J. Anim Sci. 2007. 85:2140-2146. doi:10.2527/jas.2006-754
© 2007 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Effect of dietary lactoferrin on the immune functions and serum iron level of weanling piglets1
T. Shan,
Y. Wang2,
Y. Wang,
J. Liu and
Z. Xu
Institute of Feed Science, Zhejiang University, The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, No. 164 Qiutao North Road, Hangzhou 310029, P. R. China
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Abstract
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A total of 90 weanling female pigs (Duroc x Landrace x Yorkshire) were used in a 30-d growth experiment to investigate the effect of lactoferrin (LF) on growth performance, immune function, and serum iron concentrations. The pigs were allocated on the basis of BW and litter to 3 dietary treatments in a randomized complete block design. The dietary treatments were: control group (basal diet), antibiotics group (basal diet + 20 mg/kg of flavomycin + 110 mg/kg of aureomycin), and LF group (basal diet + 1.0 g/kg of LF). There were 3 replicate pens per treatment, and pigs were grouped with 10 pigs per pen. Six pigs, randomly selected from each treatment (2 pigs/pen), were slaughtered for serum and spleen samples on d 15 and 30. Supplementation with LF improved the phytohemag-glutinin (PHA)-stimulated peripheral lymphocyte proliferation by 36% (P < 0.01), increased concanavalin A (ConA)- and PHA-induced spleen lymphocyte proliferation by 332% (P < 0.01) and 258% (P < 0.01), enhanced serum IgG by 20% (P < 0.05), IgA by 13% (P < 0.05), IgM by 15% (P < 0.05), complement 4 (C4) by 29% (P < 0.05), IL-2 by 12% (P < 0.01), and serum iron values by 22% (P < 0.05) on d 15 compared with the control. Lactoferrin supplementation increased PHA-stimulated lymphocyte proliferation (P < 0.01), serum IgG by 16% (P < 0.05), IgA by 17% (P < 0.05), C4 by 11% (P < 0.05), IL-2 by 14% (P < 0.05), and serum iron values by 23% (P < 0.01), and decreased the diarrhea ratio (P < 0.05) relative to the control on d 30. Compared with the controls, supplementation with antibiotic increased ConA- and PHA-induced spleen lymphocyte proliferation (P < 0.05) on d 15, decreased the diarrhea ratio (P < 0.05), and increased the PHA-induced spleen lymphocyte proliferation (P < 0.05) and serum iron values (P < 0.01) on d 30. These results support the possible use LF as an immunostimulant to improve immune functions and strengthen host defenses and would seem to be a good method for defending weanling piglets from infections and weanling stress.
Key Words: growth performance • immune function • lactoferrin • serum iron • weanling piglet
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INTRODUCTION
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Weaning stress, a time of depressed feed intake and growth performance and of increased disease and mortality, is one of the most prevalent problems in the pig industry. This has led to the development of feed additives with high efficiency and low toxicity in order to boost the immune systems and improve the host defenses of young pigs during weaning.
Lactoferrin (LF), a member of the transferrin family of iron-binding glycoproteins, is an important component of the nonspecific immune system, which has been attributed many physiological roles, including regulation of iron metabolism (Suzuki et al., 2001
; Ward and Conneely, 2004), protection against microbial infection (Pyong et al., 2001), regulation of immune function (Esteban et al., 2005; Chand et al., 2006), stimulation of nonspecific immune responses (Kamilya et al., 2006), and modulation of the inflammatory response (Hayashida et al., 2004). The various biological functions of LF have received extensive attention, especially in host defense where it has an extended role in the defense mechanism of the body through its immune modulatory actions (Machnicki et al., 1993). Previous studies proved that orally administered LF could induce changes in immunity level (e.g., blood phagocytic activities, serum IL-18, interferon-
) and disease resistance (e.g., hepatitis C virus, influenza virus) in fish (Kumari and Sahoo, 2006), mice (Shin et al., 2005), and humans (Ishii et al., 2003). However, there are no data about the effect of LF on the immune function of weanling piglets.
Therefore, using antibiotic treatment as a positive control, this study was conducted to evaluate the effect of LF on growth performance and immune functions of weanling piglets. The effect of supplemented LF on serum iron concentrations and total iron-binding capacity of weanling piglets was also studied.
