抗菌肽(antimicrobial peptides,AMPs)是一类具有广谱抗菌活性、结构多样性的短肽。在脊椎动物中,许多抗菌肽可以为机体提供保护,并在先天免疫系统中起调节作用[1]。与抗生素通常作用于少数特定靶点的作用机理不同,大部分抗菌肽通过物理性吸附并迅速渗透和破坏菌膜来杀死细菌[2-3],抗菌肽还可作用于微生物生物合成过程,如DNA、蛋白质、细胞壁合成和蛋白质折叠等(图 1)[1, 4-5]。病原微生物几乎不可能对抗菌肽产生耐药性,因为这需要改变整个膜结构或多个生化传递途径全部改变。此外,抗菌肽可高效广谱抗菌,包括许多对常规抗生素已产生耐药性的病原微生物[6-7]。抗菌肽生物学活性高、绿色无残留、不易产生耐药性病原菌,是较为合适的饲料添加剂,适合在动物生产中使用。
近年来,抗菌肽在动物生产中的应用性试验探索发展较快,并取得了阶段性的成果[8]。在动物生产中,抗菌肽替代抗生素作为新型的饲料添加剂,可降低抗生素的使用,减少抗生素残留和畜牧养殖源耐药菌的产生,保护环境安全和人类健康。同时,研究表明抗菌肽对畜禽还表现出提高生产性能、增强免疫力、防治疾病、改善肠道健康等积极作用。因此,本文就近些年来抗菌肽在猪、鸡等畜禽上的应用研究进展及前景进行简要综述。
1 抗菌肽在猪生产中的应用 1.1 抗菌肽在妊娠母猪养殖中的应用母猪提供的健康断奶仔猪数是养猪企业获得生产效益的基础。在妊娠母猪基础饲粮中添加天蚕素抗菌肽可提高母猪的平均窝产仔数、健仔数,降低总死胎率,并且哺乳仔猪头均净增重和头均日增重相比基础饲粮组均提高,同时腹泻率降低[9]。此外,在妊娠母猪基础饲粮中添加复合抗菌肽可显著提高妊娠母猪血液中蓝耳病抗体水平,减少急性感染或继发病毒血症比例[10]。由此可见,在妊娠母猪饲粮中添加适量抗菌肽对其健康状况及繁殖力均有促进作用,可提高猪生产中的经济效益。
1.2 抗菌肽在断奶仔猪养殖中的应用 1.2.1 抗菌肽对断奶仔猪生长性能及腹泻率的影响断奶是猪生产周期中最关键的过渡阶段之一,断奶仔猪的胃肠道组织器官和微生物需要迅速适应饮食和环境条件的变化。断奶常会引起仔猪胃肠道的功能紊乱,进而导致营养物质消化率降低和对病原体感染的敏感性增加[11-13]。研究表明,在饲粮中添加抗菌肽可有效降低断奶仔猪的腹泻率,减轻断奶仔猪腹泻引起的炎症反应[14],并可提高断奶仔猪的平均日增重、平均日采食量和饲料转化效率[15]。例如,Hu等[16]使用抗菌肽治疗腹泻,可有效降低断奶仔猪的腹泻率和腹泻指数,并显著降低血清中白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的含量,这表明抗菌肽能有效改善断奶仔猪的肠道炎症,减轻腹泻症状。此外,与硫酸黏菌素对照组相比,使用猪重组β-防御素2(rpBD2)作为断奶仔猪的饲料添加剂可显著提高断奶仔猪的体增重、平均日增重和平均日采食量,同时仔猪腹泻率降低了2%[17]。进一步的研究表明,在断奶仔猪基础饲粮中添加500 g/t肠杆菌肽可有效提高仔猪的平均日增重和平均日采食量,并且显著降低料重比,极显著降低腹泻率,在试验第14天时,添加500 g/t肠杆菌肽组仔猪腹泻率比添加30 g/t硫酸黏菌素组还要低43.53%[18]。这表明抗菌肽对断奶仔猪的生长性能及腹泻的预防和治疗具有促进作用,在一定条件下,其效果比硫酸黏菌素更佳。
