvre, F. Le Gouevec, and N. Mézière from INRA UMR 1079 for their technical assistance.

² Corresponding author: nathalie.lefloch{at}rennes.inra.fr

Received for publication March 3, 2008. Accepted for publication July 21, 2008.

	LITERATURE CITED

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