CN107075460B - 具有增强免疫及抗病毒活性的丁酸梭菌菌株及其用途 - Google Patents
具有增强免疫及抗病毒活性的丁酸梭菌菌株及其用途 Download PDFInfo
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- CN107075460B CN107075460B CN201680003213.7A CN201680003213A CN107075460B CN 107075460 B CN107075460 B CN 107075460B CN 201680003213 A CN201680003213 A CN 201680003213A CN 107075460 B CN107075460 B CN 107075460B
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Abstract
本发明提供具有增强免疫及抗病毒活性的丁酸梭菌(Clostridium butyricum)菌株、含有所述菌株或其培养液作为有效成分的增强免疫及抗病毒用组合物、益生菌组合物、抗菌用组合物、丁酸或乙酸生产用组合物及包括培养所述菌株的步骤的丁酸或乙酸的生产方法。
Description
技术领域
本发明涉及具有增强免疫及抗病毒活性的丁酸梭菌(Clostridium butyricum)菌株及其用途,更详细地,涉及具有增强免疫及抗病毒活性的丁酸梭菌菌株、含有所述菌株或其培养液作为有效成分的增强免疫及抗病毒用组合物、益生菌组合物、抗菌用组合物、丁酸(butyric acid)或乙酸(acetic acid)生产用组合物及包括培养所述菌株的步骤的丁酸或乙酸的生产方法。
背景技术
免疫大体上分为从出生时就带有的先天免疫(innate immunity)和在后天通过适应生活而获得的获得性免疫(acquired immunity)。先天免疫也被称为“自然免疫”,具有对抗原进行非特异性反应的特征。作为先天性免疫体系,则包括阻断抗原侵入的皮肤、粘液组织、酸性的胃酸、存在于血液中的补体(complement)类及抗微生物肽和包含Toll样受体(Toll like receptor,TLR)在内的模式识别受体(Pattern Recognition Receptors)等,作为细胞,则有担任吞噬作用的巨噬细胞(macrophage)和多形核白细胞(polymorphonuclear leukocyte)、能够杀灭感染细胞的K细胞等。实际上,大部分的病原体感染是通过该先天免疫在初期就被防御。
先天免疫系统基本上分为自身和非自身先天免疫。即,通过区分自身和病原体来进行识别,而被识别为非自身的要素具有固有的分子生物化学特性,将其称为病原体相关分子模式(Pathogen-Associated Molecular Pattern,PAMP),将识别其的受体称为模式识别受体(Pattern Recognition Receptor,PRR)。到目前为止已知的PRR可以分为四种,其为Toll样受体(Toll like receptor,TLR)、RIG-I-样解旋酶(RIG-I-like helicase,RLH)、NOD样受体(Nod-like receptor,NLR)及C型凝集素受体(C-type lectin receptor,CLR)等。各个PRR根据所识别的PAMP的特异性而显示出差异,并在先天免疫系统的活化机理方面起到开始的作用。
在活体内先天性防御免疫系统中,作为对于病毒感染的防御机理,最近最受重视的研究领域为通过干扰素(interferon)诱导的先天性免疫领域,这种干扰素介导免疫的活化可以成为对于多种病毒性传染病病原体的根本性预防方法。因此,正在活跃地展开对于干扰素活化机理方面的研究,以及能够诱导干扰素的免疫调节制剂的开发研究。
此外,作为病原体感染所引起的先天免疫的防御机制之一,则会分泌免疫因子(炎症细胞因子),并通过这些因子诱发炎症反应,从而形成对于病原体的防御。因此,诱导适当水平的炎症反应也可以成为预防及治疗多种传染病病原体的方法,开发研究能够诱导其的免疫增强制剂是必要的。
病毒(virus)在拉丁语中是指毒性物质,表示能够通过细菌滤纸(0.22μm)的一组感染型病原性颗粒。就病毒而言,根据宿主细胞的种类可以分为噬菌体、植物病毒、动物病毒,根据核酸的种类可以分为DNA病毒和RNA病毒。最近,作为病毒疾病的甲型H1N1流感、禽流感(AI)及口蹄疫等多种病毒疾病在社会上引起很大问题,关于应对病毒疾病的有效对策的苦恼正在社会上引起很大的关注。
目前,用于预防病毒性疾病的最好方法为接种疫苗。尽管如此,就RNA病毒所引起的疾病而言,大体上多种病毒血清型(亚型)的生成等引发的疫苗的效率性问题正在成为重要的问题,因此,能够解决疫苗问题的病毒预防用抑制剂的开发和普及是非常重要的事项,为此,尤其是通过刺激活体内先天性免疫系统来提高个体免疫力的预防制剂的发掘及开发可以成为重要的制剂开发方法,其中所述活体内先天性免疫系统是对于病毒的初期防御系统。作为通过刺激活体内先天性免疫系统来提高个体免疫力的方法,也可以摄取具有免疫调节作用的食品,作为这种功能性食品材料有益生菌正在市售。被利用为益生菌的代表性微生物有乳酸杆菌、酪酸菌、杆菌、酵母菌及霉菌等,作为乳酸杆菌,则可以列举如属于乳杆菌属、乳球菌属、链球菌属、片球菌属、肠球菌属等的种属,作为酪酸菌具代表性的为丁酸梭菌。据报告益生菌分布在人及动物的肠内,显示出抑制肠内有害微生物的生长、治疗异常发酵、降低血中的胆固醇、增强免疫功能等效果,还具有抗癌作用。为了使人摄取这种益生菌来增强健康,含乳酸杆菌的发酵乳制品及整肠剂正在被商用化而广泛地被饮用或食用。最近,报告有通过乳酸杆菌来抑制病毒感染的研究结果。据报告摄取加入了两岐双岐杆菌(Bifidobacterium bifidum)和嗜热链球菌(Streptococcus thermophilus)的奶粉对预防因轮状病毒引起的幼儿腹泻症具有效果,还报告有能够抑制禽流感病毒增殖的源于植物的乳酸杆菌。此外,乳酸杆菌作为发酵产业的代表性微生物,对乳酸杆菌的大部分研究主要是针对具有耐酸性、耐胆汁酸性及有害微生物抑制活性的乳酸杆菌进行的。
单纯疱疹病毒(HSV)是引起以充满透明液体的水泡形态表现出的、伴有疼痛的皮肤或黏膜病变的原因。单纯疱疹病毒(HSV)1型(HSV-1)主要感染口、脸及眼睛。单纯疱疹病毒(HSV)2型(HSV-2)主要感染生殖系统及臀部。但是,1型及2型血清型各自可以在所有的部位引起感染。由单纯疱疹病毒(HSV)引起的一次感染一般在感染部位引起微弱的发热病变。治疗时间平均为8~12天,在此期间,病毒移动至神经节,并在该处以潜伏状态存在。潜伏状态的病毒可以因包括身体上或情感上的压力、冷、热、免疫功能降低或不明原因等在内的各种原因而再次被活化。如果被活化,则由此引发二次感染。
水泡性口炎病毒(VSV)是会感染大部分的哺乳类细胞,并表达被感染细胞的全部蛋白质中的最多60%的病毒蛋白质的负链(negative stranded)RNA病毒。自然性地,VSV会感染猪、牛和马,并在口和足周围引起水泡病(vesicular disease)。虽然报告有关于由VSV引起的人体感染,但VSV对人不会引起严重的症状。