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MATERIALS AND METHODS
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Materials
Lactoferrin was provided by the Institute of Feed Science (Zhejiang University, Hangzhou, China). Flavomycin (purity: 4% by HPLC) and aureomycin (purity: 15% by HPLC) were obtained from the National Institute for the Control of Pharmaceutical and Biological Products (NICPBP, Beijing, China).
Animals and Experimental Design
All procedures were approved by the University of Zhejiang Institutional Animal Care and Use Committee. The feeding trial was carried out in the Swine Research and Teaching Farm of Zhejiang University. A total of 90 female weanling piglets (Duroc x Landrace x Yorkshire, weaned at 28 d) with an average initial BW of 7.05 ± 0.4 kg were allocated on the basis of BW and litter of origin to 3 dietary treatments in a randomized complete block design for 30 d. Treatments began at weaning, and each treatment consisted of 3 replicate pens with 10 pigs per pen. Treatments consisted of control group (basal diet), antibiotics group (basal diet + 20 mg/kg of flavomycin + 110 mg/kg of aureomycin), and LF group (basal diet + 1.0 g/kg of LF). Diets were formulated to meet or exceed NRC (1998) requirements for 10- to 20-kg pigs. No antibiotic was included in the basal diet (Table 1). All pigs were housed in temperature-controlled nursery rooms and grouped in elevated pens with wire flooring. Feed and water were available to the pigs ad libitum. The pigs were weighed individually and weekly, and feed consumption per pen was measured weekly throughout the study. Growth performance results, such as ADG, ADFI, and G:F, were subsequently determined for each pen. The diarrhea ratio was evaluated according to a previous study (Wang et al., 2006a).
Sample Collection and Assay
On d 15 and 30 of the feeding trial, 6 pigs per treatment, randomly selected from each treatment (2 pigs/pen), were slaughtered, and samples from the spleen were obtained for cell culture. Blood samples (15 mL per pig) were collected by venipuncture of an anterior vena cava, and 5-mL blood samples per pig were transferred immediately into aseptic capped tubes with sodium heparin (30 U/mL). The remaining blood (10 mL) was allowed to clot at 37 ° C for 2 h for collection of serum. Serum was separated by centrifugation (2,000 x g at 5 ° C for 10 min) and stored at – 20 ° C.
Preparation and Proliferation Assay of Spleen and Peripheral Lymphocyte
Mitogen-induced spleen lymphocyte proliferation was examined by methyl thiazolyl tetrazolium assay (Kong et al., 2004; Zhou et al., 2005). Blood samples with sodium heparin were diluted with an equal volume of Hanks’ solution, and peripheral blood mononuclear cells were separated according to the method of Bright et al. (1978). Spleen samples were gently smashed by pressing with the flat surface of a syringe plunger against a stainless steel sieve (200 mesh). The splenocytes were washed twice with 5 mL of cold Roswell Park Memorial Institute (RPMI) 1640 (Gibco BRL, Grand Island, NY) and then resuspended in complete medium (RPMI 1640 supplemented with 100 IU/mL of benzyl-penicillin, 100 IU/mL of streptomycin, and 10% fetal bovine serum, Gibco BRL). The spleen lymphocytes were collected by gradient centrifugation and washed twice with RPMI 1640 without fetal bovine serum. Viability and number of cells were determined microscopically by trypan blue (Carl Roth GmbH, Karlsruhe, Germany) staining. The peripheral lymphocytes were adjusted to 2 x 106/mL with RPMI 1640 and incubated in 96-well tissue culture plates (Costar, Cambridge, MA) containing 100 µL/well of cell suspension in the presence of 100 µL of PHA (25 µg/mL, Sigma, St. Louis, MO) or complete medium (controls).
