恩拉霉素对断奶仔猪生产性能和免疫功能的影响及机制研究
摘要
抗生素对幼龄动物具有明显的促生长作用,而幼龄阶段正是动物建立免疫系统的关键时期。日粮中添加抗生素,在抑制病原微生物的同时,也杀灭了机体内的有益微生物,破坏了机体正常的微生态平衡体系。从畜产品安全出发,对饲用抗生素规定了停药期。关于恩拉霉素(Enramycin)在停药期以及在条件下对仔猪免疫功能的调节与促生长之间的关系尚未见报道。因此,本研究拟通过实验初步探索正常与超剂量添加恩拉霉素对断奶仔猪生产性能与免疫功能的影响及其调节作用。
试验一日粮添加恩拉霉素对断奶仔猪生长性能和血清生化指标的影响
本试验通过在断奶仔猪日粮中正常与超剂量添加恩拉霉素,研究恩拉霉素在加药期与停药期对仔猪生产性能和血液生化指标的影响。36头21日龄断奶、健康、DLY阉公仔猪,按体重相近的原则随机分为3个处理,每个处理12个重复,每个重复1头猪(单笼饲养),分别饲喂3个不同恩拉霉素水平日粮：处理1(对照组),基础日粮；处理2,基础日粮+5mg/kg恩拉霉素；处理3,基础日粮+80mg/kg恩拉霉素。试验期28d,0-21d各处理组按试验设计饲喂不同日粮,22-28d各处理组均饲喂基础日粮。在试验第22d和第29d早上,所有仔猪空腹称重、采血,制备血清保存待测。
试验结果表明,日粮中添加5 mg/kg和80 mg/kg恩拉霉素不同程度提高各阶段(0-7d、8-14d、15-21d和0-21d)仔猪的日增重与采食量,而对料肉比没有影响。停药一周(22-28d),前期添加了恩拉霉素组仔猪的生产性能仍略优于对照组。日粮中添加恩拉霉素使仔猪血清一氧化氮浓度有一定程度的提高,但差异不显著；恩拉霉素对仔猪血清中的尿素氮和丙二醛含量没有影响；超剂量添加恩拉霉素使仔猪血清中乳酸脱氢酶含量有所增加,但差异不显著。
本试验表明,仔猪日粮添加恩拉霉素可以改善仔猪生产性能,对机体代谢无明显不良影响。
试验二日粮添加恩拉霉素对免疫应激仔猪生产性能和血清生化指标的影响
本试验通过血液相关生化指标和生长因子的检测,探讨恩拉霉素对免疫应激仔猪生产性能与血清生化指标的影响。试验采用2×3因子设计：免疫应激处理(腹腔注射LPS或生理盐水)和日粮中恩拉霉素的添加水平(0、5和80 mg/kg)。试验一仔猪在试验第29 d早上空腹称重后每个处理根据体重一分为二,一半仔猪实施免疫应激,即腹腔注射脂多糖200μg,/kg体重；另一半的仔猪腹腔注射等量生理盐水。分别于前和后2.5 h、3d空腹称重后采血。
试验结果表明,LPS进行免疫应激后3 d,仔猪平均日增重和平均日采食量显著下降(P<0.05)；日粮中恩拉霉素的添加显著提高了仔猪平均日采食量(P<0.05)；恩拉霉素的添加与LPS攻毒对断奶仔猪平均日采食量的影响具有互作效应的趋势,即恩拉霉素的添加有缓解LPS攻毒引起的断奶仔猪平均日采食量降低的趋势。注射LPS前,恩拉霉素处理组血清中一氧化氮、尿素氮、丙二醛、乳酸脱氢酶、皮质醇和类胰岛素生长因子1浓度没有显著差异(P>0.05)。注射LPS后2.5 h,仔猪血清中丙二醛、皮质醇和类胰岛素生长因子1的含量显著提高(P<0.05)；注射后3d,仔猪血清中类胰岛素生长因子1浓度显著提高(P<0.05),血清中一氧化氮浓度显著降低(P<0.05),且血清中皮质醇的浓度有提高的趋势(P<0.1)。日粮中恩拉霉素的添加显著降低了血清中类胰岛素生长因子1的浓度(P<0.05),与LPS具有显著互作效应(P<0.05),即恩拉霉素的添加可以缓解LPS攻毒引起的血清中类胰岛素生长因子1浓度的提高。
本试验表明,腹腔注射LPS显著影响了仔猪的生产性能和血清中一氧化氮、丙二醛、皮质醇、类胰岛素生长因子1的浓度,日粮中添加恩拉霉素可在一定程度上缓解了LPS攻毒带来的负面影响。
试验三日粮添加恩拉霉素对免疫应激仔猪免疫功能的影响
本试验初步探讨了日粮正常与超剂量添加恩拉霉素对免疫应激仔猪机体免疫功能的影响。本试验设计同试验二,分别于注射LPS前和注射后2.5 h和3d对DLY仔猪进行采血,并于试验结束时将仔猪全部屠宰,取肾脏、脾脏、胸腺、肺脏、腹股沟淋巴结、肠系膜淋巴结和肝脏样品,分别检测仔猪细胞免疫(包括血清中细胞因子的浓度和血液中淋巴细胞亚群变化)、体液免疫(主要是血清中免疫球蛋白的浓度)和先天性免疫(主要是不同组织中猪p-防御素和Toll样受体的基因表达)的相关指标。
试验结果表明,经过停药期后,LPS攻毒前各处理仔猪血液中淋巴细胞亚群、免疫球蛋白和细胞因子含量无显著差异(P>0.05)。LPS攻毒后,仔猪血液中淋巴细胞数量显著增加,且由于CD8+细胞亚群数量增加(P<0.05),导致CD4+/CD8+比例显著下降(P<0.05)；与未应激的仔猪相比,免疫应激仔猪血液中免疫球蛋白(IgA、IgG和IgM)和细胞因子(IL-1、IL-2、IL-6和TNF-α)浓度显著提高(P<0.05)；与未应激的仔猪相比,免疫应激仔猪各组织中pBD1、2、3和TLR3、4基因表达有不同程度的变化,各基因在胸腺中表达量均显著下调(P<0.05)。虽然经过停药期,且攻毒之前各处理仔猪体内免疫指标已无显著差异,但是,攻毒后,恩拉霉素的添加仍会显著影响血液中IL-1和IgA浓度(P<0.05),并有调节各组织(尤其是胸腺和脾脏)中pBD1、2、3和TLR3、4的表达作用,且这一作用与LPS引起的免疫应激之间存在一定程度的互作效应。
本试验表明,LPS诱导的免疫应激和日粮中恩拉霉素的添加均可对断奶仔猪体内特异性免疫应答和先天性免疫产生一定的调节作用,且二者的作用在一定程度上存在互作效应,即日粮中恩拉霉素的添加可以部分缓解LPS攻毒带来的免疫应激作用。
上述研究结果揭示：日粮添加恩拉霉素可改善仔猪生产性能,缓解免疫应激对仔猪代谢和免疫功能的破坏作用；超剂量添加没有进一步改善作用,也没有表现出明显负面作用,显示出恩拉霉素具有较宽的安全剂量范围。
The effects of antibiotics on growth-promoting of young animals were obvious. It is a crucial period for animals to produce and establish their immune system in the early stage. Antibiotics in diets depress the pathogenic microorganisms, but also kill the beneficial microorganisms, which disturb the body's micro-ecological balance. In view of animal products safety, withdrawal of antibiotics in diets is required. To our knowledge, the relationships between effect of enramycin (ER) on promoting growth and regulating immune functions during the periods of withdrawal and stress have not been reported. Therefore, the aim of this study was to investigate effects of normal and over dosage of ER on the performance, immune functions of weaned piglets.
Experiment 1 Effects of ER on growth performance and serum biochemical indexes of weaned piglets
In this experiment, the effects of normal and over dosage of ER on the performance and blood biochemical indexes of early-weaned piglets were investigated during the periods with or without the additive. A total of 36 Duroc×Landrace×Yorksire (DLY) piglets weaned at 21d were randomly assigned to 1 of 3 dietary groups of 12 pigs each on the basis of body weight. The three dietary treatments were 1) a basal diet (control) containing no ER,2) basal+5mg/kg ER, and 3) basal+80mg/kg ER. The total 28-day trial was divided into 2 phages:ER-supplemented period (ER time) of 3 weeks (phage 1), and withdrawal time of one week (phage 2). In the morning of d 22 and d 29, piglets were weighted and fasting blood samples were collected to prepare the serum.
Results showed that 5 mg/kg and 80 mg/kg ER dietary treatments resulted in the improvements of average daily gain and feed intake in various degrees during different stages (d 0-7, d 8-14, d 15-21, and d 0-21), but had no effects on feed conversion. During withdrawal time (d 22-28), the performance of early-weaned piglets fed ER diets was slightly better than the piglets fed the control diet. ER in diets increased serum nitric oxide concentration of early-weaned piglets in some cases, but had no effects on urea nitrogen and MDA.Over dosage of ER in diet increased serum LDH activity of weaned piglets in some cases.
The present study indicates that enramycin supplementation in diet may improve piglets performance, and has no significant negative effects on metabolism.
Experiment 2 Eeffects of ER on growth performance and serum biochemical indexes of LPS-challenged weaned piglets
In this experiment, blood biochemical parameters and growth performance of LPS-challenged weaned piglets were investigated by testing the blood biochemical parameters and growth factor involved in.
The experiment was conducted by 2×3 factorial design that involved immune challenge (intraperitoneal injection of LPS or saline) and three ER levels (0,5 and 80 mg/kg). At the beginning of LPS-challenged period (d 29), after fasting and weighing, piglets of each treatment in experiment 1 were divided into two groups on the basis of body weight and were injected intraperitoneally with LPS (serological type 055:B5, Sigma, USA) at a dosage of 200μg/kg body weight or equivalent saline as a control. Blood samples after fasting were collected before and 2.5 h,3 d after stress.
Results showed that on d 3 after stress, average daily gain and average daily feed intake of the piglets challenged with LPS decreased significantly (P<0.05). A significant increase of average daily feed intake was observed in LPS-challenged pigs fed the ER diet (P< 0.05). In addition, there was a tendency toward remission the LPS-induced average daily feed intake decline by ER. After the withdrawal period, nitric oxide, urea nitrogen, MDA, lactate dehydrogenase, cortisol and insulin-like growth factor 1 concentrations in the serum were not significantly affected by ER (P> 0.05). Two and a half hours after LPS injection, MDA, cortisol and insulin-like growth factor 1 levels in serum increased significantly (P<0.05). Three days after LPS injection, serum insulin-like growth factor 1 concentration was significantly increased (P<0.05), serum nitric oxide concentration was significantly decreased (P <0.05), and there was a tendency toward elevated serum cortisol concentration (P <0.1), while ER significantly reduced the serum insulin-like growth factor 1 concentrations (P< 0.05). In addition, a significant interaction effect of ER and LPS on serum insulin-like growth factor 1 regulation (P<0.05) was observed, namely, ER played remission role of LPS-induced serum insulin-like growth factor 1 concentration increase.
In conclusion, intraperitoneal injection of LPS significantly affects the growth performance of piglets and serum nitric oxide, malondialdehyde, cortisol, insulin-like growth factor 1 levels, and diets supplemented with ER could alleviate the negative effects of LPS in some extent.
Experiment 3 Effects of ER on the immune function of LPS-challenged piglets
Effects of normal and over dosage of ER on immune function of the LPS-challenged piglets were investigated in this experiment. The experimental design was the same as described in experiment 2. Fasting blood samples were collected before and 2.5 h,3 d after challenge. At the end of the trial, all piglets were slaughtered and the kidney, spleen, thymus, lung, inguinal lymph nodes, mesenteric lymph nodes and liver were taken. The concentrations of serum cytokines, blood lymphocyte subsets and serum immunoglobulins, and P-defensins and Toll-like receptor gene expression levels in different tissues were detected.