流感病毒属于正粘病毒科(Orthomyxoviridae),是具有PB2、PB1、PA、HA、NP、NA、M及NS8个负义RNA片段的病毒。其中,形成外壳蛋白的两个蛋白质血凝素(hemagglutinin:以下简称为“HA”)和神经氨酸苷酶(neuraminidase,以下简称为“NA”)是诱导免疫抗体的重要免疫原,它们具有通过抗原的大/小变异(antigenic shift and drift(抗原性转换和漂移))过程来进行变形的特征。这种流感病毒的变化也能够避免对于同一亚种内的其它流感病毒形成的免疫,通常,由流感病毒诱导的免疫会在短时间内消失,因此,对于在每个时期被预测为会流行的病毒需要诱导新的免疫。
新城疫(Newcastle disease)是对家禽来说是致命且传染性强的第一类家畜传染病,如果未接种疫苗的鸡被感染,则会导致100%的死亡率,如果未进行适当的疫苗接种,则会引起呼吸系统及消化系统症状,并降低蛋鸡的产蛋率,是引起经济性损害的致命性疾病。虽然每年都会发布注意疾病发生的公告,但其发生仍然在持续增加,并呈现出在全国发生的趋势,对养鸡农户带来很大的损失。新城疫的主要症状是最初为嗜睡,并出现鼻涕、咳嗽等呼吸系统症状,最后引起绿色腹泻至死亡。此外,在未接种适当的疫苗的情况下,疫苗抗体滴度低的蛋鸡或种鸡的产蛋率会降低或终止,即使进行了预防接种,但在接种时期或方法不当而导致抗体滴度不高的鸡的情况下,还会出现腿部和颈部出现麻痹的神经症状。
此外,韩国公开专利第2010-0044472号中公开了“起到肠内有害细菌抑制能力和增强免疫作用的丁酸梭菌IDCC9207白米发酵物”,韩国公开专利第2013-0028279号中公开了“新型丁酸生产菌株”,但是完全没有公开本发明中的具有增强免疫及抗病毒活性的丁酸梭菌菌株及其用途方面的内容。
发明内容
要解决的技术问题
本发明是基于上述要求而提出的,本发明中从成人和幼儿的粪便中分离了2种丁酸梭菌(Clostridium butyricum)菌株,并确认了所述2种菌株对于多种RNA病毒及DNA病毒显示出优异的抗病毒活性。不仅如此,还确认了对于有害细菌的抗菌活性、耐酸性及耐胆汁性、抗生素耐性及肠内粘附性优异,因此其不仅可以用于抗病毒,还可以非常有效地用作益生菌或用于抗菌。此外,确认了所述2种菌株生产丁酸(butyric acid)和乙酸(aceticacid),因此还可以用于生产丁酸或乙酸,从而完成了本发明。
技术方案
为了解决上述技术问题,本发明提供具有增强免疫及抗病毒活性的丁酸梭菌(Clostridium butyricum)菌株。
此外,本发明提供含有所述菌株或其培养液作为有效成分的增强免疫及抗病毒用组合物。
此外,本发明提供含有所述菌株或其培养液作为有效成分的益生菌组合物。
此外,本发明提供含有所述菌株或其培养液作为有效成分的抗菌用组合物。
此外,本发明提供含有所述菌株或其培养液作为有效成分的丁酸(butyric acid)或乙酸(acetic acid)生产用组合物。
此外,本发明提供包括培养所述菌株的步骤的丁酸或乙酸的生产方法。
发明的效果
根据本发明能够获得免疫及抗病毒活性优异的新型丁酸梭菌菌株,并且在利用本发明的菌株及其培养液时,可以在抗病毒用组合物、益生菌组合物、抗菌用组合物、丁酸(butyric acid)或乙酸(acetic acid)生产用相关的产业中有效使用。
附图说明
图1示出了本发明中分离的菌株丁酸梭菌(Clostridium butyricum)Fb5-3的16SrRNA基因碱基序列。
图2示出了本发明中分离的菌株丁酸梭菌S-45-5的16S rRNA基因碱基序列。
图3为本发明中分离的菌株丁酸梭菌Fb5-3的酪酸及有机酸分析结果。
图4为本发明中分离的菌株丁酸梭菌S-45-5的酪酸及有机酸分析结果。
图5为利用小鼠巨噬细胞系Raw264.7细胞分析本发明的S-45-5菌株对于水泡性口炎病毒(Vesicular stomatitis virus,VSV)(1.0MOI)的抗病毒性的结果。
图6为利用小鼠巨噬细胞系Raw264.7细胞分析本发明的S-45-5菌株对于流感病毒(Influenza virus,PR8)的抗病毒性的结果。
图7为利用人胚肾细胞HEK293T细胞分析本发明的S-45-5菌株对于水泡性口炎病毒(VSV)(0.01MOI)的抗病毒性的结果。
图8为利用人胚肾细胞HEK293T细胞分析本发明的S-45-5菌株对于单纯疱疹病毒(Herpes simplex virus,HSV)(3.0MOI)的抗病毒性的结果。
图9为利用小鼠巨噬细胞系Raw264.7细胞分析本发明的S-45-5菌株对于新城疫病毒(Newcastle disease virus,NDV)(1.0MOI)的抗病毒性的结果。
图10为利用小鼠巨噬细胞系Raw264.7细胞分析本发明的S-45-5菌株对于单纯疱疹病毒(Herpes simplex virus,HSV)(3.0MOI)的抗病毒性的结果。
图11为以Raw264.7细胞及HEK293T细胞为对象,对本发明的S-45-5菌株的诱导先天免疫因子(促炎细胞因子&干扰素(pro-inflammatory Cytokine&Interferon))的功效进行验证的结果。
图12为对小鼠巨噬细胞系中的S-45-5菌株的诱导抗病毒相关基因(IFN-β、ADAR1、GBP1、ISG20、ISG56、Mx1、OAS-1β、P56、PKR、ISG15、OAS)的表达进行验证的结果。
图13为对小鼠巨噬细胞系中的S-45-5菌株的活化抗病毒相关信号传递分子进行验证的结果。
图14为在小鼠中进行的S-45-5菌株的抑制流感病毒感染的实验结果。
图15示出了在小鼠中进行的S-45-5菌株的诱导细胞因子和IgA分泌的实验(DPT是感染后的天数(Day Post-Infection))。
图16为利用Raw264.7细胞分析本发明的Fb5-3菌株对于水泡性口炎病毒(VSV)(1.0MOI)的抗病毒性的结果。
图17为利用Raw264.7细胞分析本发明的Fb5-3菌株对于流感病毒(PR8)(1.0MOI)的抗病毒性的结果。
图18为利用Raw264.7细胞分析本发明的Fb5-3菌株对于新城疫病毒(NDV)(1.0MOI)的抗病毒性的结果。
图19为利用Raw264.7细胞分析本发明的Fb5-3菌株对于单纯疱疹病毒(HSV)(3.0MOI)的抗病毒性的结果。
图20为利用HEK293T细胞分析本发明的Fb5-3菌株对于水泡性口炎病毒(VSV)(0.01MOI)的抗病毒性的结果。
图21为利用HEK293T细胞分析本发明的Fb5-3菌株对于单纯疱疹病毒(HSV)(3.0MOI)的抗病毒性的结果。
图22为以Raw264.7细胞为对象,对本发明的Fb5-3菌株的诱导先天免疫因子(促炎细胞因子&干扰素)的功效进行验证的结果。
图23为对本发明中分离的两种菌株的耐胆汁性进行调查的结果。
具体实施方式
为了实现上述目的,本发明提供具有增强免疫及抗病毒活性的丁酸梭菌(Clostridium butyricum)菌株。
本发明一实施方式的菌株中,所述丁酸梭菌菌株具有抗菌性、耐酸性及耐胆汁性,可以是生产丁酸(butyric acid;酪酸)及乙酸(acetic acid)的菌株,但并不限定于此。
本发明是从成人和幼儿的粪便中分离出菌株,并在其中分离出对病毒的抗病毒活性优异的菌株,将其鉴定为丁酸梭菌。所述丁酸梭菌菌株可以是丁酸梭菌Fb5-3菌株(保藏编号为KCTC12753BP)或丁酸梭菌S-45-5菌株(保藏编号为KCTC12754BP),于2015年02月03日保藏于韩国生命工学研究院。
此外,本发明提供含有所述菌株或其培养液作为有效成分的增强免疫及抗病毒用组合物。所述增强免疫及抗病毒用组合物可以利用为增强免疫及抗病毒用药物组合物或健康功能食品组合物。