The spleen lymphocytes were adjusted to 6 x 106/mL with RPMI 1640 medium and incubated in 96-well tissue culture plates with 100 µL/well, adding 100 µL of concanavalin A (ConA; 25 µg/mL, Sigma), phytohemagglutinin (PHA; 25 µg/mL, Sigma), or complete medium (controls). Each sample seeded 5 wells. After a 44-h incubation at 37 ° C in a 5% CO2, humidified incubator, 20 µL of methyl thiazolyl tetrazolium (5 mg/mL, Amresco, Solon, OH) was added into each well and incubated for another 4 h, and then 100 µL of DMSO was added into each well and shaken for 10 min to dissolve the precipitate completely. Absorbance was measured at 570 nm with and ELISA Reader (Model BioRad-550, Hercules, CA). The stimulation index was calculated as the absorbance of mitogen-stimulated cells divided by the absorbance of unstimulated, control (media only) cells.
Serum Immune Indexes
Concentrations of IL-1
and IL-2 in the serum were determined using commercial ELISA kits (Pharmingen, San Diego, CA) according to the manufacturer’s instructions. Serum IgG, IgM, IgA, complement 3 (C3), and complement 4 (C4) concentrations were measured by using immunoturbidimetric assay (Biesma et al., 2001; Madhavan et al., 2002). Serum iron and total iron-binding capacity were measured directly by colorimetric method with a CV of <5% (Hachiro et al., 1997).
Statistical Analysis
Data were analyzed as a randomized complete block using the GLM procedure (SAS Inst. Inc., Cary, NC). A pen of pigs served as the experimental unit for all data. Differences between treatments were analyzed according to the Bonferroni/Dunn method (Duncan, 1955). Effects were considered significant at P < 0.05.
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RESULTS
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Growth Performance
Supplementation with LF and antibiotics decreased (P < 0.05) the diarrhea ratio, but the ADG, ADFI, and G:F of weanling piglets were not affected (P = 0.09 to 0.19; Table 2). There was no difference between LF treatment and antibiotic treatment.
Lymphocyte Proliferation
Supplemental LF improved the PHA-stimulated peripheral lymphocyte proliferation by 36% (P < 0.01), increasing ConA- and PHA-induced spleen lymphocyte proliferation by 332% (P < 0.01) and 258% (P < 0.01), respectively, compared with controls on d 15. An increase in the PHA-stimulated lymphocyte proliferation (P < 0.01) on d 30 was also observed (Table 3). Antibiotic supplementation also increased (P < 0.01) the PHA-stimulated spleen lymphocyte proliferation on d 15 and 30 as well as the ConA-induced spleen lymphocyte proliferation on d 15 compared with controls. Compared with the antibiotic treatment, LF treatment increased (P < 0.01) the PHA-stimulated spleen lymphocyte proliferation on d 15.
Effect on Serum IgG, IgA, IgM
Supplementation with LF increased (P < 0.05) the serum IgG (20%), IgA (13%), and IgM (15%) concentrations relative to the control on d 15 (Table 4). Supplementation with LF increased (P < 0.05) serum IgG (16%) and IgA (17%) on d 30 compared with control. As compared with the antibiotic treatments, LF supplementation increased (P < 0.05) serum IgG (14%) and IgM (9%) on d 15, but did not increase serum IgA concentrations on d 15 and IgG, IgA, and IgM concentrations on d 30. Antibiotic supplementation had no effect (P > 0.05) on the serum IgG, IgA, and IgM concentrations compared with the control.
Effect on Serum C3 and C4
Supplemental LF increased (P < 0.05) the serum C4 concentration by 29% on d 15 and by 11% on d 30, but did not affect (P > 0.05) serum C3 concentration (Table 5). Supplementation with antibiotic had no effect (P > 0.05) on serum C3 and C4 concentrations compared with control. There were no differences between LF and antibiotic treatment.
Effect on the Serum IL-1 and IL-2
Compared with the control group, LF treatment increased serum IL-2 concentrations by 12% (P < 0.01) on d 15 and by 14% (P < 0.05) on d 30, but did not affect (P > 0.05) serum IL-1 concentrations (Table 6). Supplementation with LF increased the serum IL-2 concentrations by 11% (P < 0.05) on d 15 and by 13% (P < 0.05) on d 30, but did not affect (P > 0.05) serum IL-1 concentrations compared with the antibiotic group. Antibiotic supplementation had no effect (P > 0.05) on serum IL-1 and IL-2 concentrations compared with the control.