1.2.2 抗菌肽对断奶仔猪免疫功能的影响提高免疫功能可增强仔猪抵御疾病的能力,减少断奶应激。在饲粮中添加适量抗菌肽可增强断奶仔猪的免疫功能。在断奶仔猪基础饲粮中添加抗菌肽,可提高其血清中免疫球蛋白G(IgG)、免疫球蛋白A(IgA)和免疫球蛋白M(IgM)的含量[19]。此外,有研究表明,断奶仔猪饲喂抗菌肽可以降低空肠黏膜中Toll样受体-4(TLR-4)、TNF-α、白细胞介素-1β(IL-1β)和白细胞介素-8(IL-8)的表达[20],还可以减弱脂多糖(LPS)诱导的断奶仔猪肠道炎症反应,恢复屏障功能,减少炎症介质的分泌[21],这可能是抗菌肽在肠道内发挥免疫调节作用的效果。
1.2.3 抗菌肽对断奶仔猪肠道菌群的影响健康的肠道菌群在动物机体免疫和腹泻等疾病的预防中有重要作用。研究表明,断奶仔猪口服猪β-防御素2可显著增加盲肠中乳酸杆菌和双歧杆菌的数量,同时显著减少大肠杆菌、脆弱拟杆菌和链球菌的数量[20]。Yu等[22]研究发现,在断奶仔猪基础饲粮中添加1.0或2.0 mg/kg的MccJ25抗菌肽,可使断奶仔猪粪便中乳酸杆菌和双歧杆菌的数量明显提高,同时大肠杆菌的数量呈明显的下降趋势。类似的,研究发现,在已建立腹泻模型(使用产肠毒素大肠杆菌K88灌胃攻毒3 d)的断奶仔猪基础饲粮中添加50 mg/kg的抗菌肽WK3,连续饲喂6 d后,发现断奶仔猪盲肠食糜中乳杆菌属和双歧杆菌属的数量较基础饲粮组极显著提高,肠杆菌属的数量极显著降低,但是盲肠中细菌总数及肠球菌属的数量均无显著变化[23]。此外,在饲粮中添加抗菌肽还能有效提高仔猪十二指肠、空肠和回肠的绒毛高度,显著降低空肠隐窝深度[24]。这表明在断奶仔猪饲粮中添加抗菌肽能调节断奶仔猪的肠道菌群结构,改善肠道屏障功能,促进肠道健康。
1.3 抗菌肽在育肥猪养殖中的应用饲喂抗菌肽对育肥猪的影响主要体现在对猪生长性能的促进作用上。在育肥猪的基础饲粮中添加抗菌肽可使其平均日采食量、平均日增重和饲料转化效率增加,料重比及氮排放量下降[25-26]。例如,张彬等[27]研究发现,在育肥猪基础饲粮中添加0.1%的“肽轻松”或0.1%的“肽菌素”均可不同程度地提高育肥猪的体重和平均日增重,降低料重比;但是,添加0.2%的“肽菌素”则会降低育肥猪的体重、平均日增重,且料重比升高。这说明抗菌肽在饲粮中的添加量存在一个潜在的阈值,超过该值则可能会出现相反的结果。此外,有研究表明,饲粮添加抗菌肽制剂还可以改善育肥猪的胴体性状及肉品质[28]。
1.4 抗菌肽在公猪精液储存中的应用由于猪精子质膜成分的特殊性,其不同于马等其他物种精液常在4 ℃下保存,液态公猪精液通常保存在15~20 ℃。在此温度下微生物更容易繁殖,因此公猪精液保存液中需要添加抑制微生物繁殖的抗生素[29]。Puig-Timonet等[30]通过2个单独的试验探究了猪β-防御素1(PBD1)和β-防御素2(PBD2)替代抗生素在液态公猪精液中的实际应用效果,2个试验均是用液体储存的公猪精液在17 ℃下保存9~10 d。在第1个试验中,他们评估了添加3种浓度(1.5、3和5 μmol/L)的PBD1或PBD2对保存10 d的公猪精液中细菌生长和精子质量的影响,结果表明,PBD1或PBD2在5 μmol/L时显著降低精子活力[第10天精子总活力:对照组为(31.6±1.2)%,PBD1组为(6.5±0.3)%,PDB2组为(5.6±0.4)%],但是2种抗菌肽在1.5或3 μmol/L时对精子活力无显著影响。