所述组合物为增强免疫及抗病毒用药物组合物的情况下,可以含有药学上可接受的载体、赋形剂或稀释剂,例如,可以含有填充剂、膨胀剂、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂、甜味剂、芳香剂、保存剂等。作为药学上可接受的载体、赋形剂或稀释剂的代表性例子,则可以列举如乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、麦芽糖醇、淀粉、明胶、甘油、阿拉伯树胶、褐藻胶、磷酸钙、碳酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油、丙二醇、聚乙二醇、植物性油、可注射的酯、Witepsol、聚乙二醇(Macrogol)、吐温(tween)61、可可脂、月桂脂等。本发明的增强先天免疫及抗病毒用药物组合物可以为选自片剂、丸剂、散剂、颗粒剂、胶囊剂、悬浮液、乳液、糖浆剂、气雾剂、外用剂、栓剂及注射剂中的形态。药物组合物的制剂化方法可以通过技术领域中公知的常规方法来实施,并不受特别的限定。
“抗病毒(antiviral)”的意思是指在一定浓度下减少、防止、抑制或去除病毒的生长或存活的能力。
本发明一实施方式的抗病毒用组合物中,所述病毒可以是选自正粘病毒科(Orthomyxoviridae)、弹状病毒科(Rhabdoviridae)、副粘病毒科(Paramyxoviridae)及疱疹病毒科(Herpesviridae)中的一种以上的病毒。优选地,所述正粘病毒科(Orthomyxoviridae)可以为流感病毒(Influenza virus),弹状病毒科(Rhabdoviridae)可以为水泡性口炎病毒(Vesicular stomatitis virus),副粘病毒科(Paramyxoviridae)可以为新城疫病毒(Newcastle disease virus),疱疹病毒科(Herpesviridae)可以为单纯疱疹病毒,但并不限定于此。
此外,本发明提供含有所述菌株或其培养液作为有效成分的益生菌组合物。
本发明的丁酸梭菌Fb5-3菌株、丁酸梭菌S-45-5菌株或其培养液各自的肠细胞附着性、耐酸性及耐胆汁性优异,抗生素耐性转变的危险低,抑制肠内有害的病原性细菌,显示出抗病毒及增强免疫的效果,因此显著性地满足作为益生菌所需具备的所述的所有条件,因此可以有效地用作益生菌组合物。
本发明的组合物可以通过常规的益生菌组合物的制备方法来制备,通常,可以为冷冻干燥或胶囊化的形态,或者可以为培养悬浮液或干燥粉末形态。此外,可以在作为主成分的所述丁酸梭菌Fb5-3菌株、丁酸梭菌S-45-5菌株或其培养液的有效量中,选择一种或两种以上的药学上可接受的常规载体或一种或两种以上的添加剂来制备成常规剂型的组合物。
载体可以使用选自稀释剂、润滑剂、粘合剂、崩解剂、甜味剂、稳定剂、防腐剂中的一种或两种以上,添加剂可以使用选自香料、维生素类、抗氧化剂中的一种或两种以上。
在本发明中,载体和添加剂只要是药学上可接受的均可以使用,具体地,稀释剂优选为乳糖(乳糖一水合物(lactose monohydrate))、海藻糖(Trehalose)、玉米淀粉(cornstarch)、大豆油(soybean oil)、微晶纤维素(microcrystalline cellulose)或甘露醇(D-甘露醇(D-mannitol)),润滑剂优选为硬脂酸镁(magnesium stearate)或滑石(talc),粘合剂优选选自聚乙烯吡咯烷酮(PVP:polyvinylpyrrolidone)或羟丙基纤维素(HPC:hydroxypropylcellulose)。此外,崩解剂优选选自羧甲基纤维素钙(Ca-CMC:carboxymethylcellulose calcium)、羟基乙酸淀粉钠(sodium starch glycolate)、波拉克林钾(polacrilin potassium)或交联聚乙烯吡咯烷酮(cross-linkedpolyvinylpyrrolidone),甜味剂选自白糖、果糖、山梨醇(sorbitol)或阿斯巴甜(aspartame),稳定剂选自羧甲基纤维素钠(Na-CMC:carboxymethylcellulose sodium)、β-环糊精(β-cyclodextrin)、白蜂蜡(white bee's wax)或黄原胶(xanthan gum),防腐剂优选选自对羟基苯甲酸甲酯(methyl p-hydroxy benzoate,methylparaben)、对羟基苯甲酸丙酯(propyl p-hydroxybenzoate,propylparaben)或山梨酸钾(potassium sorbate)。
此外,在接种所述丁酸梭菌Fb5-3菌株、丁酸梭菌S-45-5菌株并进行培养而获得的菌株培养物中进一步接种具有益生菌活性的微生物并进行培养的菌株培养物可以作为具有益生菌活性的益生菌施用于动物或与食品、药品、动物药品或乳酸杆菌剂一起施用于动物,优选地,用作家畜的饲料添加剂或辅助饲料,将所述益生菌供给于猪时,作为初乳中含有的丰富的营养素和有效生理活性物质,可以增加猪的增重率,并可以使断奶仔猪不会发生腹泻。
此外,本发明提供含有所述菌株或其培养液作为有效成分的抗菌用组合物。
“抗菌(antimicrobial)”是指在一定浓度下减少、防止、抑制或去除细菌的生长或存活的能力。
本发明一实施方式的抗菌用组合物中,所述抗菌性可以为对于选自肠杆菌属(Enterobacter sp.)、假单胞菌属(Pseudomonas sp.)、弧菌属(Vibrio sp.)、肠杆菌属(Enterobacter sp.)及梭杆菌属(Fusobacterium sp.)中的一种以上的抗菌性,优选地,可以为对于选自阴沟肠杆菌(Enterobacter cloacea)、铜绿假单胞菌(Pseudomonasaeroginosa)、副溶血性弧菌(Vibrio parahaemolyticus)、产气肠杆菌(Enterobacteraerogenes)及变形梭杆菌(Fusobacterium varium)中的一种以上的抗菌性,但并不限定于此。
本发明一实施方式的抗菌用组合物中,所述组合物可以为食品、食品添加剂、饲料或饲料添加剂形态,所述食品可以选自乳制品(牛奶、豆乳、加工牛奶)、发酵乳(液状酸奶、糊状酸奶)、功能饮料、肉类、香肠、面包、巧克力、糖果类、点心类、饼干类、披萨、拉面、口香糖类、冰淇淋类、汤、饮料、酒精饮料及维生素复合剂,但并不限定于此。
本发明的食品可以包括功能性食品,本发明的功能性食品中除了所述有效成分之外,根据需要还可以进一步含有多种辅助成分。在本发明的功能性食品的情况下,可以包含维生素A、维生素B1、维生素B2、维生素B3、维生素B6、维生素B12、叶酸(folic acid)、维生素C、维生素D3、维生素E等维生素类,以及铜、钙、铁、镁、钾、锌等矿物质或乳酸杆菌等。
此外,在本发明的功能性食品中,健康饮料可以像常规饮料一样包含各种香味剂或天然碳水化合物等附加成分。作为香味剂,则可以列举如奇异果甜蛋白、甜菊提取物等天然甜味剂,或者如糖精、阿斯巴甜等合成甜味剂等。作为天然碳水化合物,则可以列举如葡萄糖、果糖等单糖类,麦芽糖、蔗糖等二糖类,糊精、环糊精等多糖类,木糖醇、山梨醇、赤藓糖醇等糖醇类等。
将在本发明的培养菌株的步骤中获得的所述菌株或其培养液用作食品添加剂的情况下,可以直接添加所述菌株或其培养液,或者可以与其它食品或食品成分一起使用,并可以根据常规方法适当使用。有效成分的混合量可以根据其的使用目的(预防、健康或治疗性处置)来适当地确定。