Results showed that, after the withdrawal period, there was no significant difference in the lymphocyte subsets, immunoglobulin and cytokine levels before LPS challenge (P>0.05). After LPS challenge, blood lymphocytes increased significantly, and the increase of CD8+cell subsets (P< 0.05) resulted in a significant decline of CD4+/CD8+ratio (P<0.05). Compared with the non-immune stress piglets, blood immunoglobulin (IgA, IgG and IgM) and cytokines (IL-1, IL-2, IL-6 and TNF-α) levels were significantly increased (P<0.05), and pBDl,2,3, and TLR3,4 gene expression levels in the thymus were significantly decreased (P<0.05), in piglets challenged with LPS. After the withdrawal period, there was no significant difference in immune parameters among each treatment before LPS injection. However, ER significantly affected blood IL-1 and IgA concentrations (P<0.05) of LPS-challenged piglets, and adjusted the gene expression of pBD1,2,3, and TLR3,4 in different organizations (especially in the thymus and spleen), and in which there were some interaction effects between ER and the immune stress caused by LPS.
In conclusion, both the LPS-induced immune stress and dietary ER regulated the specific and innate immune responses of weaned piglets, and there were interaction effects to some extent. Diets supplemented with ER could alleviate the immunological stress induced by LPS.
Implications
Supplementation of Enramycin in diets may improve the performance of early weaned piglets, also could alleviate the negative effects of immunological stress on metabolism and immune function of piglets.
Neither further improvement nor significant negative effects of over dosage of ER on immune function of LPS-challenged piglets had been observed. It implicated that ER was safe for pigs at wide dose of dietary supplementation.
试验一日粮添加恩拉霉素对断奶仔猪生长性能和血清生化指标的影响
本试验通过在断奶仔猪日粮中正常与超剂量添加恩拉霉素,研究恩拉霉素在加药期与停药期对仔猪生产性能和血液生化指标的影响。36头21日龄断奶、健康、DLY阉公仔猪,按体重相近的原则随机分为3个处理,每个处理12个重复,每个重复1头猪(单笼饲养),分别饲喂3个不同恩拉霉素水平日粮：处理1(对照组),基础日粮；处理2,基础日粮+5mg/kg恩拉霉素；处理3,基础日粮+80mg/kg恩拉霉素。试验期28d,0-21d各处理组按试验设计饲喂不同日粮,22-28d各处理组均饲喂基础日粮。在试验第22d和第29d早上,所有仔猪空腹称重、采血,制备血清保存待测。
试验结果表明,日粮中添加5 mg/kg和80 mg/kg恩拉霉素不同程度提高各阶段(0-7d、8-14d、15-21d和0-21d)仔猪的日增重与采食量,而对料肉比没有影响。停药一周(22-28d),前期添加了恩拉霉素组仔猪的生产性能仍略优于对照组。日粮中添加恩拉霉素使仔猪血清一氧化氮浓度有一定程度的提高,但差异不显著；恩拉霉素对仔猪血清中的尿素氮和丙二醛含量没有影响；超剂量添加恩拉霉素使仔猪血清中乳酸脱氢酶含量有所增加,但差异不显著。
本试验表明,仔猪日粮添加恩拉霉素可以改善仔猪生产性能,对机体代谢无明显不良影响。
试验二日粮添加恩拉霉素对免疫应激仔猪生产性能和血清生化指标的影响
本试验通过血液相关生化指标和生长因子的检测,探讨恩拉霉素对免疫应激仔猪生产性能与血清生化指标的影响。试验采用2×3因子设计：免疫应激处理(腹腔注射LPS或生理盐水)和日粮中恩拉霉素的添加水平(0、5和80 mg/kg)。试验一仔猪在试验第29 d早上空腹称重后每个处理根据体重一分为二,一半仔猪实施免疫应激,即腹腔注射脂多糖200μg,/kg体重；另一半的仔猪腹腔注射等量生理盐水。分别于前和后2.5 h、3d空腹称重后采血。
试验结果表明,LPS进行免疫应激后3 d,仔猪平均日增重和平均日采食量显著下降(P<0.05)；日粮中恩拉霉素的添加显著提高了仔猪平均日采食量(P<0.05)；恩拉霉素的添加与LPS攻毒对断奶仔猪平均日采食量的影响具有互作效应的趋势,即恩拉霉素的添加有缓解LPS攻毒引起的断奶仔猪平均日采食量降低的趋势。注射LPS前,恩拉霉素处理组血清中一氧化氮、尿素氮、丙二醛、乳酸脱氢酶、皮质醇和类胰岛素生长因子1浓度没有显著差异(P>0.05)。注射LPS后2.5 h,仔猪血清中丙二醛、皮质醇和类胰岛素生长因子1的含量显著提高(P<0.05)；注射后3d,仔猪血清中类胰岛素生长因子1浓度显著提高(P<0.05),血清中一氧化氮浓度显著降低(P<0.05),且血清中皮质醇的浓度有提高的趋势(P<0.1)。日粮中恩拉霉素的添加显著降低了血清中类胰岛素生长因子1的浓度(P<0.05),与LPS具有显著互作效应(P<0.05),即恩拉霉素的添加可以缓解LPS攻毒引起的血清中类胰岛素生长因子1浓度的提高。
本试验表明,腹腔注射LPS显著影响了仔猪的生产性能和血清中一氧化氮、丙二醛、皮质醇、类胰岛素生长因子1的浓度,日粮中添加恩拉霉素可在一定程度上缓解了LPS攻毒带来的负面影响。
试验三日粮添加恩拉霉素对免疫应激仔猪免疫功能的影响
本试验初步探讨了日粮正常与超剂量添加恩拉霉素对免疫应激仔猪机体免疫功能的影响。本试验设计同试验二,分别于注射LPS前和注射后2.5 h和3d对DLY仔猪进行采血,并于试验结束时将仔猪全部屠宰,取肾脏、脾脏、胸腺、肺脏、腹股沟淋巴结、肠系膜淋巴结和肝脏样品,分别检测仔猪细胞免疫(包括血清中细胞因子的浓度和血液中淋巴细胞亚群变化)、体液免疫(主要是血清中免疫球蛋白的浓度)和先天性免疫(主要是不同组织中猪p-防御素和Toll样受体的基因表达)的相关指标。
试验结果表明,经过停药期后,LPS攻毒前各处理仔猪血液中淋巴细胞亚群、免疫球蛋白和细胞因子含量无显著差异(P>0.05)。LPS攻毒后,仔猪血液中淋巴细胞数量显著增加,且由于CD8+细胞亚群数量增加(P<0.05),导致CD4+/CD8+比例显著下降(P<0.05)；与未应激的仔猪相比,免疫应激仔猪血液中免疫球蛋白(IgA、IgG和IgM)和细胞因子(IL-1、IL-2、IL-6和TNF-α)浓度显著提高(P<0.05)；与未应激的仔猪相比,免疫应激仔猪各组织中pBD1、2、3和TLR3、4基因表达有不同程度的变化,各基因在胸腺中表达量均显著下调(P<0.05)。虽然经过停药期,且攻毒之前各处理仔猪体内免疫指标已无显著差异,但是,攻毒后,恩拉霉素的添加仍会显著影响血液中IL-1和IgA浓度(P<0.05),并有调节各组织(尤其是胸腺和脾脏)中pBD1、2、3和TLR3、4的表达作用,且这一作用与LPS引起的免疫应激之间存在一定程度的互作效应。
本试验表明,LPS诱导的免疫应激和日粮中恩拉霉素的添加均可对断奶仔猪体内特异性免疫应答和先天性免疫产生一定的调节作用,且二者的作用在一定程度上存在互作效应,即日粮中恩拉霉素的添加可以部分缓解LPS攻毒带来的免疫应激作用。
上述研究结果揭示：日粮添加恩拉霉素可改善仔猪生产性能,缓解免疫应激对仔猪代谢和免疫功能的破坏作用；超剂量添加没有进一步改善作用,也没有表现出明显负面作用,显示出恩拉霉素具有较宽的安全剂量范围。
The effects of antibiotics on growth-promoting of young animals were obvious. It is a crucial period for animals to produce and establish their immune system in the early stage. Antibiotics in diets depress the pathogenic microorganisms, but also kill the beneficial microorganisms, which disturb the body's micro-ecological balance. In view of animal products safety, withdrawal of antibiotics in diets is required. To our knowledge, the relationships between effect of enramycin (ER) on promoting growth and regulating immune functions during the periods of withdrawal and stress have not been reported. Therefore, the aim of this study was to investigate effects of normal and over dosage of ER on the performance, immune functions of weaned piglets.
Experiment 1 Effects of ER on growth performance and serum biochemical indexes of weaned piglets
In this experiment, the effects of normal and over dosage of ER on the performance and blood biochemical indexes of early-weaned piglets were investigated during the periods with or without the additive. A total of 36 Duroc×Landrace×Yorksire (DLY) piglets weaned at 21d were randomly assigned to 1 of 3 dietary groups of 12 pigs each on the basis of body weight. The three dietary treatments were 1) a basal diet (control) containing no ER,2) basal+5mg/kg ER, and 3) basal+80mg/kg ER. The total 28-day trial was divided into 2 phages:ER-supplemented period (ER time) of 3 weeks (phage 1), and withdrawal time of one week (phage 2). In the morning of d 22 and d 29, piglets were weighted and fasting blood samples were collected to prepare the serum.
Results showed that 5 mg/kg and 80 mg/kg ER dietary treatments resulted in the improvements of average daily gain and feed intake in various degrees during different stages (d 0-7, d 8-14, d 15-21, and d 0-21), but had no effects on feed conversion. During withdrawal time (d 22-28), the performance of early-weaned piglets fed ER diets was slightly better than the piglets fed the control diet. ER in diets increased serum nitric oxide concentration of early-weaned piglets in some cases, but had no effects on urea nitrogen and MDA.Over dosage of ER in diet increased serum LDH activity of weaned piglets in some cases.
The present study indicates that enramycin supplementation in diet may improve piglets performance, and has no significant negative effects on metabolism.
Experiment 2 Eeffects of ER on growth performance and serum biochemical indexes of LPS-challenged weaned piglets
In this experiment, blood biochemical parameters and growth performance of LPS-challenged weaned piglets were investigated by testing the blood biochemical parameters and growth factor involved in.
The experiment was conducted by 2×3 factorial design that involved immune challenge (intraperitoneal injection of LPS or saline) and three ER levels (0,5 and 80 mg/kg). At the beginning of LPS-challenged period (d 29), after fasting and weighing, piglets of each treatment in experiment 1 were divided into two groups on the basis of body weight and were injected intraperitoneally with LPS (serological type 055:B5, Sigma, USA) at a dosage of 200μg/kg body weight or equivalent saline as a control. Blood samples after fasting were collected before and 2.5 h,3 d after stress.
Results showed that on d 3 after stress, average daily gain and average daily feed intake of the piglets challenged with LPS decreased significantly (P<0.05). A significant increase of average daily feed intake was observed in LPS-challenged pigs fed the ER diet (P< 0.05). In addition, there was a tendency toward remission the LPS-induced average daily feed intake decline by ER. After the withdrawal period, nitric oxide, urea nitrogen, MDA, lactate dehydrogenase, cortisol and insulin-like growth factor 1 concentrations in the serum were not significantly affected by ER (P> 0.05). Two and a half hours after LPS injection, MDA, cortisol and insulin-like growth factor 1 levels in serum increased significantly (P<0.05). Three days after LPS injection, serum insulin-like growth factor 1 concentration was significantly increased (P<0.05), serum nitric oxide concentration was significantly decreased (P <0.05), and there was a tendency toward elevated serum cortisol concentration (P <0.1), while ER significantly reduced the serum insulin-like growth factor 1 concentrations (P< 0.05). In addition, a significant interaction effect of ER and LPS on serum insulin-like growth factor 1 regulation (P<0.05) was observed, namely, ER played remission role of LPS-induced serum insulin-like growth factor 1 concentration increase.
In conclusion, intraperitoneal injection of LPS significantly affects the growth performance of piglets and serum nitric oxide, malondialdehyde, cortisol, insulin-like growth factor 1 levels, and diets supplemented with ER could alleviate the negative effects of LPS in some extent.
Experiment 3 Effects of ER on the immune function of LPS-challenged piglets
Effects of normal and over dosage of ER on immune function of the LPS-challenged piglets were investigated in this experiment. The experimental design was the same as described in experiment 2. Fasting blood samples were collected before and 2.5 h,3 d after challenge. At the end of the trial, all piglets were slaughtered and the kidney, spleen, thymus, lung, inguinal lymph nodes, mesenteric lymph nodes and liver were taken. The concentrations of serum cytokines, blood lymphocyte subsets and serum immunoglobulins, and P-defensins and Toll-like receptor gene expression levels in different tissues were detected.