PBD1或PBD2在3和5 μmol/L时均可有效抑制液态公猪精液中细菌的生长,但是抑制效果不如卡那霉素(50 mg/mL)。在第2个试验中,他们用2个剂量(107和108 CFU/mL)的大肠杆菌人工接种到液态公猪精液中,在9 d的时间内测定了这2种抗菌肽抑制细菌生长的能力,结果表明,在第9天,PBD1或PBD2浓度为3和5 μmol/L时的抑制细菌能力、精子活率、精子前向运动活力和总活力均高于对照组及PBD1或PBD2浓度为1.5 μmol/L时,但是效果均不及卡那霉素。这表明抗菌肽添加到猪精液中具有替代抗生素起到防止微生物污染的潜力,但需要进一步提高抗菌肽的抑菌活性,同时降低细胞毒性。Bussalleu等[31]的研究发现了相似的结果,他们发现在精液中添加3 μmol/L的PMAP-37抗菌肽可有效控制细菌负荷,并且几乎不会损害精子活力。此外,抗菌肽具有中和LPS的能力,研究发现,当其用于精液保存时,可有效缓解LPS诱导的精子凋亡[32]。虽然抗菌肽具有替代抗生素用于公猪精液保存液的潜力,但是与抗生素相比,使用较低浓度的抗菌肽其抑菌能力较弱,使用高浓度的抗菌肽则会对精子细胞产生较高的细胞毒性,因此抗菌肽在精液保存中的使用还需进一步的探究。
2 抗菌肽在家禽生产中的应用 2.1 抗菌肽在鸡养殖中的应用 2.1.1 抗菌肽对鸡生产性能、消化能力及肉品质等的影响抗菌肽可提高鸡的生长性能、消化能力及屠宰性能,改善肉品质和产蛋性能。肉仔鸡饲养的第1~42天,在基础饲粮中添加抗菌肽可不同程度地提高肉仔鸡的平均日增重,并降低平均日采食量、料重比、发病率及死亡率[33]。抗菌肽添加量对生长性能指标有不同的影响,这可能是抗菌肽增强了鸡的肠道屏障功能、免疫性能和消化吸收能力[34]。此外,当在鸡饲粮中添加抗菌肽及酵母活菌组成的抗菌肽制剂时,芦花鸡终末体重及平均日增重较单独添加抗菌肽组提高程度更高,平均日耗料及料重比较单独添加抗菌肽组下降更明显[35]。添加抗菌肽还可改善鸡对营养素的消化率。例如,董丽娜等[36]通过在肉仔鸡饮水中添加8 mg/L含抗菌肽的酵母工程菌,结果发现试验组肉仔鸡的干物质、粗蛋白质、中性洗涤纤维、酸性洗涤纤维和粗灰分的代谢率均较基础饲粮组有提高的趋势。
在基础饲粮中添加不同浓度的抗菌肽还可提高鸡的屠宰性能,其中全净膛率、胸肌率和腿肌率均有不同程度提高[37]。此外,郭忠欣等[38]研究发现,饲喂抗菌肽可显著降低肉鸡的肌肉滴水损失率和烹煮损失率,提高肉品质。对于产蛋后期的鸡,饲喂抗菌肽粗提物可提高产蛋率,降低料蛋比,增加蛋壳厚度和蛋壳相对质量[39]。但是需要注意的是,这些试验都没有进一步探究抗菌肽引起这些变化的内在机制,因此抗菌肽通过怎样的调控机制来影响鸡的生长性能、消化能力、屠宰性能、肉品质及产蛋性能还需深入研究。
2.1.2 抗菌肽对鸡免疫功能的影响抗菌肽可通过促进免疫器官发育来提高机体免疫功能。例如,Xie等[40]在1日龄健康818肉仔鸡饲粮中添加100 g/t Plectasin+100 g/t Cecropins抗菌肽,结果发现,21、40及50日龄时,抗菌肽组胸腺指数和法氏囊指数与对照组相比均有升高趋势,脾脏指数在21日龄时显著高于对照组,但是在40和50日龄时低于对照组,这表明在鸡饲粮中添加抗菌肽可促进鸡主要免疫器官法氏囊和胸腺的发育。抗菌肽还通过提高免疫细胞转化率和免疫因子含量来提高鸡的免疫功能。例如,孙全友等[41]在肉仔鸡饲粮中添加200 g/t天蚕素抗菌肽,结果发现抗菌肽添加组T淋巴细胞和B淋巴细胞转化率、血清IgG和IgM含量均极显著高于基础饲粮组,血清IgA含量较基础饲粮组提高了27.3%,但差异不显著。Bai等[42]研究发现,在基础饲粮中添加海带粉及天蚕素抗菌肽可显著提高鸡在21和42日龄时的血清新城疫病毒抗体滴度及淋巴细胞数。这表明抗菌肽可通过改善促炎和抗炎调节、趋化因子活性和对适应性免疫的直接调节作用来提高鸡的先天性免疫和适应性免疫。
