CN107802654A - 灭活乳酸菌在防治牛细菌性疾病药物中的应用 - Google Patents
灭活乳酸菌在防治牛细菌性疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种灭活乳酸菌在制备防治牛细菌性疾病药物中的用途，属于生物医药领域，药物的主要成分是灭活乳酸菌，可以通过将活的乳酸菌经过常规方法灭活制备，灭活乳酸菌静脉给药可以用于牛的各种细菌性疾病的预防、治疗或辅助治疗，具有广阔的应用前景。
Description
技术领域
本发明属于生物医药领域，尤其涉及灭活乳酸菌在防治牛细菌性疾病中的新用途。
背景技术
细菌性疾病对肉牛和奶牛养殖业造成了巨大经济损失。牛的常见细菌性疾病包括：牛布氏杆菌病、奶牛乳房炎、奶牛子宫内膜炎、牛结核病、牛副结核病、牛出血性败血病、牛沙门氏菌病、牛大肠杆菌病、牛支原体病、牛生殖器弯曲杆菌病、牛传染性胸膜肺炎、牛放线菌病等。牛的这些细菌性疾病会导致牛的生产性能下降，母牛流产、产乳下降、肉牛生长缓慢甚至死亡等。其中一些牛的致病菌还可引起人畜共患病(如布氏杆菌、牛型结核分枝杆菌、沙门氏菌)，威胁着人的健康。另外，奶牛发生的乳房炎、子宫内膜炎等疾病，由于细菌耐药性严重而难以治愈。目前，细菌性疾病严重困扰着养牛业的发展。目前临床上，仍多采用抗菌药如β-内酰胺类、喹诺酮类、氨基糖苷类等药物治疗，但随着国家对抗菌药的严格管制和细菌耐药问题严重，抗菌药防治牛细菌性疾病往往失效。中药及其提取物也常用于牛的细菌性疾病的防治，如双黄连口服液、鱼腥草注射液、杨树花口服液、玉屏风散、黄芪多糖等，但疗效很难达到理想效果。因此，寻找新的应对牛细菌性疾病的药物非常重要。
本发明将灭活乳酸菌对牛进行静脉给药可以达到有效防治细菌性疾病的目的。这是一种全新的可用于牛细菌性疾病防治的药物，特别对于牛肉产品和牛奶来说，无有害物质残留，不存在食品安全问题，未来应用前景广阔。另外，这种药物可能会“以不变应万变”，未来也可能用于产生耐药性致病菌的防治。
发明内容
本发明提供了一种全新的可以用于牛细菌性疾病防治的灭活乳酸菌混悬液，这种药物的主要成分为灭活的乳酸菌。该药物通过静脉给药可以有效防治牛细菌性疾病。
灭活乳酸菌在制备防治牛细菌性疾病药物中的用途，对所述的灭活乳酸菌进行革兰氏染色，在油镜下观察，灭活乳酸菌保持完整菌体形态，药物的给药方式为注射给药。所述的保持完整菌体形态是指与灭活前活菌菌体的轮廓和形态基本一致。所说的基本一致实质上是指乳酸菌灭活过程中菌体细胞壁可能会出现轻微变化，比如部分表面成分的流失，但这种变化微乎其微或很少发生。
所述乳酸菌种类包括：(1)乳杆菌属：德氏乳杆菌(L.delbrueckii)、保加利亚乳杆菌(L.bulgaricus)、瑞士乳杆菌(L.helviticus)、嗜酸乳杆菌(L.acidophlus)、格氏乳杆菌(L.gasseri)、唾液乳杆菌(L.salivarius)、植物乳杆菌(L.plantarum)、罗伊氏乳杆菌(L.reuteri)、短乳杆菌(L.brevis)、干酪乳杆菌(L.casei)、发酵乳杆菌(L.fementi)等；(2)片球菌属：如乳酸片球菌(P.acidi1actic)、戊糖片球菌(P.pentasiaceus)、小片球菌(P.parvulus)等；(3)明串球菌属：肠膜明串球菌(L.mesenteroides)及其乳脂亚种(L.cremoris)和葡聚糖亚种(Leuc.dextranicun)、乳酸明串球菌(L.lactis)、酒明串球菌(L.oenos)等；(4)肠球菌属：屎肠球菌(E.faecium)、粪肠球菌(E.faecalis)等；(5)乳球菌属：乳酸乳球菌乳酸亚种(L.lactis subsp.lactis)、乳酸乳球菌乳脂亚种(L.lactissubsp.cremoris)、乳酸乳球菌叶蝉亚种(L.lactis subsp.hordniae)等；(6)链球菌属：乳酸链球菌(S.lactis)、丁二酮乳酸链球菌(S.diacetilactis)、乳酪链球菌(S.creamoris)、嗜热乳链球菌(S.thermophilus)等；(7)双歧杆菌属：两歧双歧杆菌(B.bifidum)、长双歧杆菌(B.longum)、短双歧杆菌(B.breve)、婴儿双歧杆菌(B.infantis)、青春双歧杆菌(B.adolescentis)、动物双歧杆菌(B.animalis)等；(8)其他种属的乳酸菌。