本发明的饲料添加剂是以一定比例添加到基础饲料中。所述基础饲料的主成分可以由玉米、大豆粕、乳清、鱼粉、糖蜜、盐、维生素预混料及矿物质预混料等组成。维生素预混料可以由维生素A、维生素D、维生素E、核黄素及烟酸组成,矿物质预混料可以由锰、铁、锌、钙、铜、钴及硒等组成。所述饲料是家畜的饲料,可以包括肉鸡饲料、养猪饲料或养牛饲料等,但并不限定于此。
此外,本发明提供含有所述菌株或其培养液作为有效成分的丁酸(butyric acid)或乙酸(acetic cid)生产用组合物。
此外,本发明提供包括培养所述菌株的步骤的丁酸或乙酸的生产方法。培养本发明的菌株的方法可以根据本领域通常利用的方法来培养,并不受特殊方法的限定。
下面,通过实施例对本发明进行详细的说明。但是,下述实施例仅用于例示本发明,本发明的内容并不受限于下述实施例。
材料及方法
酪酸菌的分离
以厌氧方式从成人和新生儿采集粪便并进行稀释,然后涂抹接种于强化梭菌培养基(Reinforced Clostridial Medium)(RCM,Difco),然后以厌氧方式(厌氧系统(Anaerobic system),H2O:CO2:N2=8:5:88%,Forma Scientific)在37℃下培养48小时。纯分离培养后出现的菌落,在-80℃下保存并用于实验。为了进行鉴定,分离的菌株是通过16SrRNA基因分析来进行鉴定。具体地,为了对各个分离菌株进行菌落样品的16S rDNA扩增,使用正向引物27F(5'-agagtttgatccctcag-3':SEQ ID No:3)和反向引物1492R(5'-ggttaccttgttacgactt-3':SEQ ID No:4),第一次循环是在95℃下实施2分钟,第30次循环是在95℃下实施20秒,在50℃下实施40秒,在72℃下实施1分30秒,最后一次循环是在72℃下实施5分钟及在4℃下实施10分钟的条件实施了聚合酶链反应(Polymerase chainreaction,PCR)。对于PCR产物,通过电泳对扩增的基因(gene)的大小进行一次确认,然后委托BIOFACT公司进行序列分析。
酪酸生成能力的分析
利用气相色谱分析(Gas chromatography,GC)来实施酪酸及有机酸代谢产物分析。使用的试样是将酪酸菌Fb5-3及S-45-5在PYG液体培养基中于37℃下培养48小时的培养上清液,用于分析的标准试剂则使用了乙醇、乙酸、丁醇及丁酸。用0.22μm的过滤器来过滤酪酸菌培养上清液和标准试剂,并与同等量的10%(v/v)的磷酸进行混合,然后将1μl的混合物注入到安装有HP-INNOWax柱(60m×250μm×0.25μm,安捷伦科技公司(AgilentTechnologies))的GC-FID中。氦气是以1ml/分钟的流速用作载气。烘箱温度是设定为以10℃的速度,从50℃增加到170℃。注射器及检测器温度是设定为250℃。
酪酸菌的抗病毒功效验证及细胞毒性试验
利用小鼠巨噬细胞系Raw264.7细胞和在进行增殖的同时显示荧光的GFP-VSV(水泡性口炎病毒(vesicular stomatitis virus)),对酪酸菌实施了抗病毒功效实验。在抗病毒功效实验之前,实施了酪酸菌对于Raw264.7细胞的细胞毒性实验。其结果,通过5×107菌数以下的酪酸菌未能观察到细胞的死亡。然后,为了确定显示出抗病毒活性的最小限度的酪酸菌数,实施了根据酪酸菌数的抗病毒功效实验的结果,在1×103的酪酸菌数中确认了部分的抑制GFP-VSV增殖的酪酸菌,基于此,以1×103的菌数实施了对于125个酪酸菌菌株的抗病毒功效实验。
通过下述方法确认了酪酸菌S-45-5及Fb5-3菌株的对于RNA病毒(水泡性口炎病毒(Vesicular stomatitis virus)、流感病毒(Influenza virus)、新城疫病毒(Newcastledisease virus))、DNA病毒(单纯疱疹病毒(Herpes simplex virus))的抗病毒活性实验。培养小鼠巨噬细胞系Raw264.7细胞和人胚肾细胞HEK293T细胞并用于实验中(Raw264.7细胞为8×105细胞/孔;HEK293T细胞为3×105细胞/孔)。在12孔(well)TC板中接种细胞(Cellseeding),然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用小鼠或人IFN-B(500单位(units)/ml)进行处理。在酪酸菌处理12小时后,接种VSV-gfp(MOI:1.0)、PR8-gfp(MOI:1.0)、NDV-gfp(MOI:1.0)、HSV-gfp(MOI:3.0)。在接种2小时后去除接种液,并用PBS清洗3次,然后替换为添加有10%的FBS的DMEM。在10~12小时后测定病毒感染程度。
此外,通过下述方法实施细胞存活度测定实验。培养小鼠巨噬细胞系Raw264.7细胞和人胚肾细胞HEK293T细胞并用于实验中(Raw264.7细胞为8×105细胞/孔,HEK293T细胞为3×105细胞/孔)。在12孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用小鼠或人IFN-B(500单位/ml)进行处理。在酪酸菌处理12小时后,接种VSV-gfp(MOI:1.0或0.01)、PR8-gfp(MOI:1.0)、NDV-gfp(MOI:1.0)、HSV-gfp(MOI:3.0)。在接种2小时后去除接种液,并用PBS清洗三次,然后替换为添加有10%的FBS的DMEM。在12小时、24小时后,用0.4%的色氨酸蓝进行染色,从而确认细胞死亡。
S-45-5菌株的诱导先天免疫因子(促炎细胞因子&干扰素(pro-inflammatoryCytokine&Interferon))的功效验证
培养小鼠巨噬细胞系Raw264.7细胞和人胚肾细胞HEK293T细胞并用于实验中(Raw264.7细胞为8×105细胞/孔;HEK293T细胞为3×105细胞/孔)。在6孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用脂多糖(lipopolysaccharide,LPS)粉末(100ng/ml)进行处理。在处理后,利用ELISA测定第12小时、第24小时的上清液的IFN-β、TNF-α、IL-6的值。
在小鼠巨噬细胞系中的S-45-5菌株的诱导抗病毒相关基因的表达的验证
培养小鼠巨噬细胞系Raw264.7细胞并用于实验中(Raw264.7细胞为8×105细胞/孔)。在6孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理。处理后,在第12小时时收集细胞,并利用实时荧光定量PCR(real-time qPCR)测定IFN-β和IFN相关基因的mRNA值。
在小鼠巨噬细胞系中的S-45-5菌株的活化抗病毒相关信号传递分子的验证