2.1.3 抗菌肽对鸡肠道菌群及肠道健康的影响抗菌肽可改善鸡的肠道菌群,维护肠道健康。Ma等[33]以雄性1日龄肉仔鸡作为研究对象,在基础饲粮的基础上添加100或200 mg/kg Plectasin抗菌肽,结果发现,在21日龄时,抗菌肽组肉鸡空肠的绒毛高度较基础饲粮组增高,隐窝深度降低;在42日龄时,绒毛高度与隐窝深度的比值极显著高于基础饲粮组。此外,在基础饲粮或饮水中添加抗菌肽可显著降低鸡肠道中大肠杆菌[43]和沙门氏菌的数量,增加双歧杆菌和乳酸杆菌的数量[44]。消化道内的乳酸菌可通过提高绒毛高度,增加小肠吸收面积,改善小肠形态[45]。小肠形态的改善对营养物质的消化和代谢有积极的影响。
2.1.4 抗菌肽对鸡热应激及疾病的预防及治疗作用热应激通常会损害畜禽的生长和产品质量,造成巨大的经济损失。鸡由于羽毛厚、汗腺少,更容易产生热应激。Hu等[46]通过灌胃方式给16日龄爱拔益加(AA)雄性肉鸡灌注抗菌肽(猪肠道抗菌肽SGAMP),结果发现SGAMP可有效预防由热应激引起的肠黏膜损坏、绒毛破裂及上皮细胞的水肿和坏死,预防由热应激导致的上皮细胞间隙扩大、黏液增多及红细胞的渗出。此外,抗菌肽还可以在慢性热应激条件下维持鸡正常的肠道结构、肠道吸收和黏膜免疫功能,并可消除由慢性热应激导致的生长抑制[46-47]。
抗菌肽具有广泛的抑制和杀灭微生物作用,在鸡疾病的预防及治疗中,抗菌肽也表现出良好的应用效果。钟宏鹏等[48]研究发现,雏鸡攻毒鸡白痢沙门氏菌C79-13后,饲喂MSL抗菌肽可大幅度降低雏鸡感染鸡白痢的概率,还可降低采食量,提高体增重。郭文洁等[49]研究发现,在已发生腹泻的鸡饮水中添加粗提蝇蛆抗菌肽可极显著降低发病鸡血液中白细胞、红细胞和淋巴细胞数,腹泻治愈率达56.0%,高于空白对照组的12.0%,但是低于恩诺沙星治疗组的72.0%。上述结果说明抗菌肽在治疗鸡的腹泻病具有一定的效果,但是效果不及抗生素。更多的研究表明,抗菌肽可改善由寄生虫、大肠杆菌或坏死性肠炎引起的鸡肠道病变,提高机体免疫,降低死亡率,恢复肠道绒毛形态及菌群平衡,并通过增强与肠道完整性和肠道健康相关的蛋白质表达来减少肠道损伤,提高鸡的健康状态及生长性能[50-52]。
2.2 抗菌肽在鸭养殖中的应用在饲粮中添加抗菌肽对鸭生产性能的促进作用与对猪和鸡的促进作用类似,主要体现在对生长性能、肠道菌群和血液生化指标等的影响上。例如,陈晓生等[53]在肉鸭基础饲粮中添加蚕抗菌肽AD-酵母液体制剂,结果提高了肉鸭的日增重、采食量及净肉率,降低了腹脂率,对料重比没有显著影响。在肉鸭基础饲粮中添加抗菌肽可降低肠道大肠杆菌和乳酸菌的数量,而添加金霉素没有显著抑制大肠杆菌的作用,但可显著降低肠道乳酸菌的数量,因此抗菌肽对鸭肠道菌群在的调节作用优于抗生素[54]。此外,在肉鸭基础饲粮中添加抗菌肽还可提高血清中胰岛素样生长因子-1(IGF-1)及三碘甲状腺原氨酸(T3)的含量,降低四碘甲状腺原氨酸(T4)的含量[55]。