优选的，乳酸菌选自乳酸乳球菌乳酸亚种(拉丁名称：Lactococcus lactissubsp.Lactis，保藏编号：CICC 6246)、植物乳杆菌植物亚种(拉丁名称：Lactobacillusplantarum subsp.Plantarum，保藏编号：CICC 6240)、长双歧杆菌(拉丁名称：Bifidobacterium longum，保藏编号：CICC 6196)、短乳杆菌(拉丁名称：Lactobacillusbrevis，保藏编号：CICC 6239)、屎肠球菌(拉丁名称：Enterococcus faecium，保藏编号：CICC 6049)。灭活乳酸菌为一种或两种以上灭活乳酸菌混合物，注射时，每mL剂量药物中包含灭活乳酸菌完整菌体数量为105—1012个。优选，所述的注射给药为静脉注射给药。
乳酸菌灭活方法包括高温高压灭活、紫外线灭活、化学试剂灭活、辐射灭活等。
防治牛细菌性疾病药物可以制成粉针剂或混悬注射剂。用于本发明的灭活乳酸菌的给药方式包括：静脉推注和静脉滴注等。
本发明采用常规方法灭活了屎肠球菌，发现灭活的屎肠球菌仍然可以进行革兰氏染色，油镜下观察灭活的屎肠球菌与活的屎肠球菌保持一致的菌体轮廓和形态。然后对灭活屎肠球菌生理盐水混悬液进行离心，弃上清留沉淀，提取DNA，采用PCR技术仍可以扩增出16s rDNA基因片段，通过测序还可以进行乳酸菌种类鉴别。进一步研究发现，将灭活屎肠球菌对患有乳房炎的奶牛颈静脉注射给药，可以有效地减轻奶牛乳房炎的症状。研究还发现，将灭活的乳酸乳球菌乳酸亚种对患有乳房炎的奶牛颈静脉注射给药，可以有效地减轻奶牛乳房炎的症状。将灭活的植物乳杆菌植物亚种对患有子宫内膜炎的奶牛颈静脉给药，可以有效地减轻奶牛子宫内膜炎的症状。说明灭活乳酸菌静脉给药可以用于牛细菌性疾病的防治。
本发明的灭活乳酸菌混悬液可以用于牛各种细菌性疾病的防治，包括：牛布氏杆菌病、奶牛乳腺炎、奶牛子宫内膜炎、牛结核病、牛副结核病、牛出血性败血病、牛沙门氏菌病、牛大肠杆菌病、牛支原体病、牛生殖器弯曲杆菌病、牛传染性胸膜肺炎、牛放线菌病等。
灭活乳酸菌混悬液防治牛细菌性疾病的机制目前尚不完全清楚，推测可能的机制是：灭活乳酸菌静脉给药，可能与牛的致病菌发生相互作用，阻断牛的致病菌感染组织器官；也可能灭活乳酸菌静脉给药后经牛机体代谢产生了抗菌物质；或者灭活乳酸菌静脉给药后可激活牛的免疫系统，间接发挥抗菌作用等。
附图说明
图1奶牛患乳房炎照片
图2灭活乳酸菌静脉给药后症状明显减轻照片
图3灭活乳酸菌静脉给药前奶牛乳区肿胀照片
图4灭活乳酸菌静脉给药后乳区肿胀减轻照片
具体实施方式
实施例1
将屎肠球菌(购于中国工业微生物菌种保藏管理中心，拉丁名称：Enterococcusfaecium，保藏编号：CICC 6049)接种于MRS培养基，于37℃温箱培养24小时，然后3000转离心5分钟，去除上层培养液保留沉淀，加入无菌生理盐水清洗沉淀，离心5分钟，重复清洗3次后，加入无菌生理盐水，与沉淀混匀。取一定量的屎肠球菌生理盐水混悬液，于分光光度计690nm处测量其OD值，当用无菌生理盐水稀释的最终浓度的OD值为0.38时，将这样稀释浓度的屎肠球菌生理盐水混悬液作为1倍(1×)浓度，经过THOMA细菌计数板进行细菌计数测定该浓度下每mL混悬液中含有约108个屎肠球菌菌体。取少量的1×浓度的屎肠球菌生理盐水混悬液，进行革兰氏染色，在油镜下观察活菌的形态。此后将配制好的1×浓度的屎肠球菌生理盐水混悬液于121℃、压力0.12MPa，灭活15min，得到灭活屎肠球菌混悬液，取少量灭活屎肠球菌混悬液进行革兰氏染色，在油镜下观察灭活菌体的形态。发现灭活乳酸菌保持完整菌体形态，与其灭活前活菌菌体轮廓和形态一致，灭活前后完整细菌数没有明显变化。
实施例2