Effect on the Serum Iron and Total Iron-binding Capacity
Lactoferrin treatment increased serum iron values by 22% (P < 0.05) on d 15 and by 23% (P < 0.01) on d 30 compared with the control group but did not affect (P > 0.05) serum total iron-binding capacity at either time (Table 7). There was no difference between LF and antibiotic treatment.
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DISCUSSION
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Weaning is probably the most stressful time in the life of a pig and can lead to depressed feed intake and growth (Okai et al., 1976) and outbreaks of diarrhea (Pluske et al., 1997). Consistent with our previous study (Wang et al., 2006a), the results of this study revealed that supplementation with LF decreased the diarrhea ratio of weanling piglets. Our previous studies also demonstrated that supplemental LF could effectively stimulate expression of PR-39 and Protegrin-1, affecting the small intestinal morphology, and consequently improving growth performance of the weaned piglets (Wang et al., 2006a,b). In the current study, supplementation with LF only tended to increase ADG, ADFI, and G:F. From these results, we deduced that the efficiency of dietary LF on the growth performance of weanling piglets may be related to the weaning age of the animal and BW. It has been demonstrated that increasing weanling BW and weaning age could improve growth performance of the animal (Patience et al., 2000; Wolter and Ellis, 2001; Main et al., 2004). In addition, pigs weaned at an older age, heavier BW, or both have a more developed digestive system and a better immune system than pigs weaned earlier (Carroll, 2003). In our previous study, treatment began at weaning on d 21, and the average initial BW of weanling piglets was about 6.1 kg (Wang et al., 2006a); in the current study, the treatment started at weaning on d 28, and the average initial BW was about 7.1 kg. The pigs weaning at an older age, heavier initial BW, and better immune system could be responsible for the lack of effect of LF on growth performance and G:F in the current study, as well as the differences in growth performance between the current study and our previous report (Wang et al., 2006a). The immune system of the piglet begins developing but is not able to mount an effective active immune response until the pig is about 5 wk of age (Wang et al., 2004). During the first 2 wk postweaning, the newly weaned piglets were very susceptible to disease and pathogenic stressors. At this time, nonspecific immunity factors are more important to the growth and immunity in weaning phase of the weanling pig (Bosi et al., 2003). Lactoferrin is an important component of the nonspecific immune system, and supplemental LF could improve the growth performance of piglets weaned at 28 d for about 2 wk after weaning (Wang et al., 2006b) but lack an effect on the pigs weaned 28 d for 30 d in the current study. These results indicated that the greatest growth-promoting effects of LF on weanling pigs were in the first 2 wk after weaning.
The possible roles of LF in the modulation of the immune response have been reported in animals and humans. Oral administration of LF has been used to stimulate the immune system of various animal species, such as Asian catfish (Kumari et al., 2003; Kumari and Sahoo, 2006), gilthead seabream (Esteban et al., 2005), prawn (Chand et al., 2006), mice (Haversen et al., 2003; Takakura et al., 2004; Shin et al., 2005), and guinea pig (Wakabayashi et al., 2002). In humans, LF treatment reduced the clinical severity of contact allergy (Griffiths et al., 2001) and inhibited hepatitis C virus viremia in patients with chronic hepatitis C (Iwasa et al., 2002; Ishii et al., 2003). However, there were no reports about the effect of LF on the immune response of weanling piglets. In this study, we determined cell-mediated immune function using lymphocyte proliferation rates (Lee et al., 2000). The results showed that supplemental LF enhanced the PHA-stimulated proliferation of peripheral blood lymphocyte and spleen lymphocyte on d 15 and 30, and enhanced ConA-induced spleen lymphocyte proliferation on d 15. These results indicated that LF could improve the T-lymphocyte proliferation and regulate the cell-mediated immune function of weanling piglets, which would benefit weanling piglet growth and health (Hiss and Sauerwein, 2003; Davis et al., 2004). It has been illustrated that LF has immunomodulatory activities affecting the function of many immune cell types including lymphocytes, macrophages, and Langerhans cells (Ward et al., 2002). It has been reported that LF has a stimulatory effect on lymphocyte proliferation in human and animals (Bi et al., 1997; Artym et al., 2003). Our study first confirmed that oral administration of LF can enhance the porcine peripheral blood and spleen lymphocyte proliferation.