Results showed that, after the withdrawal period, there was no significant difference in the lymphocyte subsets, immunoglobulin and cytokine levels before LPS challenge (P>0.05). After LPS challenge, blood lymphocytes increased significantly, and the increase of CD8+cell subsets (P< 0.05) resulted in a significant decline of CD4+/CD8+ratio (P<0.05). Compared with the non-immune stress piglets, blood immunoglobulin (IgA, IgG and IgM) and cytokines (IL-1, IL-2, IL-6 and TNF-α) levels were significantly increased (P<0.05), and pBDl,2,3, and TLR3,4 gene expression levels in the thymus were significantly decreased (P<0.05), in piglets challenged with LPS. After the withdrawal period, there was no significant difference in immune parameters among each treatment before LPS injection. However, ER significantly affected blood IL-1 and IgA concentrations (P<0.05) of LPS-challenged piglets, and adjusted the gene expression of pBD1,2,3, and TLR3,4 in different organizations (especially in the thymus and spleen), and in which there were some interaction effects between ER and the immune stress caused by LPS.
In conclusion, both the LPS-induced immune stress and dietary ER regulated the specific and innate immune responses of weaned piglets, and there were interaction effects to some extent. Diets supplemented with ER could alleviate the immunological stress induced by LPS.
Implications
Supplementation of Enramycin in diets may improve the performance of early weaned piglets, also could alleviate the negative effects of immunological stress on metabolism and immune function of piglets.
Neither further improvement nor significant negative effects of over dosage of ER on immune function of LPS-challenged piglets had been observed. It implicated that ER was safe for pigs at wide dose of dietary supplementation.
引文
[1]Martin, GJ.Aminobenzoic acid and sulfonamides in rat nutrition[J]. Proc Soc Exp Biol Med,1942,51:56.
[2]Moore, P. R., A. Evenson, T. D. Luckey, et.al. Use of sulphasuccidine, streptothricin and streptomycin in nutrition studies with the chick[J]. J. Biol. Chem, 1946,165:437-441.
[3]Jukes, T. H., E. L. R. Stokstad, R. R. Taylor, et.al. Growth promoting effect of aureomycin on pigs[J]. Arch. Biochem,1950,26:324-330.
[4]佟建明.饲用抗生素研究进展[M].见：许振英,张子仪编.动物营养研究进展.北京,中国农业科技出版社,1994,255-264.
[5]中华人民共和国农业部公告第168号.饲料药物添加剂使用规范,2001.
[6]Witte W. Medical consequences of antibiotic use in agriculture [J]. Science,1998,279:996-997.
[7]Cassell GH, Mekalanos J. Development of antimicrobial agents in the era of new and reemerging infectious diseases and increasing antibiotic resistance[J]. JAMA, 2001,285:601-605.
[8]Katherine M. Shea. Antibiotic Resistance:What Is the Impact of Agricultural Uses of Antibiotics on Children's Health? [J].Pediatrics,2003,112:253-258.
[9]J. J. Dibner, and J. D. Richards. Antibiotic growth promoters in agriculture:history and mode of action. Poultry Science[J],2005,84:634-643.
[10]卜仕金.欧盟禁用抗生素促生长剂的利与弊[J].中国家禽,2006,13：50-52.
[11]佟建明.饲用抗生素、动物免疫系统和肠道微生物的三元平衡[J].动物科学与动物医学,2000,4：38-40.
[12]Liebbrandt, V. C. and R. C. Ewan. Effect of weaning and age at weaning on performance by baby pigs[J]. J. Anim. Sci,1972,35:1107 (Abstr.).
[13]Funderburke,D. W. and R. W. Seerly. The effects of postweaning stressors on pig weight change, blood, liver and digestive tract characteristics[J].J. Anim. Sci 1990,68:155-162.
[14]Cook M.E, C.C.Miller, Y.Park, et al. Immnue modulation by altered nutrient metabolism:nutritional control of immune-induced growth depression[J]. Poul. Sci, 1993,72:1301-1305.
[15]Johnson R.W. Inhibition of growth by pro-inflammatory cytokines:an integrated view[J]. Journal of animal science,1997,75(5):1244-1255.
[16]Klasing K.C. Nutritional aspects of leukocytic cytokines[J]. The Journal of nutrition,1988,118(12):1436-1446.
[17]H. R. Gaskins, C. T. Collier,land D. B. Anderson. Antibiotics as growth promotants:mode of action[J]. Animal Biotechnology,2002,13:29-42.
[18]Hays, V. W. Benefits:Antibacterials. In:Drugs in Livestock Feed, Vol. I. Tech. Rep. [M]. Office of Technology Assessment, Congress of the United States, Washington, DC,1979,p29-36.
[19]Dean R. Zimmerman. Role of subtherapeutic levels of antimicrobials in pig production[J]. J. Anim. Sci.,1986,62(Suppl.3):6-17.
[20]Jones, P.W.,Tarrant, M.E. The effect of various factors on the efficacy of Tylosin as a growth promoter in clinically healthy pigs [J]. Anim. Prod.,1982,34:115-121.
[21]Weldon, W.C. Tylosin:effects on nutrient metabolism. In Proceedings of World Pork Exposition Swine Research Review[M]. Elanco Animal Health, Greenfield,IN,1997.
[22]Roth, F.X.; Kirchgessner, M. Influence of avilamycin and tylosin on retention and excretion of nitrogen in finishing pigs[J]. J. Anim. Physiol.1993,69:245-250.
[23]Impacts of antimicrobial growth promoter termination in Denmark[M]. World Health Organization(WHO). Foulum, Denmark.6-9 November,2002.
[24]Hayes DJ, Jensen HH and Fabiosa J.Technology choice and the economic effects of a ban on the use of antimicrobial feed additives in swine rations. Food Control[J], 2002,13:97-101.
[25]Francois, A.C. Mode of action of antibiotics on growth[J]. World Review of Nutrition and Dietetics,1962,3:21.
[26]Visek, W.J. The mode of growth promotion by antibiotics[J]. J. Anim. Sci.,1978,46:1447-1469.
[27]Coates, M. E., Davies, M. K., Harrison, G. F., et.al. The mode of action of antibiotics in chick nutrition, Ⅱ. The effect of penicillin in clean and stale premises,[J].J. Sc. Food and Agrlc.,1955,6:419.
[28]Coates, M. E., R. Fuller, G. F. Harrison, M. et.al. Comparison of the growth of chicks in the Gustafsson germ-free apparatus and in a conventional environment, with and without dietary supplements of penicillin[J]. Br. J.Nutr.,1963,17:141-151.
[29]Hays, V.W. Biological basis for the use of antibiotics in livestock production.The use of drugs in animal feeds[M], National Research Council Publication; National Academy of Sciences,1969,11-30.
[30]Coates, M.E. The gut microflora and growth[M]. In:growth in animals; Lawrence, T.L.J., Ed.; Butterworths:Boston,1980,175-188.
[31]Roura, E., J. Homedes, and K. C. Klasing. Prevention of immunologic stress contributes to the growth-permitting ability of dietary antibiotics in chicks [J]. J. Nutr.,1992,122:2382-2390.
[32]Needham J.Chemical embryology[M]. Cambridge University Press, London, Volume 1,1931,page 384.
[33]Fuller, R., Cole, C.B., Coates, M.E. The role of streptococcus faecium in antibiotic-relieved growth depression in chickens[M]. In:Antimicrobials and Agriculture; Woodbine, M., Ed.; Butterworths, London,1984,395-403.
[34]Coates ME, Dickinson CD, Harrison GF, et.al. A mode of action of antibiotics in chick nutrition[J]. J Sci Food Agric,1952,3:43.
[35]Coates ME.The mode of action of antibiotics in animal nutrition[J]. Chem Indust, 1953,50:1333.
[36]Coates ME, Davies MK and Kon SK. The effects of antibiotics on the intestine of the chick[J]. Brit J Nutr,1955,9:110.
[37]Rusoff LL, Landogora FI and Hester HH. Effect of aureomycin on certain blood constituents (Hb, packed RBC, Ca, P, RBC and WBC), body temperatures, weights of organs and tissues, and thickness of small intestine[J]. J Dairy Sci.,1954,37:654.
[38]Braude R, Coates ME, Davies MK, et.al. The effect of aureomycin on the gut of the pig [J]. Br J Nutr.,1955,9:363-368.
[39]Hill CH, Keeling AD and Kelley JW. Studies on the effect of antibiotics on the intestinal weights of chicks [J]. J Nutr.,1957,62:255.
[40]Stutz MW and Johnson SL.The effect of bacitracin on the intestine of the chick[J]. Poultry Science,1976,55(5):2097.
[41]Gordon HA.A morphological and biochemical approach[M]. In:Studies on the growth effect of antibiotics in germ-free animals. Colloquium, Lobund Institute, University of Notre Dame, South Bend, Indiana, June 4,1952.
[42]Taylor JH and Harrington G. Influence of dietary antibiotic supplements on the visceral weights of pigs [J].Nature,1955,175:643-644.
[43]Shajahan GM and Coligado EC.The effect of zinc bacitracin, copper and quindoxin on the small intestine of broilers [J]. Bangladesh Veterinary Journal,1982,16:71-77.
[44]Jukes, T. H., D. C. Hill and H. D. Branion. Effect of feeding antibiotics on the intestinal tract of the chick[J]. Poult. Sci.,1956,35:716-723.
[45]Franti, C. E., L. M. Julian, H. E. Adler, et.al. Antibiotic growth promotion: Effects of zinc bacitracin and oxytetracycline on digestive circulatory, and excretory systems of New Hampshire cockerels [J]. Poult. Sci.,1972,51:1137-1145.
[46]Eyssen H, DeSomer P. The mode of action of antibiotics in stimulating growth in chicks[J].J Exp Med,1963,117:127-138.
[47]Anderson, D. B., V. J. McCracken, R. I. Aminov, et.al. Gut microbiology and growth-promoting antibiotics in swine [J]. Pig News Inf.,1999,20:115N-122N.
[48]Speer VC, Vohs RL, Catron DV, et.al. Effect of aureomycin and animal protein factor on healthy pigs[J]. Arch Biochem,1950,29:452.
[49]Catron DV, Maddock HM, Speer VC, et.al. Effect of different levels of aureomycin with and without vitamin B12 on growing-fattening swine[J]. Antibiot Chemother,1951,1:31.
[50]Coates ME, Dickinson CD, Harrison GF, et.al. Mode of action of antibiotics in stimulating growth of chicks[J]. Nature,1951,168:332.
[51]Hill DC, Branion HD and Slinger SJ. Influence of environment on the growth response of chicks to penicillin[J]. Poult Sci,1952,31:920.
[52]March B and Biely J.The effect of feeding aureomycin on the bacterial content of chick feces [J]. Poult Sci.,1952,31:177.
[53]Anderson GW, Cunningham JD and Slinger SJ. Effect of protein level and penicillin on growth and intestinal flora of chickens [J]. J Nutr.,1952,47:175.
[54]Johansson KR and Sarles WB.Some considerations of the biological importance of intestinal microorganisms[J].Bacteriol Rev.,1949,13:25.
[55]李同洲,臧素敏,李德发.饲用抗生素对仔猪肠道菌群及肠道物质代谢影响的研究[J].饲料研究,1999,5：3-5.
[56]Kellogg TF, Hays VW, Catron DV, et.al. Effect of level and source of dietary protein on performance and fecal flora of baby pigs[J]. J Anim Sci.,1964,23:1089.
[57]Kellogg TF, Hays VW, Catron DV, et.al. Effect of dietary chemotherapeutics on the performance and fecal flora of pigs [J]. J Anim Sci.,1966,25:1102.
[58]Catron DV, Jensen AH, Homeyer PG, et.al.Reevaluation of protein requirements of growing-fattening swine as influenced by feeding an antibiotic[J]. J Anim Sci., 1952,11:221.
[59]Burnside JE, Grummer RH, Phillips PH, et.al. The influence of crystalline aureomycin and vitamin B12 on the protein utilization of growing-fattening swine [J]. J Anim Sci.,1954,13:184.
[60]Beacom SE. Chlortetracycline and protein level in rations for market hogs.Ⅱ. Effect on rate of gain and efficiency of feed utilization [J]. Can J Anim Sci.,1959a,39:71-78.
[61]Beacom SE.Chlortetracycline and protein level in rations for market hogs. Ⅱ. Effect on carcass quality [J]. Can J Anim Sci.,1959b,39:79.