干扰素(Interefron)或促炎细胞因子(proinflammatory cytokine)等的分泌是对应侵入到体内的病毒的重要的先天免疫的机理因素,为了分泌这些细胞因子,对刺激到细胞的信号产生反应的特异分子的活化是重要的。在上述结果中,酪酸菌诱导了包括免疫细胞及上皮细胞的干扰素等在内的细胞因子的分泌,并且干扰素和IFN-相关基因水平也得到了增加。因此,在本发明中利用特异抗体来确认了细胞内信号传递分子的活化程度。培养小鼠巨噬细胞系Raw264.7细胞并用于实验中(Raw264.7细胞为8×105细胞)。在6孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用脂多糖(lipopolysaccharide,LPS)粉末(100ng/ml)进行处理。处理后,在第0小时、第8小时、第12小时、第24小时时收集细胞,并与对应于各个蛋白质的抗体实施蛋白质印迹,从而确认了与信号传递相关的蛋白质的活化型的磷酸化形态(phosphorylation form)的蛋白质。
在小鼠中的S-45-5菌株的抑制流感病毒感染的实验
为了实施通过口服施用酪酸菌的活体内(in vivo)抗流感功效验证(挑战性试验(Challenge test))试验,按照下述方法实施了实验。使用6周龄的雌性Balb/c小鼠,阴性对照区组是每天口服施用PBS,实验组是每天口服施用S-45-5菌株的酪酸菌(1×103),共施用21天,阳性对照区组是在感染病毒12小时之前通过鼻腔施用IFN-β。在进行预处理后,以5LD50使各个组感染流感(H3N2或H5N2)。在13天期间测定体重变化和致死率。
在小鼠中的S-45-5菌株的诱导细胞因子和IgA分泌的实验
将6周龄的雌性Balb/c小鼠用于实验。每天给小鼠口服施用PBS或S-45-5菌株(1×103),共施用10天或21天。在第10天和第21天时通过鼻腔感染流感病毒(H1N1),然后分别在第12小时、第24小时、第36小时时采集血清、BAL流体(fluid)、小肠液(small intestinalfluid)。通过ELISA来测定IL-6、IFN-β、IgA的分泌量。
Fb5-3菌株的抗病毒活性实验及细胞毒性试验
实施了对于RNA病毒(水泡性口炎病毒、流感病毒、新城疫病毒)、DNA病毒(单纯疱疹病毒)的抗病毒活性实验。培养小鼠巨噬细胞系Raw264.7细胞和人胚肾细胞HEK293T细胞并用于实验中(Raw264.7细胞为8×105细胞/孔;HEK293T细胞为3×105细胞/孔)。将细胞接种到12孔TC板中,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用小鼠或人IFN-B(500单位/ml)进行处理。在酪酸菌处理12小时后,接种VSV-gfp(MOI:1.0)、PR8-gfp(MOI:1.0)、NDV-gfp(MOI:1.0)、HSV-gfp(MOI:3.0)。在接种2小时后去除接种液,并用PBS清洗3次,然后替换为添加有10%的FBS的DMEM。在10~12小时后测定病毒感染程度。
细胞存活度测定实验则按照下述方法来实施。培养小鼠巨噬细胞系Raw264.7细胞和人胚肾细胞HEK293T细胞并用于实验中(Raw264.7细胞为8×105细胞/孔,HEK293T细胞为3×105细胞/孔)。在12孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理,阳性对照区是使用小鼠或人IFN-B(500单位/ml)进行处理。在酪酸菌处理12小时后,接种VSV-gfp(MOI:1.0或0.01)、PR8-gfp(MOI:1.0)、NDV-gfp(MOI:1.0)、HSV-gfp(MOI:3.0)。在接种2小时后去除接种液,并用PBS清洗三次,然后替换为添加有10%的FBS的DMEM。在12、24小时后,用0.4%的色氨酸蓝进行染色,从而确认细胞死亡。
Fb5-3菌株的诱导先天免疫因子(促炎细胞因子&干扰素)的功效验证
培养小鼠巨噬细胞系Raw264.7细胞并用于实验中(8×105细胞/孔)。在6孔TC板中接种细胞,然后使用1×103的数量的酪酸菌处理了添加有1%的FBS的DMEM。阴性对照区是仅使用添加有1%的FBS的DMEM进行处理。阳性对照区是使用脂多糖(lipopolysaccharide,LPS)粉末(100ng/ml)进行处理。在处理后,利用ELISA测定第12小时、第24小时的上清液的IL-6、TNF-α的值。
分离菌株的耐酸性及耐胆汁性
对于耐酸性实验,在用HCl将pH分别调节为1.0~6.0的RCM液体培养基中,将酪酸菌株处理2小时后进行接种,并在37℃下培养48小时后利用吸光度(OD 600)测定存活率。对于耐胆汁性,将细菌-牛胆汁(Bacto oxgall)(Difco)分别以0.3、1.0、3.0%(w/v)的浓度添加到RCM平板培养基中,并在培养酪酸菌株后测定生长度。
分离菌株的有害细菌拮抗能力试验
有害菌主要是与肠内疾病相关,将从KCTC(韩国生命工学研究院微生物资源中心)获得的大肠杆菌KCTC2441、肺炎克雷伯氏菌(Klebsiella pneumoniae)KCTC2208、福氏志贺菌(Shigella flexneri)KCTC22192、阴沟肠杆菌(Enterobacter cloacea)KCTC1685、铜绿假单胞菌(Pseudomonas aeroginosa)KCTC2004、副溶血性弧菌(Vibrioparahaemolyticus)KCTC2729、金黄色葡萄球菌(Staphylococcus aureus)KCTC3881、产气肠杆菌(Enterobacter aerogenes)KCTC2190、艰难梭状芽胞杆菌(Clostridiumdifficile)KCTC5009、空肠弯曲杆菌(campylobacter jejuni)KCTC5327、产气荚膜梭菌(Clostridium perfringens)KCTC3269、变形梭杆菌(fusobacterium varium)KCTC15085等12种菌株和从疾病管理本部获得的大肠杆菌O157、鼠伤寒沙门氏菌(Salmonellatyphimurium)、肠炎沙门氏菌(Salmonella enteritidis)等3种菌株,共15种菌株用作指示菌株。
有害细菌拮抗能力试验是利用纸片(8mm,Yoyo Roshi Kaisha公司,日本)来测定抑制圈的直径(mm,直径)。将培养约24小时的指示菌株的浓度调整为106-7CFU/ml,并涂抹于Mueller-Hinton琼脂(agar)培养基进行干燥,然后将100μl的分离菌株的培养上清液接种到经过灭菌的纸片中培养48小时。上清液是以下述方法准备的,即,将液体培养液调节为pH4及pH6,并用膜(0.22μl气孔大小,赛多利斯(Sartorius),法国)去除菌体来准备。对照区是使用等量的未接种菌的RCM液体培养基,并对抗菌力进行比较。
分离菌株的抗生素敏感性试验
抗生素是使用了卡那霉素(30μg/片(disc))、青霉素(10μg)、先锋霉素(30μg)、克林霉素(2μg)、四环素(30μg)、庆大霉素(10μg)、链霉素(10μg)、氨苄青霉素(10μg)、万古霉素(30μg)等共9种抗生素。对于抗生素试验,在Mueller-Hinton培养基上涂抹分离菌株,使得分离菌株达到106-7CFU/ml,然后将抗生素纸片接种于培养基上。在37℃下培养48小时,然后测定抑制圈的直径(mm,直径),从而根据大小来确认耐性的程度。
分离菌株的促进乳酸杆菌增殖的试验