Cytokines are extremely important regulators of cellular infiltration, tissue damage, ulceration, diarrhea, motility, and fibrosis (Isaacs et al., 1992). It has been demonstrated that oral administration of LF increases the production of some cytokines, such as interferon- (Teraguchi et al., 2004; Takakura et al., 2006), TNF- (Takakura et al., 2004), IL-12 (Wakabayashi et al., 2004), IL-4 and IL-10 (Togawa et al., 2002), and IL-18 (Iigo et al., 2004), and also increases serum concentrations of IgG (Chodaczek et al., 2006). From the findings that supplemental LF enhanced serum IgG, IgA, IgM, C4, and IL-2 concentrations, we concluded that LF can regulate the immune function of the weanling piglets. The increased concentrations of serum immunoglobulins, cytokines, and C4 could regulate and enhance the immune functions that provide health benefits for combating disease challenges in addition to a diminishment in weaning stress and improvement in health status and growth performance of weanling pigs (Turner et al., 2002).
The immunomodulatory activities of LF, such as regulation of cellular differentiation and iron homeostasis and modulation of host defense, are clearly dependent on the iron binding properties of the protein (Ward and Conneely, 2004). A previous study demonstrated that oral administration of bovine LF increased total serum iron values in women (Paesano et al., 2006). In the current study, we also found that LF treatment could increase serum iron values compared with the control group. This increase of serum iron in all LF-treated piglets led us to hypothesize that LF could influence iron homeostasis. It is likely that LF could act not only by directly supplying iron to intestinal epithelial cells through a specific LF-binding receptor (Suzuki et al., 2005), but also by a more complex mechanism of modulation of other proteins involved in iron transport out of the intestinal cells and into the blood (Fleming and Bacon, 2005).
In the current study, we also found that supplemental antibiotic had an effect on the diarrhea and immune function of piglets, but did not affect the ADG and G:F. The lack of effect on the ADG and G:F from dietary antibiotic supplementation in the current study may have been due to the minimal disease status, developed digestive system, and better immune system of the pigs on test. Pigs weaned at older age and heavier BW or both are more mature at weaning with a more developed digestive system and a better immune system than pigs weaned earlier (Carroll, 2003). In our previous study, the pigs used for 30-d trial were weaned at 21 d with a less-developed digestive system and a worse immune system than the pigs used here; consequently, a significant effect on ADG of pigs in our previous study was found (Wang et al., 2006a), but not in the current study. Another previous study used similar animals as in the current study also demonstrated that the inclusion of antibiotic at the concentrations employed in the current study did not have a statistically significant effect on the ADG and G:F (Wang et al., 2006b). From these results, we concluded that the level of antibiotic we used in our studies could significantly affect the growth performance of pigs weaned earlier, but only tended to affect the pigs weaned older. In addition, the individual differences of the pigs in the current study may be associated with the lack of antibiotic treatment effect on the ADG and G:F. Previous studies showed that the continuous use or misuse of antibiotics have led to the emergence of the drug-resistance and antibiotic-residue in the animal products (Monroe and Polk, 2000; Schwarz et al., 2001). Lactoferrin is a multifunctional glycoprotein without any drug resistance or antibiotic residue. The current study indicated that LF could reduce diarrhea as effectively as antibiotics, and with a better effect on immune function (e.g., serum IgG, IgM, and IL-2 concentrations) of weanling piglets; therefore, it could be used instead of antibiotic in preventing the weanling pigs from diarrhea and in improving immune functions of piglets.
In conclusion, the current study demonstrated that supplemental LF could enhance the proliferation of peripheral blood and spleen lymphocyte, effectively increase the serum IgG, IgA, IgM, C4, IL-2, and serum iron concentrations, and regulate immune functions and, consequently, tended to improve the growth performance of weanling piglets. The results could provide information needed for the use of LF in improving immune functions of pigs as protection against infections and weaning stress.
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Footnotes
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1 This work was supported by Program for New Century Excellent Talents in University (NCET-04-0543), the National Natural Science Foundation of China (30571348) and the National Basic Research Program of China (2004CB117506). 
2 Corresponding author: yzwang{at}zju.edu.cn
Received for publication November 14, 2006.
Accepted for publication May 10, 2007.
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Abstract
INTRODUCTION