某奶牛场，奶牛患乳房炎，主要由金黄色葡萄球菌、链球菌、大肠杆菌、支原体等致病菌感染引起。该患病奶牛的乳汁有絮状物质(参见附图1)，已用过几个兽药厂的抗菌药治疗无明显效果，花费五百多元。使用实施例1制备的20×浓度的灭活屎肠球菌混悬液，给该患病奶牛静脉推注22毫升，第二天又推注20毫升。发现用药两天后乳房炎症状明显减轻，牛奶絮状物消失，手摸肿块变软，肿区变小(参见附图2)。
实施例3
某奶牛场，奶牛患乳房炎，主要由金黄色葡萄球菌、链球菌、大肠杆菌、支原体等致病菌感染引起。该患病奶牛的奶汁稀薄如水，手摸乳区肿胀疼痛，坚实(参见附图3)。将乳酸乳球菌乳酸亚种(购于中国工业微生物菌种保藏管理中心，拉丁名称：Lactococcus lactissubsp.Lactis，保藏编号：CICC 6246)。根据实施例1的方法制备20×浓度的灭活乳酸乳球菌乳酸亚种混悬液，给该奶牛静脉推注25毫升，第二天又推注25毫升。用药4天后奶水明显好转，手摸肿块明显减轻，乳区肿胀症状明显改善(参见附图4)。
实施例4
某奶牛场，奶牛患子宫内膜炎，主要由化脓性放线菌、坏死梭杆菌、拟杆菌、大肠杆菌、溶血性链球菌、变形杆菌、假单胞菌、梭状芽孢杆菌等致病菌感染引起，该患病奶牛子宫内充满炎性分泌物且自动流出。将植物乳杆菌植物亚种(购于中国工业微生物菌种保藏管理中心，拉丁名称：Lactobacillus plantarum subsp.Plantarum，保藏编号：CICC 6240)根据实施例1的方法制备得到20×浓度的灭活植物乳杆菌植物亚种混悬液，给该奶牛颈静脉推注25毫升，第二天又推注25毫升。发现用药3天后不见炎性分泌物流出，经手掏才有一些炎性分泌物，已经大大减少，由此可见效果明显。
Claims (10)
1.灭活乳酸菌在制备防治牛细菌性疾病药物中的用途，其特征在于，对所述的灭活乳酸菌进行革兰氏染色，在油镜下观察，灭活乳酸菌保持完整菌体形态，药物为混悬剂或粉针剂，给药方式为注射给药。
2.根据权利要求1的用途，其特征在于，所述的乳酸菌选自乳杆菌属、肠球菌属、乳球菌属、双歧杆菌属、明串球菌属、链球菌属。
3.根据权利要求1所述的用途，其特征在于，所述乳酸菌选自乳酸乳球菌乳酸亚种(拉丁名称：Lactococcus lactis subsp.Lactis，保藏编号：CICC 6246)、植物乳杆菌植物亚种(拉丁名称：Lactobacillus plantarum subsp.Plantarum，保藏编号：CICC 6240)、长双歧杆菌(拉丁名称：Bifidobacterium longum，保藏编号：CICC 6196)、短乳杆菌(拉丁名称：Lactobacillus brevis，保藏编号：CICC 6239)、屎肠球菌(拉丁名称：Enterococcusfaecium，保藏编号：CICC 6049)。
4.如权利要求1所述的用途，其特征在于，灭活乳酸菌为一种或两种以上灭活乳酸菌混合物。
5.根据权利要求1所述的用途，其特征在于，利用高温高压灭活、紫外线灭活、化学试剂灭活或辐射灭活中的任一种灭活方法得到所述灭活乳酸菌。
6.根据权利要求1-5任一项所述的用途，其特征在于，所述的注射给药为静脉注射给药。
7.根据权利要求6所述的用途，其特征在于，注射时，每ml剂量药物中包含灭活乳酸菌完整菌体数量为105—1012个。
8.根据权利要求7任一项所述的用途，其特征在于，所述防治牛细菌性疾病药物可以制成粉针剂或混悬注射剂。
9.根据权利要求8所述的注射剂，其特征在于，所述的注射剂按照如下方法制备得到：将乳酸菌进行常规液体培养基培养12-36小时后，3000-5000转离心保留沉淀，再将沉淀充分清洗后，配制成所需浓度混悬液，于120-122℃、压力0.1-0.2MPa，灭活15-30min得到灭活乳酸菌注射剂。
10.根据权利要求1-9任一项所述的用途，其特征在于，所述牛细菌性疾病包括：牛布氏杆菌病、奶牛乳腺炎、奶牛子宫内膜炎、牛结核病、牛副结核病、牛出血性败血病、牛沙门氏菌病、牛大肠杆菌病、牛支原体病、牛生殖器弯曲杆菌病、牛传染性胸膜肺炎、牛放线菌病。
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