为了促进乳酸杆菌增殖的试验,选定乳杆菌及双歧杆菌并分析生长效果。使用的分离菌株为植物乳杆菌(Lactobacillus plantarum)K3108、罗伊氏乳杆菌(Lactobacillusreuteri)K3564、唾液乳杆菌(Lactobacillus salivarius)K3600、鼠李糖乳杆菌(Lactobacillus rhamnosus)K3237、副干酪乳杆菌副干酪亚种(Lactobacillus paracaseisubsp.paracasei)K3510、清酒乳杆菌清酒亚种(Lactobacillus sakei subsp.sakei)K3603、长双歧杆菌长亚种(Bifidobacterium longum subsp.longum)K3128、链状双歧杆菌(Bifidobacterium catenulatum)K3221、长双歧杆菌婴儿亚种(Bifidobacterium longumsubsp.infantis)K3249、两岐双岐杆菌(Bifidobacterium bifidum)K3202。将酪酸菌培养液和乳酸杆菌以1:1的比例在MRS液体培养基中混合培养,从而分析乳酸杆菌的CFU(菌落形成单位)/ml。
分离菌株的肠内定着力试验
为了肠内定着力试验,对分离菌株的Caco-2细胞系和HT29细胞系的附着能力进行了了解。将107~109的酪酸菌对细胞系(5.0x105)感染2小时,然后实施实时荧光定量PCR(real-time qPCR)。将各个样品的CT值代入标准曲线,从而测定细菌数量。
实施例1.酪酸菌的分离
为了进行鉴定,分离的菌株是通过PCR来扩增16S rRNA基因,并决定1,400bp的部分碱基序列。使用NCBI的BLAST分析程序对所决定的碱基序列的同源性进行比较的结果,在成人中是Fb5-3(SEQ ID No:1)与丁酸梭菌(Clostridium butyricum)显示出同源性,在新生儿中是S-45-5(SEQ ID No:2)与丁酸梭菌显示出同源性(图1及图2)。
实施例2.酪酸生成能力的分析
对酪酸及有机酸进行分析的结果,Fb5-3及S-45-5两种菌株都是所生成的丁酸最多,其次,确认到生成了乙酸。确认了Fb5-3是生成的丁酸最多为60%,其次生成了32%的乙酸。确认了S-45-5是生成的丁酸最多为56%,其次生成了35%的乙酸(图3及图4)。
实施例3.酪酸菌的抗病毒功效验证及细胞毒性试验
利用小鼠巨噬细胞系Raw264.7细胞和在进行增殖的同时显示荧光的GFP-VSV(水泡性口炎病毒(vesicular stomatitis virus)),对酪酸菌实施了抗病毒功效实验。在抗病毒功效实验之前,实施了酪酸菌对于Raw264.7细胞的细胞毒性实验。其结果,通过5×107菌数以下的酪酸菌未能观察到细胞的死亡。然后,为了确定显示出抗病毒活性的最小限度的酪酸菌数,实施了根据酪酸菌数的抗病毒功效实验的结果,在1×103的酪酸菌数中确认了部分的抑制GFP-VSV增殖的酪酸菌,基于此,以1×103的菌数实施了对于125个酪酸菌菌株的抗病毒功效实验。实施对于125个酪酸菌菌株的抗病毒功效实验的结果,确认了在125个菌株中S-45-5和Fb5-3菌株显示出最大的抗病毒功效(未公开数据)。
此外,如图5~图10所示,为了证明对于作为RNA病毒的水泡性口炎病毒、流感病毒及新城疫病毒和作为DNA病毒的单纯疱疹病毒的酪酸菌(S-45-5)的抗病毒效果,通过在免疫细胞和上皮细胞中的GFP的表达来确认了病毒的增殖程度。其结果,如使用干扰素-β进行预处理的细胞一样,在使用酪酸菌处理的细胞中不仅是RNA病毒的增殖得到了显著减少,而且DNA病毒的增殖也得到了显著减少(参考图5~图10的用病毒滴度(Viral Titer)或病毒复制(Viral Replication)表示的值)。此外,进行细胞毒性实验的结果,显示出由病毒增殖所引起的细胞死亡也得到减少,结果为,证明了通过酪酸菌的抗病毒功效(图5~图10)
实施例4.本发明的S-45-5菌株的诱导先天免疫因子(促炎细胞因子&干扰素)的功效验证
如图11所示,酪酸菌使得Raw264.7细胞和HEK293T细胞中显示出强的诱导先天免疫因子细胞因子及干扰素-β的能力。干扰素-β是与病毒、癌细胞等外部物质进行反应而分泌的细胞因子,在细胞内起到抗癌及抗病毒作用而诱导免疫反应的物质。TNF-α是免疫及炎症反应的介导物质,活化巨噬细胞系,并使B-细胞得到增殖,IL-6是活化B-细胞而加强抗体的生产,从而促进抗原特异性免疫反应的重要的细胞因子。因此,可以知到通过酪酸菌增强了免疫作用,并显示出抗病毒效果(图11)。
实施例5.在小鼠巨噬细胞系中的S-45-5菌株的诱导抗病毒相关基因表达的验证
如图12所示,确认了在免疫细胞Raw264.7细胞中酪酸菌使得与干扰素相关的基因及与抗病毒相关的基因的表达量得到增加。结论为,在通过酪酸菌受到刺激的免疫细胞中,先天免疫的主要基因的转录得到诱导,并且包括由被诱导的主要基因所制备的干扰素的细胞因子能够抑制外部RNA或DNA病毒的复制(图12)。
实施例6.在小鼠巨噬细胞系中的S-45-5菌株的活化抗病毒相关信号传递分子的验证
如图13所示,确认了如使用TLR4配体LPS来处理的Raw264.7细胞一样,在使用酪酸菌处理的细胞中随着时间的经过与干扰素信号传递路径的活化相关的IRF3、TBK1、STAT1分子的磷酸化,并通过p65、ERK、p38等的磷酸化确认了与炎症作用相关的细胞因子的分泌相关的NF-kB信号传递路径的活化(图13)。与对照区的Raw264.7细胞进行比较,并确认了在使用TLR4配体LPS来处理的Raw264.7细胞和使用酪酸菌处理的Raw264.7细胞中,在使用LPS及酪酸菌处理后的第8小时开始形成了IRF3、TBK1、STAT1分子的磷酸化及p65、ERK、p38等的磷酸化,从而确认已形成了干扰素信号传递路径的活化和与炎症作用相关的细胞因子的分泌活化。
实施例7.在小鼠中的S-45-5菌株的抑制流感病毒感染的实验
如图14所示,在受到病毒的攻击后,在对照区组中9天内全部死亡,另一方面,口服施用酪酸菌(S-45-5)的组中仅死亡了20%,还确认了体重变化也得到了恢复。确认了这种结果是通过口服施用酪酸菌使得小鼠的先天免疫得到增强而抑制流感病毒的感染及增殖,从而对小鼠的生存显示出卓越的功效(图14)。
实施例8.在小鼠中的S-45-5菌株的诱导细胞因子和IgA分泌的实验
确认了口服施用酪酸菌的小鼠的血清、支气管肺泡灌洗液(bronchoalveolarlavage fluid,BALF)及小肠内IFN-Β和促炎细胞因子IL-6的分泌量得到增加,并且分泌型IgA得到诱导。结论为,口服施用酪氨酸能够促进血液内、消化系统、呼吸系统中的各种免疫因子的分泌,由此可分析为,酪酸菌对全身的免疫增强显示出卓越的功效(图15)。
实施例9.Fb5-3菌株的抗病毒活性实验及细胞毒性试验
如图16~图21所示,为了证明酪酸菌(Fb5-3)的抗病毒效果,通过免疫细胞和上皮细胞中的GFP的表达来确认了病毒的增殖程度,其结果,如使用干扰素-β进行预处理的细胞一样,在使用酪酸菌处理的细胞中不仅是RNA病毒的增殖得到了显著减少,而且DNA病毒的增殖也得到了显著减少(参考图16~图21的用病毒滴度(Viral Titer)或病毒复制(ViralReplication)表示的值)。此外,进行细胞毒性实验的结果,显示出由病毒增殖所引起的细胞死亡也得到减少,结论为,如S-45-5菌株一样,Fb5-3菌株的抗病毒功效得到了证实(图16~图21)。
实施例10.Fb5-3菌株的诱导先天免疫因子(促炎细胞因子&干扰素)的功效验证
如图22所示,酪酸菌使得免疫细胞Raw264.7细胞中显示出强的诱导先天免疫因子细胞因子的能力。TNF-α是免疫及炎症反应的介导物质,活化巨噬细胞系,并使B-细胞得到增殖,IL-6是活化B-细胞而加强抗体的生产,从而促进抗原特异性免疫反应的重要的细胞因子。因此,可以说通过酪酸菌增强了免疫作用(图22)。