[62]Hogue DE, Warner RG, Loosli JK, et.al. Comparison of antibiotics for dairy calves on two levels of milk feeding[J]. J Dairy Sci.,1957,40:1072.
[63]West JW and Hill JE.Protein requirement of broilers as influenced by antibiotics [J]. Poult Sci.,1955,34:628.
[64]RavindranV,KornegayE T and WebbK E. Effects of fiber and virginiamycin on nutrient absorption, nutrient retention and rate of passage in growing swine[J]. J. Anim. Sci.,1984,59 (2):400-408.
[65]Catron DV, Lane MD, Quinn LY, et.al.Mode of action of antibiotics in swine nutrition [J]. Antibiot Chemother.,1953,3:571.
[66]Eyssen H and de Somer P.Effect of Streptococcus faecalis and a filterable agent on growth and nutrient absorption in gnotobiotic chicks[J]. Poultry Science,1967,46: 323-333.
[67]Ford D J and Coates M E. Absorption of glucose and vitamins of the B complex by germ-free and convenitional chicks[M]. Proceedings of the Nutrition Society, 1971,30:10-11.
[68]Vervaeke IJ, Decuypere JA, Dierick NA, et.al. Quantitative in vitro evaluation of the energy metabolism influenced by virginiamycin and spiramycin used as growth promoters in pig nutrition[J]. Journal of Animal Science,1979,49:846-856.
[69]Heneghan JB. Influence of microbial flora on xylose absorption in rats and mice[J]. Amer J Physiol,1963,205:417.
[70]Herskovic T, Katz J, Floch MH, et. al. Small intestinal absorption and morphology in germ-free, monocontaminated and conventional mice[J]. Gastroenterology,1967, 52:1136.
[71]Harms RH, Ruiz N and Miles RD.Influence of virginiamycin on broilers fed four levels of energy [J]. Poultry Science,1986,65:1984-1986.
[72]Sreenivas PT and Devegowda G.Influence of virginiamycin with varying levels of energy and protein on broiler performance. [J] Indian Journal of Poultry Science, 1994,29:245-248.
[73]Burnside JE, Cunha TJ, Pearson AM, et.al.Effect of APF supplement on pigs fed different protein supplements [J]. Arch Biochem,1949,23:328-330.
[74]Just A, Fernandez JA and Jorgensen H. The influence of virginiamycin on the ileal and faecal digestibility of nutrients in differently composed diets and the utilization of digestible crude protein and energy[M]. Proc 3rd Int Seminar:Digestive physiology in the pig, Copenhagen,1985,pp 292-295.
[75]Wuethrich AJ, Richardson LF, Mowrey DH. et.al.The, effect of narasin on apparent nitrogen digestibility and large intestine volatile fatty acid concentrations in finishing swine[J]. J Anim Sci,1998,76 (4):1056-63.
[76]Miles RD, Janky DM and Harms RH. Virginiamycin and broiler performance [J]. Poultry Science,1984,63:1218-1221.
[77]Abdel Hakim NF, Hilali EA, Amer AA, et. al. Effect of some antibiotics as growth promoters on performance of broiler chicks fed different protein levels [J]. Archives of Animal Nutrition,1989,39:97-104.
[78]姚浪群.安普霉素对仔猪蛋白质营养、内分泌和低温影响的研究[D].北京：中国农业科学院,2000.
[79]佟建民,张日俊,萨仁娜等.持续、低剂量金霉素对肉仔鸡免疫机能的抑制作用研究[J].中国农业科学,2001,34(2),200-204.
[80]王中华.黄霉素对绵羊消化道蛋白质合成代谢的影响[J].动物营养学报,2002,14(2)：57-59.
[81]MigicovskyB B,NeilsonA M and Gluck Metal. Penicillin and calcium absorption[J]. Arch. Biochem.,1951,34:479.
[82]Gabuten AR and Shafner CS. A study of the physiological mechanisms affecting specific gravity of chicken eggs [J]. Poult. Sci.,1952,31:917.
[83]Kirchgessner M,Windisch W and Roth F X. Effect of avilamycin and tylosinon apparent digestibility of iron, zinc, copper, manganese and selenium in growing and finishing Pigs[J]. Archives of Animal Nutrition,1994,46 (4):321-325.
[84]Buresh RE, Miles RD and Harms RH. Influence of virginiamycin on phosphorus Utilization by broiler chicks [J]. Poult. Sci.,1985,64:757-758.
[85]Hellen Linkswiler, C. A. Baumann and Esmond E. S. Effect of aureomycin on the response of rats to various form of vitamine B6[J]. J Nutr.,1951,43:565-573.
[86]Monson WF, Harper AE, Winje ME, et.al.Mechanism of the vitamin-sparing effect of antibiotics[J]. J Nutr.,1952,52:628.
[87]Barber RS, Braude R, Kon SK, et.al.Effect of supplementing an all-vegetable pig-fattening meal with antibiotics[J]. Chem Indust.,1952,29:713.
[88]Mackie, R. I., A. Sghir, and H. R. Gaskins. Developmental microbial ecology of the neonatal gastrointestinal tract [J]. Am. J. Clin. Nutr.,1999.,69:1035S.
[89]Lev M, Forbes. Growth response to dietary penicillin of germ free chicks with a defined intestinal microflora[J]. Br J Nutri,1959,13:78-84.
[90]Stutz MW,Johnson SL,Judith FR. Efects of diet, and bacitracin on growth,feed efficiency and populations of clostridium perfringens on the intestinal of broiler chicks[J]. Poult Sci,1983,62:1619-1625.
[91]Stutz MW,Lawton GS. Effect of diet and antimicrobial on growth, feed eficiency, intestinal clostridium perfringens,and ilea weight of broiler chicks[J]. Poult Sci, 1984,63:2036-2042.
[92]Dafwang II,Cook ME,BUNde ML, et.al.Bursal,intestinal,and spleen weights and antibody response of chicks fed subtherapeutic levels of dietary antibiotics[J].Poult.Sci.,1985,64:634-639.
[93]Brown H, Speer VC, Quinn LY, et.al. Studies on colostrum-acquired immunity and active antibody production in baby pigs [J] J. Anim.Sci.,1961,20:323.
[94]Harmon BG, Jensen AH and Baker DH. Influehce of dietary antibiotics on antibody response to specific antigens [J].J of Anim.Sci.,1973,37 (5):1155-1158.
[95]K. YAMAMOTO, M. TAKAGI, Y. S. ENDOH, et.al.Influence of antibiotics used as feed additives on the immune effect of erysipelas live vaccine in swine [J]. J. Vet. Med. B,2000,47:453-460.
[96]Skrivanova V, Marounek M, Simunek J, et. al. Effect of virginiamycin on digestibility of nutrients, blood and immunologic parameters, and quality of meat in veal calves[J]. Journal of Agricultural Science,1994,123:275-278.
[97]Kuby, J. Immunology[M]. W. H. Freeman and Company, New York,1992.
[98]保罗(Paul,W.E)编著.基础免疫学(Fundamental Immunology, Fourth Edition)[M].北京：科学出版社,2003.
[99]Klasing, K. C., and R. E. Austic. Changes in plasma, tissue and urinary nitrogen metabolites due to an inflammatory challenge[J]. Proc. Soc. Exp. Biol. Med., 1984a,176:276.
[100]Klasing, K. C., and R. E. Austic. Changes in protein synthesis due to an inflammatory challenge. [J] Proc. Soc.Exp. Biol. Med.,1984b,176:285.
[101]Wannemacher, R. W. Key role of various individual amino acids in host response to infection[J]. J. Clin. Nutr.,1977,30:1269.
[102]Scott A. McEwen and Paula J. Fedorka-Cray. Antimicrobial use and resistance in animals[J]. Clinical Infectious Diseases,2002,34(Suppl 3):S93-106.
[103]World Health Organization. The medical impact of the use of antimicrobials in food animals[M]. Report from a WHO meeting held in Berlin, Germany, WHO,1997.
[104]World Health Organization. Use of quinolones in food animals and potential impact on human health[M]. Report of a WHO meeting held in Geneva, Switzerland. WHO,1998.
[105]Salyers AA, ed. Antibiotic resistance transfer in the mammalian intestinal tract: implications for human health, food safety and biotechnology[M]. New York: Springer-Verlag,1995.
[106]Fraimow HS, Abrutyn E. Pathogens resistant to antimicrobial agents:epidemiology, molecular mechanisms, and clinical management [J]. Infect Dis Clin North Am.,1995,9:497-530.
[107]Katherine M. Shea, MD, MPH. Antibiotic resistance:What is the impact of agricultural uses of antibiotics on children's health? [J] Pediatrics,2003,112:253-258.
[108]Roderick I Mackie, Abdelghani Sghir, and H Rex Gaskins. Developmental microbial ecology of the neonatal gastrointestinal tract[J]. Am J Clin Nutr,1999,69(suppl):1035S-1045S.
[109]Klopfenstein TJ, Purser DB and Tyznik WJ. Influence of aureomycin on rumen metabolism [J]. J Anim Sci,1964,23:490-495.
[110]Merkenschlager M. The influence of the addition of antibiotics to fodder on the microbial flora of livestock[J].Arch Hyg Bakt,1965,149:659-668.
[111]余冰,张克英,郑萍等.猪营养与肠道健康[J].中国畜牧杂志,2010,46(15)：73-75.
[112]Krinke AL and Jamroz D. Efects of feed antibiotic avopramycin on organ morphology in broiler-chickens [J]. Poult. Sci.,1996,75:705-710.
[113]金久善,李庆怀.氯霉素对肉鸡免疫功能的影响[J].畜牧兽医学报,1992,23(2)：172-176.
[114]常文环,李德发,龚利敏等.黄霉素对肉仔鸡促生长作用机理的研究[M].农业部饲料工业中心年度科研报告,1997.
[115]周艳.硫酸粘杆菌素对雏鸡免疫器官生长发育及红细胞免疫功能的影响[D]. 四川：四川农业大学,2007.
[116]Cooper MS and Allen GA.The effect of chlortetracycline on the immune response.Ⅱ.Influence on development of protective antibodies after vaccination with a live, avirulent strain of erysipelothrix rhusionpathiae[J].J. Immunology,1959,83:232-236.
[117]Naqi SA,Sahin N,Wagner G and Williams J. Adverse effects of antibiotics on the development of gut-associated lymphoid tissues and the serum immunoglobulins in chickens[J]. Am. J. Vet. Res.,1984,45(7):1425-1429.
[118]Martin R R,Warr G A,Couch R B,et al. Effects of tetracline on Ieukotaxis[J]. J Infect Dis,1974,129:110.
[119]Voiculescu C, Stanciu L, Voiculescu M, et. al. Experimental study of antibiotic-induced immunosuppression in mice. I. Humoral and cell-mediated immune responsiveness related to in vivo antibiotic treatment[J].Comp.Immun.Microbial.Infect.D is,1983a,61 (4):291-299.
[120]Voiculescu C, Stanciu L, Voiculescu M, Rogoz S,Dumitriu I and Nedelcu C. Experimental study of antibiotic-induced immunosuppression in mice. Ⅱ.Th,Ts and NC cell involvement [J].Comp.Immun.Microbiol.Infect.Dis.,1983b,61(4):301-312.
[121]张日俊,佟建民,萨仁娜等.饲用金霉素对肉仔鸡免疫系统生长发育及免疫反应的研究[J].畜牧兽医学报,2000,31(3)：216-223.
[122]刘崇海,杨锡强,刘恩梅等.抗生素诱导小鼠肠道菌群失调对免疫功能和Toll样受体2、4基因表达的影响[J].重庆医科大学学报,2007,32(8)：839-842.
[123]王爱丽,武庆斌,孙庆林.抗生素对新生大鼠肠道菌群和肠道免疫发育的影响[J].中国微生态学杂志,2009,21(6)：512-518.
[124]刘伟,时衍同,杨晖.幼年小鼠应用抗生素致免疫反应亢进的研究[J].临床肺科杂志,2003,8(1)：36-37.
[125]卢建军,许梓荣.日粮添加金霉素对断奶仔猪肠道核因子NF2κB活化的影响[J].畜牧兽医学报,2006,37(9)：933-939.
[126]李丽鹃,吴志新,陈孝煊等.投喂阿维拉霉素对鲤免疫应答的影响[J].淡水渔 业,2006,36(2)：39-43.