3 抗菌肽在反刍动物生产中的应用截止目前,抗菌肽在反刍动物生产中的应用研究较少,仅见在羊生产中的少量应用研究。抗菌肽添加到羊饲粮中对羊的增益作用体现在多个方面。例如,杨颜铱等[56]在川中黑山羊普通精料中添加苍蝇抗菌肽和猪防御素的混合物,结果显示,添加抗菌肽组与普通精料组相比,黑山羊在第20、40和60天的体重均有一定程度的增加,平均日增重在整个试验期间显著提高。此外,抗菌肽的添加对山羊血清免疫球蛋白(IgA、IgG、IgM)、细胞因子[白细胞介素-2(IL-2)、IL-6、白细胞介素-10(IL-10)、白细胞介素-12(IL-12)、γ-干扰素(IFN-γ)、TNF-α]、补体[补体3(C3)、补体4(C4)]及生长激素[促肾上腺皮质激素(ACTH)、T3、T4、IGF-1]含量均有不同程度的提高,这表明饲喂山羊抗菌肽可增强其机体的免疫应答,提高其预防疾病的能力,并可增强山羊的新陈代谢,促进消化吸收及蛋白质沉积。
抗菌肽在一些条件下还可以影响山羊瘤胃中纤毛虫的种群结构。例如,刘旗等[57]在川中黑山羊的精料中添加3 g/kg复合抗菌肽,发现抗菌肽对山羊瘤胃微生物群落的丰富度、均匀度及多样性指数均无显著影响,这表明抗菌肽不影响瘤胃真核生物多样性。在属水平上,复合抗菌肽组与正常精料组相比,山羊瘤胃中头毛属(Ophryoscolex)纤毛虫的数量显著增高,内毛属(Entodinium)纤毛虫的数量降低。但是当饲喂双倍精料时,抗菌肽的额外添加对纤毛虫各种属数量的影响不显著。Liu等[58]研究表明,在幼山羊饲粮中添加复合抗菌肽可增加瘤胃内丝状杆菌属、厌氧弧菌属、解琥珀酸菌属和头毛属纤毛虫的数量,并显著提高幼山羊体增重、平均日增重和肠道果胶酶、木聚糖酶及脂肪酶活性。
4 小结抗生素在预防动物疾病、调节免疫、促进生长等方面的作用尤为重要。然而,目前“无病、防病”观念在养殖行业中盛行,导致大部分抗生素不顾实际生产的需要盲目添加[59-60],由此造成抗生素的滥用和抗生素残留,继而引发细菌耐药性、环境污染等诸多问题[61-63]。养殖业抗生素滥用造成的细菌耐药性问题已经严重影响人类的健康与生命安全[64]。许多国家已经全面禁止或部分限制抗生素在动物饲粮中的应用,我国也已禁止在动物饲粮中添加除中草药外的所有促生长类药物饲料添加剂[65]。
抗菌肽在动物生产中展现出了替代抗生素的潜力。抗菌肽作为饲料添加剂添加到畜禽饲粮中时具有诸多优点:1)抗菌肽可提高畜禽的生产性能,增强机体免疫,缓解肠道炎症,改善肠道菌群,维护肠道健康;2)抗菌肽可有效防治疾病,消除应激反应带来的负面影响;3)抗菌肽为小分子多肽物质,杀菌效率高,不易产生耐药性,排放到环境中易降解,无污染;4)目前利用基因工程菌已成功发酵表达抗菌肽,抗菌肽的产业化和成本问题得到很好的解决。
但是,抗菌肽在畜禽生产中的应用也面临着诸多问题:1)抗菌肽种类繁多,杀菌效果和功能不尽相同,添加到畜禽饲粮中对畜禽产生的效果参差不齐,有的甚至会产生相反的效果;2)抗菌肽在畜禽体内的作用机制还不明朗;3)大部分的天然抗菌肽还存在着活性低、毒性大等问题;4)至关重要的是,抗菌肽作为多肽物质极易被畜禽胃肠道蛋白酶降解而丧失生物学功能,抗菌肽的稳定性问题亟需解决。综上可知,目前抗菌肽在养殖业中的应用还处于试验探索阶段,今后还需付出诸多努力解决上述问题,为抗菌肽在动物生产中的应用打下坚实基础。
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