实施例11.分离菌株的耐酸性及耐胆汁性
耐酸性的结果为,两种酪酸菌在pH2下均显示出60%的存活率,在pH3下均显示出90%的存活率。在pH2下显示出60%以上的存活率,从而显示出相当强的耐酸性(表1)。耐胆汁性的结果为,两种酪酸菌均具有能够在含3%的胆汁酸的培养基中生长的程度的耐性,因此耐胆汁酸性高(图23)。
表1
a-,0%;w,60%以下;+,60~90%;++,90%以上
实施例12.分离菌株的有害细菌拮抗能力试验
在未调节pH的培养上清液(pH4)中,Fb5-3菌株显示出对于阴沟肠杆菌(Enterobacter cloacea)、铜绿假单胞菌(Pseudomonas aeroginosa)、副溶血性弧菌(Vibrio parahaemolyticus)、产气肠杆菌(Enterobacter aerogenes)及变形梭杆菌(Fusobacterium varium)具有抗菌力,S-45-5菌株显示出对于铜绿假单胞菌(Pseudomonasaeroginosa)、产气肠杆菌(Enterobacter aerogenes)及变形梭杆菌(Fusobacteriumvarium)具有抗菌力。在调节pH的分离菌株的培养上清液(pH6)中,则未显示出对于病原菌的抗菌力(表2)。被推测为,这些病原性细菌得到抑制的机理是与生成的酪酸和pH的降低及抗菌物质的生成等各种因素相关。
表2
a抑制圈(Inhibition zones)(mm,直径);-,0mm;w+,1mm以下;+,1mm以上
实施例13.分离菌株的抗生素敏感性试验
对抗生素的抑制圈进行分析的结果,两种酪酸菌均对于9种抗生素中的青霉素(10μg/片)、四环素(30μg)、氨苄青霉素(10μg)、万古霉素(30μg)显示出20mm以上的抑制圈,从而显示出最无耐性,对于卡那霉素(30μg)、先锋霉素(30μg)、克林霉素(2μg)、庆大霉素(10μg)显示出20mm以下的抑制圈,从而显示出微弱的敏感性。此外,确认了对于链霉素(10μg)的抗生素显示出强耐性(表3)。
表3
实施例14.分离菌株的促进乳酸杆菌增殖的试验
分析结果显示,对于Fb5-3菌株培养液,显示出植物乳杆菌(L.p lantarum)为53%、鼠李糖乳杆菌(L.rhamnosus)为50%、副干酪乳杆菌副干酪亚种(L.paracaseisubsp.Paracarei)为150%、干酪乳杆菌(L.casei)为25%、链状双歧杆菌(B.catenulatum)为114%的增殖效果。对于S-45-5菌株培养液,显示出植物乳杆菌(L.plantarum)为15%、唾液乳杆菌(L.salivarius)为100%、鼠李糖乳杆菌(L.rhamnosus)为25%、清酒乳杆菌清酒亚种(L.sakei sub.sakei)为76%、链状双歧杆菌(B.catenulatum)为71%的增殖效果。接种了Fb5-3和S-45-5的培养上清液的乳酸杆菌均对清酒乳杆菌清酒亚种(L.sakeisub.sakei)和嗜酸乳杆菌(L.acidophilus)显示出增殖效果(表4)。
表4
a-,0%;w,50%以下;+,50~99%;++,100%以上
实施例15.分离菌株的肠内定着力试验
分离菌株的肠内定着力试验结果为,在感染107CFU/ml的情况下,显示出附着的菌数约为104CFU/ml左右,在增加感染的菌数时,显示出附着的菌数也稍微增加的倾向。在感染107CFU/ml和108CFU/ml的菌株的情况下,在HT29细胞系中显示出59%的附着率,在Caco-2细胞系中显示出65%的附着率,从而在Caco-2细胞系中显示出附着得更多的倾向,但是在感染109CFU/ml情况下,在两个细胞系之间没有统计学显著性差异。
[保藏编号]
保藏机构名称:韩国生命工学研究院
保藏编号:KCTC12753BP
保藏日期:20150203
保藏机构名称:韩国生命工学研究院
保藏编号:KCTC12754BP
保藏日期:20150203
<110> 韩国生命工学研究院
<120> 具有增强免疫及抗病毒活性的丁酸梭菌菌株及其用途
<130> KHP172110189.0
<160> 4
<170> KoPatentIn
<210> 1
<211> 1388
<212> DNA
<213> 丁酸梭菌
<400> 1
nggcgtggcg gcgtgcttac catgcagtcg agcgatgaag ctccttcgga agtggattag 60
cggcggacgg gtgagtaaca cgtgggtaac ctgcctcata gaggggaata gcctttcgaa 120
aggaagatta ataccgcata agattgtagt accgcatggt acagcaatta aaggagtaat 180
ccgctatgag atggacccgc gtcgcattag ctagttggtg aggtaacggc tcaccaaggc 240
gacgatgcgt agccgacctg agagggtgat cggccacatt gggactgaga cacggcccag 300
actcctacgg gaggcagcag tggggaatat tgcacaatgg gggaaaccct gatgcagcaa 360
cgccgcgtga gtgatgacgg ccttcgggtt gtaaaactct gtctttgggg acgataatga 420
cggtacccaa ggaggaagcc acggctaact acgtgccagc agccgcggta atacgtaggt 480
ggcaagcgtt gtccggattt actgggcgta aagggagcgt aggtggatat ttaagtggga 540
tgtgaaatac tcgggcttaa cctgggtgct gcattccaaa ctggatatct agagtgcagg 600
agaggaaagg agaattccta gtgtagcggt gaaatgcgta gagattagga agaataccag 660
tggcgaaggc gcctttctgg actgtaactg acactgaggc tcgaaagcgt ggggagcaaa 720
caggattaga taccctggta gtccacgccg taaacgatga atactaggtg taggggttgt 780
catgacctct gtgccgccgc taacgcatta agtattccgc ctggggagta cggtcgcaag 840
attaaaactc aaaggaattg acgggggccc gcacaagcag cggagcatgt ggtttaattc 900
gaagcaacgc gaagaacctt acctagactt gacatctcct gaattactct gtaatggagg 960
aagccacttc ggtggcagga agacaggtgg tgcatggttg tcgtcagctc gtgtcgtgag 1020
atgttgggtt aagtcccgca acgagcgcaa cccttattgt tagttgctac catttagttg 1080
agcactctag cgagactgcc cgggttaacc gggaggaagg tggggatgac gtcaaatcat 1140
catgcccctt atgtctaggg ctacacacgt gctacaatgg tcggtacaat gagatgcaac 1200