[127]周磊.泰拉霉素对炎症反应的调节机制和体外抗菌后效应研究[D].四川：四川农业大学,2008.
[128]张乔主编.饲料添加剂大全[M].北京：北京工业大学出版社,1994.
[129]E. Higashiide, K. Hatano, M. Shibata, et.al.Enduracidin, a new antibiotic I. Streptomyces fungicidicus No. B5477, an enduracidin producing organism[J].J.Antibiot.,1968,21:126-130.
[130]许英灼,潘穗华,周玉岩等.安来霉素在小猪料中的效果试验[J].广东饲料,1996,2：18.
[131]张石蕊,谢申伍.安来霉素与几种常用抗生素添加剂在仔猪生产中应用效果比较[J].中国兽医杂志,2003,39(11)：46-48.
[132]A. A. Pedroso, J. F. M. Menten, M. R. Lambais, et. al. Intestinal bacterial community and growth performance of chickens fed diets containing antibiotics [J]. Poultry Science,2006,85:747-752.
[133]罗亚波,邹成义,陈洪等.日粮中添加及停用恩拉霉素对断奶仔猪生长性能和消化吸收功能的影响[J].动物营养学报,2010,22(1)：139-144.
[134]陈洪,余冰,陈代文等.日粮中添加恩拉霉素对仔猪生长性能和肠道菌群的影响[J].中国畜牧杂志,2010,46(19)：42-46.
[135]冷静,朱仁俊.不同日龄断奶对仔猪血液生化和免疫指标的影响[J].安徽农业科学,2010,38(4)：1853-1854,1880.
[136]刘薇,左永昌,丁桂凤等.束缚免疫抑制因子对免疫细胞功能的影响[J].北京医科大学学报,1997,29(1)：86-87.
[137]吕琼霞,张书霞,赵茹茜.运输对猪免疫机能的影响及其细胞因子的调控[J].中国农业科学,2009,42(7)：2579-2585.
[138]侯殿东,赵宝霞,刘辉.致免疫功能降低动物模型的建立[J].中国实验动物学报,2007,15(5)：330-333.
[139]Johnson R.W, von Borell E. Lipopolysaccharide-induced sickness behavior in pigs is inhibited by pretreatment with indomethacin[J]. Journal of animal science, 1994,72(2):309-314.
[140]van Heugten E, Spears J.W, Coffey MT. The effect of dietary protein on performance and immune response in weanling pigs subjected to an inflammatory challenge[J]. Journal of animal science,1994,72(10):2661-2669.
[141]J.Bassaganya-Riera, Hontecillas-Magarzo R, K. Bregendahl, et.al.Effects of dietary conjugated linoleic acid in nursery pigs of dirty and clean environments on growth, empty body composition, and immune competence[J]. Journal of animal science,2001,79(3):741-721.
[142]Balaji R, Wright KJ, Hill CM, et.al. Acute phase responses of pigs challenged orally with Salmonella typhimurium. Journal of animal science[J], 2000,78(7):1885-1891.
[143]E. B. Kegley, J. W. Spears, and S. K. Auman. Dietary phosphorus and an inflammatory challenge affect performance and immune function of weanling pigs[J]. J. Anim. Sci.2001,79:413-419.
[144]袁施彬.仔猪氧化应激及硒的抗应激效应和机理的研究[D].四川：四川农业大学,2007.
[145]Wan, J.M.F., M. P. Haw, and G. L. Blackburn. Nutrition, immune function and inflammation:An overview[J]. Proc. Nutr. Soc.,1989,48:315.
[146]Roura, E., J. Homedes, and K. C. Klasing. Potential mechanism of action of antibiotics as growth promoters:Modulation of immunologic stress [J]. Poult. Sci., 1991,70:102.
[147]van Heugten E, Coffey MT, Spears JW. Effects of immune challenge, dietary energy density, and source of energy on performance and immunity in weanling pigs[J]. Journal of animal science,1996,74(10):2431-2440.
[148]van Heugten EV, Spears JW. Immune response and growth of stressed weanling pigs fed diets supplemented with organic or inorganic forms of chromium [J]. Journal of animal science,1997,75(2):409-416.
[149]Dritz S.S, Owen K.Q, Goodband R.D, et. al. Influence of lipopolysaccharide-induced immune challenge and diet complexity on growth performance and acute-phase protein production in segregated early-weaned pigs[J]. Journal of animal science,1996,74(7):1620-1628.
[150]Williams N.H, Stahly TS,.Zimmerma DR. Effects of level of chronic immune system activation on the growth and dietary lysine needs of pigs fed from 6 to 112 kg [J]. J. Anim.Sci.,1997,75:2481-2496.
[151]Klasing K.C, Laurin DE, Peng RK, et.al.Immunologically mediated growth depression in chicks:influence of feed intake, corticosterone and interleukin-1[J]. The Journal of nutrition,1987,117(9):1629-1637.
[152]Spurlock ME. Regulation of metabolism and growth during immune challenge: an overview of cytokine function[J]. Journal of animal science, 1997,75(7):1773-1783.
[153]Webel D.M, Finck BN, Baker DH, et.al.Time course of increased plasma cytokines, cortisol, and urea nitrogen in pigs following intraperitoneal injection of lipopolysaccharide[J]. Journal of animal science,1997,75(6):1514-1520.
[154]吴春燕,张克英,陈代文.免疫应激对断奶仔猪蛋白质利用率和整体蛋白质周转代谢的影响[M].见：中国畜牧兽医学会动物营养学分会-第九届学术研讨会论文集,2004.
[155]李建文,陈代文,张克英等.免疫应激对仔猪理想氨基酸平衡模式影响的研究[J].畜牧兽医学报,2006,37(1),34-37.
[156]Rodney W. Johnson. Inhibition of Growth by Pro-Inflammatory Cytokines:An Integrated View[J]. J. Anim. Sci.,1997,75:1244-1255.
[157]董晓玲,刘国华,蔡辉益等.细菌脂多糖诱导的急性免疫应激对肉仔鸡肉品质的影响[J].动物营养学报,2007,19(5)：622-626.
[158]LindaST, Cheryl FN, Martin J. Effect of Escherichia coli on iron, copper, and zinc metabolism in chicks[J]. Avian Diseas,1988,32:779-786.
[159]Barber E.F, Cousins RJ. Interleukin-1-stimulated induction of ceruloplasmin synthesis in normal and copper-deficient rats[J]. J N utr,1988,118:375-381.
[160]Tufft L.S, Nockels C.F, Fettman M.J. Effects of Escherichia coli on iron, copper, and zinc metabolism in chicks [J]. Avian diseases,1988,32(4):779-786.
[161]Stahly T.S, Cook D.R. Dietary B vitamin needs of pigs with a moderate or high level of antigen exposure [J]. J AnimSci,1996,74(Suppl.1):170 (Abstr.).
[162]Webel DM, Mahan DC, Johnson RW, et.a;.Pretreatment of young pigs with vitamin E attenuates the elevation in plasma interleukin-6 and cortisol caused by a challenge dose of lipopolysaccharide[J]. The Journal of nutrition, 1998,128(10):1657-1660.
[163]National Researeh Council.Nutrient Requirements of Swine. lOthEd National Academic Press Washington, DC,1998.
[164]Marounek M, Suchorska O, Savka O. Effect of substrate and feed antibiotics on in vitro production of volatile fatty acids and methane in caecal contents of chickens [J].Anim Feed Sci and Tech,1999,80:223-230.
[165]Coma, J., D. Carrion, and D. R. Zimmerman. Use of plasma urea nitrogen as a rapid response criterion to determine the lysine requirement of pigs [J]. J. Anim. Sci.,1995,73:472-481.
[166]Flynn, N. E., C. J. Meininger, T. E. Haynes, et.al.The metabolic basis of arginine nutrition and pharmacotherapy[J]. Biomed. Pharmacother,2002,56:427-438.
[167]陈丽,罗二平,朱海超等.慢加急性肝衰竭患者血清中乳酸脱氢酶的临床意义.胃肠病学和肝病学杂志[J],2010,19(4)：339-341.
[168]毛湘冰.亮氨酸与瘦素协同调节生长鼠骨骼肌蛋白质代谢的研究[D].北京：中国农业大学,2010.
[169]赖长华.共轭亚油酸对断奶仔猪免疫应激的调控[D].北京：中国农业大学,2005.
[170]李媛媛,白春艳,吴潇等.促肾上腺皮质激素释放激素结合蛋白基因的研究进展[J].上海畜牧兽医通讯,2008,2：2-4.
[171]沈同,王镜岩主编.生物化学[M].第二版.北京：高等教育出版社,2000.
[172]刘伟.氧化抑制IGF-1神经保护作用机制及对策的研究[D].湖北武汉：华中科技大学,2009.
[173]杨汉春.动物免疫学(第二版)[M].北京：中国农业大学出版社,2003.
[174]陆承平.兽医微生物学[M].北京：中国内有出版社,2001.228-229.
[175]周联,俞瑜,王培训.防御素与先天性免疫及获得性免疫[J].国外医学：免疫 学分册,2005,28(2)：68-72.
[176]Takeda, K., Kaisho,T., and Akira,S. Toll-like receptors[J]. Annu Rev. Immunol,2003,21:335-376.
[177]Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR[J]. Nucleic Acids Res,2001,29:2002-2007.
[178]Mercer DW, Smith GS, Cross JM, et.al. Effects of lipopolysaccharide on intestinal injury:potential role of nitric oxide and lipid peroxidation[J]. J Surg Res,1996,63:185-192.
[179]VanderMeer TJ, Wang H & Fink MP.Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock[J]. Crit Care Med,1995,23:1217-1226.
[180]Fink MP, Antonsson JB, Wang HL, et.al. Increased intestinal permeability in endotoxic pigs. Mesenteric hypoperfusion as an etiologic factor[J]. Arch Surg,1991, 126:211-218.
[181]Liu YL, Huang JJ, Hou YQ, et.al. Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs[J]. Br J Nutr,2008,100:552-560.
[182]Carter LL, Dutton RW.Type 1 and Type 2:a fundamental dichotomy for all T-cell subsets[J]. Curr Opin Immunol,1996,8:336-342.
[183]Zamoyska R. CD4 and CD8:modulators of T-cell receptor recognition of antigen and of immune response? [J] Curr Opin Immunol,1998,10:82-87.
[184]Spiekermann GM, Walker WA. Oral tolerance and its role in clinical disease[J]. J Pediatr Gastroenterol Nutr,2001,32:237-255.
[185]Kidd P. Thl/Th2 balance:the hypothesis, its limitations, and implications for health and disease [J]. Altern Med Rev,2003,8:223-246.
[186]Sang Y, Ramanathan B, Ross C R, et.al. Gene silencing and overexpression of porcine peptidoglycan recognition protein long isoforms:involvement in beta-defensin-1 expression[J]. Infect Immun,2005,73(11):7133-7141.
[187]Fehlbaum P, Rao M, Zasloff M, et.al. An essential amino acid induces epithelial beta-defensin expression[J]. Proc Natl Acad Sci,2000,97:12723-12728.
[188]Harder J, Meyer-Hoffert U, Wehkamp K, et.al. Differential gene induction of human beta-defensins (hBD-1,-2-3, and-4) in keratinocytes is inhibited by retinoic acid[J]. J Invest Dermatol,2004,123:522-529.
[189]Sherman H, Chapnik N, Froy 0. Albumin and amino acids upregulate the expression of human beta-defensin 1[J]. Mol Immunol,2006,43:1617-1623.
[190]林洪远,盛志勇.全身炎症反应和MODS认识的变化及现状[J].中国危重病急救医学.2001,13(11)：643-646.
[191]蔺宏伟.多器官功能障碍综合征与免疫失衡[J].中国危重病急救医学,2001,13(9)：565-567.
[192]郭晓英.氟对大鼠肝脏功能和形态的影响及与氧化应激关系的实验研究[D].辽宁：中国医科大学,2003.
[193]赵丽,崔恒敏,杨帆等.高铜对雏鸭肝影响的病理学观察[J],中国兽医科学,2007,37(11)：990-993.
[194]杨帆,崔恒敏,赵丽等.高铜对雏鸭脾影响的组织病理学观察[J],中国兽医科学,2008,38(07)：616-621.
[195]崔伟,彭西,赵丽等.高铜对雏鸭肾脏影响的病理学观察[J],中国兽医学报,2009,29(9)：1212-1216.
[196]肖杰,杨帆,崔恒敏等.高钼对雏鸡肝脏和脾脏抗氧化功能的影响[J],畜牧兽医学报,2010,41(7)：883-890.
[197]柏才敏,陈涛,龚涛等.高氟致雏鸡肾脏病理学损伤和相关生化指标改变的研究[J],中国兽医学报,2011,30(4)：505-509.
[198]熊丁,徐志文,梅淼等.PRRSV感染致断奶仔猪肺脏和外周免疫器官的病理损伤[J],中国兽医学报,2011,31(5)：725-729.
[199]C.E.Stewart and P.Rotwein. Growth, differentiation, and survival:multiple physiological functions for insulin-like growth factors. Physiol Rev,1996,76(4): 1005-1026.
[2]Moore, P. R., A. Evenson, T. D. Luckey, et.al. Use of sulphasuccidine, streptothricin and streptomycin in nutrition studies with the chick[J]. J. Biol. Chem, 1946,165:437-441.
[3]Jukes, T. H., E. L. R. Stokstad, R. R. Taylor, et.al. Growth promoting effect of aureomycin on pigs[J]. Arch. Biochem,1950,26:324-330.
[4]佟建明.饲用抗生素研究进展[M].见：许振英,张子仪编.动物营养研究进展.北京,中国农业科技出版社,1994,255-264.
[5]中华人民共和国农业部公告第168号.饲料药物添加剂使用规范,2001.
[6]Witte W. Medical consequences of antibiotic use in agriculture [J]. Science,1998,279:996-997.
[7]Cassell GH, Mekalanos J. Development of antimicrobial agents in the era of new and reemerging infectious diseases and increasing antibiotic resistance[J]. JAMA, 2001,285:601-605.
[8]Katherine M. Shea. Antibiotic Resistance:What Is the Impact of Agricultural Uses of Antibiotics on Children's Health? [J].Pediatrics,2003,112:253-258.
[9]J. J. Dibner, and J. D. Richards. Antibiotic growth promoters in agriculture:history and mode of action. Poultry Science[J],2005,84:634-643.
[10]卜仕金.欧盟禁用抗生素促生长剂的利与弊[J].中国家禽,2006,13：50-52.
[11]佟建明.饲用抗生素、动物免疫系统和肠道微生物的三元平衡[J].动物科学与动物医学,2000,4：38-40.
[12]Liebbrandt, V. C. and R. C. Ewan. Effect of weaning and age at weaning on performance by baby pigs[J]. J. Anim. Sci,1972,35:1107 (Abstr.).
[13]Funderburke,D. W. and R. W. Seerly. The effects of postweaning stressors on pig weight change, blood, liver and digestive tract characteristics[J].J. Anim. Sci 1990,68:155-162.
[14]Cook M.E, C.C.Miller, Y.Park, et al. Immnue modulation by altered nutrient metabolism:nutritional control of immune-induced growth depression[J]. Poul. Sci, 1993,72:1301-1305.
[15]Johnson R.W. Inhibition of growth by pro-inflammatory cytokines:an integrated view[J]. Journal of animal science,1997,75(5):1244-1255.
[16]Klasing K.C. Nutritional aspects of leukocytic cytokines[J]. The Journal of nutrition,1988,118(12):1436-1446.
[17]H. R. Gaskins, C. T. Collier,land D. B. Anderson. Antibiotics as growth promotants:mode of action[J]. Animal Biotechnology,2002,13:29-42.
[18]Hays, V. W. Benefits:Antibacterials. In:Drugs in Livestock Feed, Vol. I. Tech. Rep. [M]. Office of Technology Assessment, Congress of the United States, Washington, DC,1979,p29-36.
[19]Dean R. Zimmerman. Role of subtherapeutic levels of antimicrobials in pig production[J]. J. Anim. Sci.,1986,62(Suppl.3):6-17.
[20]Jones, P.W.,Tarrant, M.E. The effect of various factors on the efficacy of Tylosin as a growth promoter in clinically healthy pigs [J]. Anim. Prod.,1982,34:115-121.
[21]Weldon, W.C. Tylosin:effects on nutrient metabolism. In Proceedings of World Pork Exposition Swine Research Review[M]. Elanco Animal Health, Greenfield,IN,1997.
[22]Roth, F.X.; Kirchgessner, M. Influence of avilamycin and tylosin on retention and excretion of nitrogen in finishing pigs[J]. J. Anim. Physiol.1993,69:245-250.
[23]Impacts of antimicrobial growth promoter termination in Denmark[M]. World Health Organization(WHO). Foulum, Denmark.6-9 November,2002.
[24]Hayes DJ, Jensen HH and Fabiosa J.Technology choice and the economic effects of a ban on the use of antimicrobial feed additives in swine rations. Food Control[J], 2002,13:97-101.
[25]Francois, A.C. Mode of action of antibiotics on growth[J]. World Review of Nutrition and Dietetics,1962,3:21.
[26]Visek, W.J. The mode of growth promotion by antibiotics[J]. J. Anim. Sci.,1978,46:1447-1469.
[27]Coates, M. E., Davies, M. K., Harrison, G. F., et.al. The mode of action of antibiotics in chick nutrition, Ⅱ. The effect of penicillin in clean and stale premises,[J].J. Sc. Food and Agrlc.,1955,6:419.
[28]Coates, M. E., R. Fuller, G. F. Harrison, M. et.al. Comparison of the growth of chicks in the Gustafsson germ-free apparatus and in a conventional environment, with and without dietary supplements of penicillin[J]. Br. J.Nutr.,1963,17:141-151.
[29]Hays, V.W. Biological basis for the use of antibiotics in livestock production.The use of drugs in animal feeds[M], National Research Council Publication; National Academy of Sciences,1969,11-30.
[30]Coates, M.E. The gut microflora and growth[M]. In:growth in animals; Lawrence, T.L.J., Ed.; Butterworths:Boston,1980,175-188.
[31]Roura, E., J. Homedes, and K. C. Klasing. Prevention of immunologic stress contributes to the growth-permitting ability of dietary antibiotics in chicks [J]. J. Nutr.,1992,122:2382-2390.
[32]Needham J.Chemical embryology[M]. Cambridge University Press, London, Volume 1,1931,page 384.
[33]Fuller, R., Cole, C.B., Coates, M.E. The role of streptococcus faecium in antibiotic-relieved growth depression in chickens[M]. In:Antimicrobials and Agriculture; Woodbine, M., Ed.; Butterworths, London,1984,395-403.
[34]Coates ME, Dickinson CD, Harrison GF, et.al. A mode of action of antibiotics in chick nutrition[J]. J Sci Food Agric,1952,3:43.
[35]Coates ME.The mode of action of antibiotics in animal nutrition[J]. Chem Indust, 1953,50:1333.
[36]Coates ME, Davies MK and Kon SK. The effects of antibiotics on the intestine of the chick[J]. Brit J Nutr,1955,9:110.
[37]Rusoff LL, Landogora FI and Hester HH. Effect of aureomycin on certain blood constituents (Hb, packed RBC, Ca, P, RBC and WBC), body temperatures, weights of organs and tissues, and thickness of small intestine[J]. J Dairy Sci.,1954,37:654.
[38]Braude R, Coates ME, Davies MK, et.al. The effect of aureomycin on the gut of the pig [J]. Br J Nutr.,1955,9:363-368.
[39]Hill CH, Keeling AD and Kelley JW. Studies on the effect of antibiotics on the intestinal weights of chicks [J]. J Nutr.,1957,62:255.
[40]Stutz MW and Johnson SL.The effect of bacitracin on the intestine of the chick[J]. Poultry Science,1976,55(5):2097.
[41]Gordon HA.A morphological and biochemical approach[M]. In:Studies on the growth effect of antibiotics in germ-free animals. Colloquium, Lobund Institute, University of Notre Dame, South Bend, Indiana, June 4,1952.
[42]Taylor JH and Harrington G. Influence of dietary antibiotic supplements on the visceral weights of pigs [J].Nature,1955,175:643-644.
[43]Shajahan GM and Coligado EC.The effect of zinc bacitracin, copper and quindoxin on the small intestine of broilers [J]. Bangladesh Veterinary Journal,1982,16:71-77.
[44]Jukes, T. H., D. C. Hill and H. D. Branion. Effect of feeding antibiotics on the intestinal tract of the chick[J]. Poult. Sci.,1956,35:716-723.
[45]Franti, C. E., L. M. Julian, H. E. Adler, et.al. Antibiotic growth promotion: Effects of zinc bacitracin and oxytetracycline on digestive circulatory, and excretory systems of New Hampshire cockerels [J]. Poult. Sci.,1972,51:1137-1145.
[46]Eyssen H, DeSomer P. The mode of action of antibiotics in stimulating growth in chicks[J].J Exp Med,1963,117:127-138.
[47]Anderson, D. B., V. J. McCracken, R. I. Aminov, et.al. Gut microbiology and growth-promoting antibiotics in swine [J]. Pig News Inf.,1999,20:115N-122N.
[48]Speer VC, Vohs RL, Catron DV, et.al. Effect of aureomycin and animal protein factor on healthy pigs[J]. Arch Biochem,1950,29:452.
[49]Catron DV, Maddock HM, Speer VC, et.al. Effect of different levels of aureomycin with and without vitamin B12 on growing-fattening swine[J]. Antibiot Chemother,1951,1:31.
[50]Coates ME, Dickinson CD, Harrison GF, et.al. Mode of action of antibiotics in stimulating growth of chicks[J]. Nature,1951,168:332.
[51]Hill DC, Branion HD and Slinger SJ. Influence of environment on the growth response of chicks to penicillin[J]. Poult Sci,1952,31:920.
[52]March B and Biely J.The effect of feeding aureomycin on the bacterial content of chick feces [J]. Poult Sci.,1952,31:177.
[53]Anderson GW, Cunningham JD and Slinger SJ. Effect of protein level and penicillin on growth and intestinal flora of chickens [J]. J Nutr.,1952,47:175.
[54]Johansson KR and Sarles WB.Some considerations of the biological importance of intestinal microorganisms[J].Bacteriol Rev.,1949,13:25.
[55]李同洲,臧素敏,李德发.饲用抗生素对仔猪肠道菌群及肠道物质代谢影响的研究[J].饲料研究,1999,5：3-5.
[56]Kellogg TF, Hays VW, Catron DV, et.al. Effect of level and source of dietary protein on performance and fecal flora of baby pigs[J]. J Anim Sci.,1964,23:1089.
[57]Kellogg TF, Hays VW, Catron DV, et.al. Effect of dietary chemotherapeutics on the performance and fecal flora of pigs [J]. J Anim Sci.,1966,25:1102.
[58]Catron DV, Jensen AH, Homeyer PG, et.al.Reevaluation of protein requirements of growing-fattening swine as influenced by feeding an antibiotic[J]. J Anim Sci., 1952,11:221.
[59]Burnside JE, Grummer RH, Phillips PH, et.al. The influence of crystalline aureomycin and vitamin B12 on the protein utilization of growing-fattening swine [J]. J Anim Sci.,1954,13:184.
[60]Beacom SE. Chlortetracycline and protein level in rations for market hogs.Ⅱ. Effect on rate of gain and efficiency of feed utilization [J]. Can J Anim Sci.,1959a,39:71-78.
[61]Beacom SE.Chlortetracycline and protein level in rations for market hogs. Ⅱ. Effect on carcass quality [J]. Can J Anim Sci.,1959b,39:79.
[62]Hogue DE, Warner RG, Loosli JK, et.al. Comparison of antibiotics for dairy calves on two levels of milk feeding[J]. J Dairy Sci.,1957,40:1072.
[63]West JW and Hill JE.Protein requirement of broilers as influenced by antibiotics [J]. Poult Sci.,1955,34:628.
[64]RavindranV,KornegayE T and WebbK E. Effects of fiber and virginiamycin on nutrient absorption, nutrient retention and rate of passage in growing swine[J]. J. Anim. Sci.,1984,59 (2):400-408.
[65]Catron DV, Lane MD, Quinn LY, et.al.Mode of action of antibiotics in swine nutrition [J]. Antibiot Chemother.,1953,3:571.
[66]Eyssen H and de Somer P.Effect of Streptococcus faecalis and a filterable agent on growth and nutrient absorption in gnotobiotic chicks[J]. Poultry Science,1967,46: 323-333.
[67]Ford D J and Coates M E. Absorption of glucose and vitamins of the B complex by germ-free and convenitional chicks[M]. Proceedings of the Nutrition Society, 1971,30:10-11.
[68]Vervaeke IJ, Decuypere JA, Dierick NA, et.al. Quantitative in vitro evaluation of the energy metabolism influenced by virginiamycin and spiramycin used as growth promoters in pig nutrition[J]. Journal of Animal Science,1979,49:846-856.
[69]Heneghan JB. Influence of microbial flora on xylose absorption in rats and mice[J]. Amer J Physiol,1963,205:417.
[70]Herskovic T, Katz J, Floch MH, et. al. Small intestinal absorption and morphology in germ-free, monocontaminated and conventional mice[J]. Gastroenterology,1967, 52:1136.
[71]Harms RH, Ruiz N and Miles RD.Influence of virginiamycin on broilers fed four levels of energy [J]. Poultry Science,1986,65:1984-1986.
[72]Sreenivas PT and Devegowda G.Influence of virginiamycin with varying levels of energy and protein on broiler performance. [J] Indian Journal of Poultry Science, 1994,29:245-248.
[73]Burnside JE, Cunha TJ, Pearson AM, et.al.Effect of APF supplement on pigs fed different protein supplements [J]. Arch Biochem,1949,23:328-330.
[74]Just A, Fernandez JA and Jorgensen H. The influence of virginiamycin on the ileal and faecal digestibility of nutrients in differently composed diets and the utilization of digestible crude protein and energy[M]. Proc 3rd Int Seminar:Digestive physiology in the pig, Copenhagen,1985,pp 292-295.
[75]Wuethrich AJ, Richardson LF, Mowrey DH. et.al.The, effect of narasin on apparent nitrogen digestibility and large intestine volatile fatty acid concentrations in finishing swine[J]. J Anim Sci,1998,76 (4):1056-63.
[76]Miles RD, Janky DM and Harms RH. Virginiamycin and broiler performance [J]. Poultry Science,1984,63:1218-1221.
[77]Abdel Hakim NF, Hilali EA, Amer AA, et. al. Effect of some antibiotics as growth promoters on performance of broiler chicks fed different protein levels [J]. Archives of Animal Nutrition,1989,39:97-104.
[78]姚浪群.安普霉素对仔猪蛋白质营养、内分泌和低温影响的研究[D].北京：中国农业科学院,2000.
[79]佟建民,张日俊,萨仁娜等.持续、低剂量金霉素对肉仔鸡免疫机能的抑制作用研究[J].中国农业科学,2001,34(2),200-204.
[80]王中华.黄霉素对绵羊消化道蛋白质合成代谢的影响[J].动物营养学报,2002,14(2)：57-59.
[81]MigicovskyB B,NeilsonA M and Gluck Metal. Penicillin and calcium absorption[J]. Arch. Biochem.,1951,34:479.
[82]Gabuten AR and Shafner CS. A study of the physiological mechanisms affecting specific gravity of chicken eggs [J]. Poult. Sci.,1952,31:917.
[83]Kirchgessner M,Windisch W and Roth F X. Effect of avilamycin and tylosinon apparent digestibility of iron, zinc, copper, manganese and selenium in growing and finishing Pigs[J]. Archives of Animal Nutrition,1994,46 (4):321-325.
[84]Buresh RE, Miles RD and Harms RH. Influence of virginiamycin on phosphorus Utilization by broiler chicks [J]. Poult. Sci.,1985,64:757-758.
[85]Hellen Linkswiler, C. A. Baumann and Esmond E. S. Effect of aureomycin on the response of rats to various form of vitamine B6[J]. J Nutr.,1951,43:565-573.
[86]Monson WF, Harper AE, Winje ME, et.al.Mechanism of the vitamin-sparing effect of antibiotics[J]. J Nutr.,1952,52:628.
[87]Barber RS, Braude R, Kon SK, et.al.Effect of supplementing an all-vegetable pig-fattening meal with antibiotics[J]. Chem Indust.,1952,29:713.
[88]Mackie, R. I., A. Sghir, and H. R. Gaskins. Developmental microbial ecology of the neonatal gastrointestinal tract [J]. Am. J. Clin. Nutr.,1999.,69:1035S.
[89]Lev M, Forbes. Growth response to dietary penicillin of germ free chicks with a defined intestinal microflora[J]. Br J Nutri,1959,13:78-84.
[90]Stutz MW,Johnson SL,Judith FR. Efects of diet, and bacitracin on growth,feed efficiency and populations of clostridium perfringens on the intestinal of broiler chicks[J]. Poult Sci,1983,62:1619-1625.
[91]Stutz MW,Lawton GS. Effect of diet and antimicrobial on growth, feed eficiency, intestinal clostridium perfringens,and ilea weight of broiler chicks[J]. Poult Sci, 1984,63:2036-2042.
[92]Dafwang II,Cook ME,BUNde ML, et.al.Bursal,intestinal,and spleen weights and antibody response of chicks fed subtherapeutic levels of dietary antibiotics[J].Poult.Sci.,1985,64:634-639.
[93]Brown H, Speer VC, Quinn LY, et.al. Studies on colostrum-acquired immunity and active antibody production in baby pigs [J] J. Anim.Sci.,1961,20:323.
[94]Harmon BG, Jensen AH and Baker DH. Influehce of dietary antibiotics on antibody response to specific antigens [J].J of Anim.Sci.,1973,37 (5):1155-1158.
[95]K. YAMAMOTO, M. TAKAGI, Y. S. ENDOH, et.al.Influence of antibiotics used as feed additives on the immune effect of erysipelas live vaccine in swine [J]. J. Vet. Med. B,2000,47:453-460.
[96]Skrivanova V, Marounek M, Simunek J, et. al. Effect of virginiamycin on digestibility of nutrients, blood and immunologic parameters, and quality of meat in veal calves[J]. Journal of Agricultural Science,1994,123:275-278.
[97]Kuby, J. Immunology[M]. W. H. Freeman and Company, New York,1992.
[98]保罗(Paul,W.E)编著.基础免疫学(Fundamental Immunology, Fourth Edition)[M].北京：科学出版社,2003.
[99]Klasing, K. C., and R. E. Austic. Changes in plasma, tissue and urinary nitrogen metabolites due to an inflammatory challenge[J]. Proc. Soc. Exp. Biol. Med., 1984a,176:276.
[100]Klasing, K. C., and R. E. Austic. Changes in protein synthesis due to an inflammatory challenge. [J] Proc. Soc.Exp. Biol. Med.,1984b,176:285.
[101]Wannemacher, R. W. Key role of various individual amino acids in host response to infection[J]. J. Clin. Nutr.,1977,30:1269.
[102]Scott A. McEwen and Paula J. Fedorka-Cray. Antimicrobial use and resistance in animals[J]. Clinical Infectious Diseases,2002,34(Suppl 3):S93-106.
[103]World Health Organization. The medical impact of the use of antimicrobials in food animals[M]. Report from a WHO meeting held in Berlin, Germany, WHO,1997.
[104]World Health Organization. Use of quinolones in food animals and potential impact on human health[M]. Report of a WHO meeting held in Geneva, Switzerland. WHO,1998.
[105]Salyers AA, ed. Antibiotic resistance transfer in the mammalian intestinal tract: implications for human health, food safety and biotechnology[M]. New York: Springer-Verlag,1995.
[106]Fraimow HS, Abrutyn E. Pathogens resistant to antimicrobial agents:epidemiology, molecular mechanisms, and clinical management [J]. Infect Dis Clin North Am.,1995,9:497-530.
[107]Katherine M. Shea, MD, MPH. Antibiotic resistance:What is the impact of agricultural uses of antibiotics on children's health? [J] Pediatrics,2003,112:253-258.
[108]Roderick I Mackie, Abdelghani Sghir, and H Rex Gaskins. Developmental microbial ecology of the neonatal gastrointestinal tract[J]. Am J Clin Nutr,1999,69(suppl):1035S-1045S.
[109]Klopfenstein TJ, Purser DB and Tyznik WJ. Influence of aureomycin on rumen metabolism [J]. J Anim Sci,1964,23:490-495.
[110]Merkenschlager M. The influence of the addition of antibiotics to fodder on the microbial flora of livestock[J].Arch Hyg Bakt,1965,149:659-668.
[111]余冰,张克英,郑萍等.猪营养与肠道健康[J].中国畜牧杂志,2010,46(15)：73-75.
[112]Krinke AL and Jamroz D. Efects of feed antibiotic avopramycin on organ morphology in broiler-chickens [J]. Poult. Sci.,1996,75:705-710.
[113]金久善,李庆怀.氯霉素对肉鸡免疫功能的影响[J].畜牧兽医学报,1992,23(2)：172-176.
[114]常文环,李德发,龚利敏等.黄霉素对肉仔鸡促生长作用机理的研究[M].农业部饲料工业中心年度科研报告,1997.
[115]周艳.硫酸粘杆菌素对雏鸡免疫器官生长发育及红细胞免疫功能的影响[D]. 四川：四川农业大学,2007.
[116]Cooper MS and Allen GA.The effect of chlortetracycline on the immune response.Ⅱ.Influence on development of protective antibodies after vaccination with a live, avirulent strain of erysipelothrix rhusionpathiae[J].J. Immunology,1959,83:232-236.
[117]Naqi SA,Sahin N,Wagner G and Williams J. Adverse effects of antibiotics on the development of gut-associated lymphoid tissues and the serum immunoglobulins in chickens[J]. Am. J. Vet. Res.,1984,45(7):1425-1429.
[118]Martin R R,Warr G A,Couch R B,et al. Effects of tetracline on Ieukotaxis[J]. J Infect Dis,1974,129:110.
[119]Voiculescu C, Stanciu L, Voiculescu M, et. al. Experimental study of antibiotic-induced immunosuppression in mice. I. Humoral and cell-mediated immune responsiveness related to in vivo antibiotic treatment[J].Comp.Immun.Microbial.Infect.D is,1983a,61 (4):291-299.
[120]Voiculescu C, Stanciu L, Voiculescu M, Rogoz S,Dumitriu I and Nedelcu C. Experimental study of antibiotic-induced immunosuppression in mice. Ⅱ.Th,Ts and NC cell involvement [J].Comp.Immun.Microbiol.Infect.Dis.,1983b,61(4):301-312.
[121]张日俊,佟建民,萨仁娜等.饲用金霉素对肉仔鸡免疫系统生长发育及免疫反应的研究[J].畜牧兽医学报,2000,31(3)：216-223.
[122]刘崇海,杨锡强,刘恩梅等.抗生素诱导小鼠肠道菌群失调对免疫功能和Toll样受体2、4基因表达的影响[J].重庆医科大学学报,2007,32(8)：839-842.
[123]王爱丽,武庆斌,孙庆林.抗生素对新生大鼠肠道菌群和肠道免疫发育的影响[J].中国微生态学杂志,2009,21(6)：512-518.
[124]刘伟,时衍同,杨晖.幼年小鼠应用抗生素致免疫反应亢进的研究[J].临床肺科杂志,2003,8(1)：36-37.
[125]卢建军,许梓荣.日粮添加金霉素对断奶仔猪肠道核因子NF2κB活化的影响[J].畜牧兽医学报,2006,37(9)：933-939.
[126]李丽鹃,吴志新,陈孝煊等.投喂阿维拉霉素对鲤免疫应答的影响[J].淡水渔 业,2006,36(2)：39-43.
[127]周磊.泰拉霉素对炎症反应的调节机制和体外抗菌后效应研究[D].四川：四川农业大学,2008.
[128]张乔主编.饲料添加剂大全[M].北京：北京工业大学出版社,1994.
[129]E. Higashiide, K. Hatano, M. Shibata, et.al.Enduracidin, a new antibiotic I. Streptomyces fungicidicus No. B5477, an enduracidin producing organism[J].J.Antibiot.,1968,21:126-130.
[130]许英灼,潘穗华,周玉岩等.安来霉素在小猪料中的效果试验[J].广东饲料,1996,2：18.
[131]张石蕊,谢申伍.安来霉素与几种常用抗生素添加剂在仔猪生产中应用效果比较[J].中国兽医杂志,2003,39(11)：46-48.
[132]A. A. Pedroso, J. F. M. Menten, M. R. Lambais, et. al. Intestinal bacterial community and growth performance of chickens fed diets containing antibiotics [J]. Poultry Science,2006,85:747-752.
[133]罗亚波,邹成义,陈洪等.日粮中添加及停用恩拉霉素对断奶仔猪生长性能和消化吸收功能的影响[J].动物营养学报,2010,22(1)：139-144.
[134]陈洪,余冰,陈代文等.日粮中添加恩拉霉素对仔猪生长性能和肠道菌群的影响[J].中国畜牧杂志,2010,46(19)：42-46.
[135]冷静,朱仁俊.不同日龄断奶对仔猪血液生化和免疫指标的影响[J].安徽农业科学,2010,38(4)：1853-1854,1880.
[136]刘薇,左永昌,丁桂凤等.束缚免疫抑制因子对免疫细胞功能的影响[J].北京医科大学学报,1997,29(1)：86-87.
[137]吕琼霞,张书霞,赵茹茜.运输对猪免疫机能的影响及其细胞因子的调控[J].中国农业科学,2009,42(7)：2579-2585.
[138]侯殿东,赵宝霞,刘辉.致免疫功能降低动物模型的建立[J].中国实验动物学报,2007,15(5)：330-333.
[139]Johnson R.W, von Borell E. Lipopolysaccharide-induced sickness behavior in pigs is inhibited by pretreatment with indomethacin[J]. Journal of animal science, 1994,72(2):309-314.
[140]van Heugten E, Spears J.W, Coffey MT. The effect of dietary protein on performance and immune response in weanling pigs subjected to an inflammatory challenge[J]. Journal of animal science,1994,72(10):2661-2669.
[141]J.Bassaganya-Riera, Hontecillas-Magarzo R, K. Bregendahl, et.al.Effects of dietary conjugated linoleic acid in nursery pigs of dirty and clean environments on growth, empty body composition, and immune competence[J]. Journal of animal science,2001,79(3):741-721.
[142]Balaji R, Wright KJ, Hill CM, et.al. Acute phase responses of pigs challenged orally with Salmonella typhimurium. Journal of animal science[J], 2000,78(7):1885-1891.
[143]E. B. Kegley, J. W. Spears, and S. K. Auman. Dietary phosphorus and an inflammatory challenge affect performance and immune function of weanling pigs[J]. J. Anim. Sci.2001,79:413-419.
[144]袁施彬.仔猪氧化应激及硒的抗应激效应和机理的研究[D].四川：四川农业大学,2007.
[145]Wan, J.M.F., M. P. Haw, and G. L. Blackburn. Nutrition, immune function and inflammation:An overview[J]. Proc. Nutr. Soc.,1989,48:315.
[146]Roura, E., J. Homedes, and K. C. Klasing. Potential mechanism of action of antibiotics as growth promoters:Modulation of immunologic stress [J]. Poult. Sci., 1991,70:102.
[147]van Heugten E, Coffey MT, Spears JW. Effects of immune challenge, dietary energy density, and source of energy on performance and immunity in weanling pigs[J]. Journal of animal science,1996,74(10):2431-2440.
[148]van Heugten EV, Spears JW. Immune response and growth of stressed weanling pigs fed diets supplemented with organic or inorganic forms of chromium [J]. Journal of animal science,1997,75(2):409-416.
[149]Dritz S.S, Owen K.Q, Goodband R.D, et. al. Influence of lipopolysaccharide-induced immune challenge and diet complexity on growth performance and acute-phase protein production in segregated early-weaned pigs[J]. Journal of animal science,1996,74(7):1620-1628.
[150]Williams N.H, Stahly TS,.Zimmerma DR. Effects of level of chronic immune system activation on the growth and dietary lysine needs of pigs fed from 6 to 112 kg [J]. J. Anim.Sci.,1997,75:2481-2496.
[151]Klasing K.C, Laurin DE, Peng RK, et.al.Immunologically mediated growth depression in chicks:influence of feed intake, corticosterone and interleukin-1[J]. The Journal of nutrition,1987,117(9):1629-1637.
[152]Spurlock ME. Regulation of metabolism and growth during immune challenge: an overview of cytokine function[J]. Journal of animal science, 1997,75(7):1773-1783.
[153]Webel D.M, Finck BN, Baker DH, et.al.Time course of increased plasma cytokines, cortisol, and urea nitrogen in pigs following intraperitoneal injection of lipopolysaccharide[J]. Journal of animal science,1997,75(6):1514-1520.
[154]吴春燕,张克英,陈代文.免疫应激对断奶仔猪蛋白质利用率和整体蛋白质周转代谢的影响[M].见：中国畜牧兽医学会动物营养学分会-第九届学术研讨会论文集,2004.
[155]李建文,陈代文,张克英等.免疫应激对仔猪理想氨基酸平衡模式影响的研究[J].畜牧兽医学报,2006,37(1),34-37.
[156]Rodney W. Johnson. Inhibition of Growth by Pro-Inflammatory Cytokines:An Integrated View[J]. J. Anim. Sci.,1997,75:1244-1255.
[157]董晓玲,刘国华,蔡辉益等.细菌脂多糖诱导的急性免疫应激对肉仔鸡肉品质的影响[J].动物营养学报,2007,19(5)：622-626.
[158]LindaST, Cheryl FN, Martin J. Effect of Escherichia coli on iron, copper, and zinc metabolism in chicks[J]. Avian Diseas,1988,32:779-786.
[159]Barber E.F, Cousins RJ. Interleukin-1-stimulated induction of ceruloplasmin synthesis in normal and copper-deficient rats[J]. J N utr,1988,118:375-381.
[160]Tufft L.S, Nockels C.F, Fettman M.J. Effects of Escherichia coli on iron, copper, and zinc metabolism in chicks [J]. Avian diseases,1988,32(4):779-786.
[161]Stahly T.S, Cook D.R. Dietary B vitamin needs of pigs with a moderate or high level of antigen exposure [J]. J AnimSci,1996,74(Suppl.1):170 (Abstr.).
[162]Webel DM, Mahan DC, Johnson RW, et.a;.Pretreatment of young pigs with vitamin E attenuates the elevation in plasma interleukin-6 and cortisol caused by a challenge dose of lipopolysaccharide[J]. The Journal of nutrition, 1998,128(10):1657-1660.
[163]National Researeh Council.Nutrient Requirements of Swine. lOthEd National Academic Press Washington, DC,1998.
[164]Marounek M, Suchorska O, Savka O. Effect of substrate and feed antibiotics on in vitro production of volatile fatty acids and methane in caecal contents of chickens [J].Anim Feed Sci and Tech,1999,80:223-230.
[165]Coma, J., D. Carrion, and D. R. Zimmerman. Use of plasma urea nitrogen as a rapid response criterion to determine the lysine requirement of pigs [J]. J. Anim. Sci.,1995,73:472-481.
[166]Flynn, N. E., C. J. Meininger, T. E. Haynes, et.al.The metabolic basis of arginine nutrition and pharmacotherapy[J]. Biomed. Pharmacother,2002,56:427-438.
[167]陈丽,罗二平,朱海超等.慢加急性肝衰竭患者血清中乳酸脱氢酶的临床意义.胃肠病学和肝病学杂志[J],2010,19(4)：339-341.
[168]毛湘冰.亮氨酸与瘦素协同调节生长鼠骨骼肌蛋白质代谢的研究[D].北京：中国农业大学,2010.
[169]赖长华.共轭亚油酸对断奶仔猪免疫应激的调控[D].北京：中国农业大学,2005.
[170]李媛媛,白春艳,吴潇等.促肾上腺皮质激素释放激素结合蛋白基因的研究进展[J].上海畜牧兽医通讯,2008,2：2-4.
[171]沈同,王镜岩主编.生物化学[M].第二版.北京：高等教育出版社,2000.
[172]刘伟.氧化抑制IGF-1神经保护作用机制及对策的研究[D].湖北武汉：华中科技大学,2009.
[173]杨汉春.动物免疫学(第二版)[M].北京：中国农业大学出版社,2003.
[174]陆承平.兽医微生物学[M].北京：中国内有出版社,2001.228-229.
[175]周联,俞瑜,王培训.防御素与先天性免疫及获得性免疫[J].国外医学：免疫 学分册,2005,28(2)：68-72.
[176]Takeda, K., Kaisho,T., and Akira,S. Toll-like receptors[J]. Annu Rev. Immunol,2003,21:335-376.
[177]Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR[J]. Nucleic Acids Res,2001,29:2002-2007.
[178]Mercer DW, Smith GS, Cross JM, et.al. Effects of lipopolysaccharide on intestinal injury:potential role of nitric oxide and lipid peroxidation[J]. J Surg Res,1996,63:185-192.
[179]VanderMeer TJ, Wang H & Fink MP.Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock[J]. Crit Care Med,1995,23:1217-1226.
[180]Fink MP, Antonsson JB, Wang HL, et.al. Increased intestinal permeability in endotoxic pigs. Mesenteric hypoperfusion as an etiologic factor[J]. Arch Surg,1991, 126:211-218.
[181]Liu YL, Huang JJ, Hou YQ, et.al. Dietary arginine supplementation alleviates intestinal mucosal disruption induced by Escherichia coli lipopolysaccharide in weaned pigs[J]. Br J Nutr,2008,100:552-560.
[182]Carter LL, Dutton RW.Type 1 and Type 2:a fundamental dichotomy for all T-cell subsets[J]. Curr Opin Immunol,1996,8:336-342.
[183]Zamoyska R. CD4 and CD8:modulators of T-cell receptor recognition of antigen and of immune response? [J] Curr Opin Immunol,1998,10:82-87.
[184]Spiekermann GM, Walker WA. Oral tolerance and its role in clinical disease[J]. J Pediatr Gastroenterol Nutr,2001,32:237-255.
[185]Kidd P. Thl/Th2 balance:the hypothesis, its limitations, and implications for health and disease [J]. Altern Med Rev,2003,8:223-246.
[186]Sang Y, Ramanathan B, Ross C R, et.al. Gene silencing and overexpression of porcine peptidoglycan recognition protein long isoforms:involvement in beta-defensin-1 expression[J]. Infect Immun,2005,73(11):7133-7141.
[187]Fehlbaum P, Rao M, Zasloff M, et.al. An essential amino acid induces epithelial beta-defensin expression[J]. Proc Natl Acad Sci,2000,97:12723-12728.
[188]Harder J, Meyer-Hoffert U, Wehkamp K, et.al. Differential gene induction of human beta-defensins (hBD-1,-2-3, and-4) in keratinocytes is inhibited by retinoic acid[J]. J Invest Dermatol,2004,123:522-529.
[189]Sherman H, Chapnik N, Froy 0. Albumin and amino acids upregulate the expression of human beta-defensin 1[J]. Mol Immunol,2006,43:1617-1623.
[190]林洪远,盛志勇.全身炎症反应和MODS认识的变化及现状[J].中国危重病急救医学.2001,13(11)：643-646.
[191]蔺宏伟.多器官功能障碍综合征与免疫失衡[J].中国危重病急救医学,2001,13(9)：565-567.
[192]郭晓英.氟对大鼠肝脏功能和形态的影响及与氧化应激关系的实验研究[D].辽宁：中国医科大学,2003.
[193]赵丽,崔恒敏,杨帆等.高铜对雏鸭肝影响的病理学观察[J],中国兽医科学,2007,37(11)：990-993.
[194]杨帆,崔恒敏,赵丽等.高铜对雏鸭脾影响的组织病理学观察[J],中国兽医科学,2008,38(07)：616-621.
[195]崔伟,彭西,赵丽等.高铜对雏鸭肾脏影响的病理学观察[J],中国兽医学报,2009,29(9)：1212-1216.
[196]肖杰,杨帆,崔恒敏等.高钼对雏鸡肝脏和脾脏抗氧化功能的影响[J],畜牧兽医学报,2010,41(7)：883-890.
[197]柏才敏,陈涛,龚涛等.高氟致雏鸡肾脏病理学损伤和相关生化指标改变的研究[J],中国兽医学报,2011,30(4)：505-509.
[198]熊丁,徐志文,梅淼等.PRRSV感染致断奶仔猪肺脏和外周免疫器官的病理损伤[J],中国兽医学报,2011,31(5)：725-729.
[199]C.E.Stewart and P.Rotwein. Growth, differentiation, and survival:multiple physiological functions for insulin-like growth factors. Physiol Rev,1996,76(4): 1005-1026.