ctcgcgagag tgagcaaaac tataaaaccg atctcagttc ggattgtagg ctgaaactcg 1260
cctacatgaa gctggagttg ctagtaatcg cgaatcagaa tgtcgcggtg aatacgttcc 1320
cgggccttgt acacaccgcc cgtcacacca tgagagttgg caatacccaa agttcgtgag 1380
ctaacccg 1388
<210> 2
<211> 1424
<212> DNA
<213> 丁酸梭菌
<400> 2
gncggngtgc taccatgcag tcgagcgatg aagctccttc gggagtggat tagcggcgga 60
cgggtgagta acacgtgggt aacctgcctc atagagggga atagcctttc gaaaggaaga 120
ttaataccgc ataagattgt agtaccgcat ggtacagcaa ttaaaggagt aatccgctat 180
gagatggacc cgcgtcgcat tagctagttg gtgaggtaac ggctcaccaa ggcgacgatg 240
cgtagccgac ctgagagggt gatcggccac attgggactg agacacggcc cagactccta 300
cgggaggcag cagtggggaa tattgcacaa tgggggaaac cctgatgcag caacgccgcg 360
tgagtgatga cggtcttcgg attgtaaagc tctgtcttta gggacgataa tgacggtacc 420
taaggaggaa gccacggcta actacgtgcc agcagccgcg gtaatacgta ggtggcaagc 480
gttgtccgga tttactgggc gtaaagggag cgtaggtgga tatttaagtg ggatgtgaaa 540
tacccgggct taacctgggt gctgcattcc aaactggata tctagagtgc aggagaggaa 600
aggagaattc ctagtgtagc ggtgaaatgc gtagagatta ggaagaatac cagtggcgaa 660
ggcgcctttc tggactgtaa ctgacactga ggctcgaaag cgtggggagc aaacaggatt 720
agataccctg gtagtccacg ccgtaaacga tgaatactag gtgtaggggt tgtcatgacc 780
tctgtgccgc cgctaacgca ttaagtattc cgcctgggga gtacggtcgc aagattaaaa 840
ctcaaaggaa ttgacggggg cccgcacaag cagcggagca tgtggtttaa ttcgaagcaa 900
cgcgaagaac cttacctaga cttgacatct cctgaattac tctgtaatgg aggaagccac 960
ttcggtggca ggaagacagg tggtgcatgg ttgtcgtcag ctcgtgtcgt gagatgttgg 1020
gttaagtccc gcaacgagcg caacccttat tgttagttgc taccatttag ttgagcactc 1080
tagcgagact gcccgggtta accgggagga aggtggggat gacgtcaaat catcatgccc 1140
cttatgtcta gggctacaca cgtgctacaa tggtcggtac aatgagatgc aacctcgcga 1200
gagtgagcaa actataaaac cgatctcagt tcggattgta ggctgaaact cgcctacatg 1260
aagctggagt tgctagtaat cgcgaatcaa atgtcgcggt gaatacgttc ccgggccttg 1320
tacacacgcc cgtcacacca tgagagttgg cataccaagt tcgtgagcta accgcagagc 1380
agcgacctat ggtaggtcag cgattgnggt gagncgtaac aggg 1424
<210> 3
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 3
agagtttgat ccctcag 17
<210> 4
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 4
ggttaccttg ttacgactt 19
Claims (13)
1.一种丁酸梭菌(Clostridium butyricum)菌株,所述丁酸梭菌菌株为保藏号为KCTC12753BP的丁酸梭菌Fb5-3菌株或保藏号为KCTC12754BP的丁酸梭菌S-45-5菌株。
2.含有权利要求1所述的菌株或其培养液作为有效成分的增强免疫及抗病毒用组合物,所述病毒为流感病毒(Influenza virus)、水泡性口炎病毒(Vesicular stomatitisvirus)、新城疫病毒(Newcastledisease virus)以及单纯疱疹病毒中的一种以上的病毒。
3.含有权利要求1所述的菌株或其培养液作为有效成分的益生菌组合物。
4.含有权利要求1所述的菌株或其培养液作为有效成分的抗菌用组合物,所述菌株为保藏号为KCTC12753BP的丁酸梭菌Fb5-3菌株,所述抗菌用组合物对选自阴沟肠杆菌(Enterobacter cloacea)、铜绿假单胞菌(Pseudomonas aeroginosa)、副溶血性弧菌(Vibrio parahaemolyticus)、产气肠杆菌(Enterobacter aerogenes)及变形梭杆菌(Fusobacterium varium)中的一种以上细菌具有抗菌性。
5.含有权利要求1所述的菌株或其培养液作为有效成分的抗菌用组合物,所述菌株为保藏号为KCTC12754BP的丁酸梭菌S-45-5菌株,所述抗菌用组合物对选自铜绿假单胞菌(Pseudomonas aeroginosa)、产气肠杆菌(Enterobacter aerogenes)及变形梭杆菌(Fusobacterium varium)中的一种以上细菌的具有抗菌性。
6.根据权利要求4或5所述的抗菌用组合物,其特征在于,所述抗菌用组合物为食品、食品添加剂、饲料或饲料添加剂形态。
7.含有权利要求1所述的菌株或其培养液作为有效成分的丁酸或乙酸生产用组合物。
8.包括培养权利要求1所述的菌株的步骤的丁酸或乙酸的生产方法。
9.权利要求1所述的菌株或其培养液在制备增强免疫及抗病毒用组合物中的用途,所述病毒为流感病毒(Influenza virus)、水泡性口炎病毒(Vesicular stomatitis virus)、新城疫病毒(Newcastledisease virus)以及单纯疱疹病毒中的一种以上的病毒。
10.权利要求1所述的菌株或其培养液在制备益生菌组合物中的用途。
11.保藏号为KCTC12753BP的丁酸梭菌Fb5-3菌株在制备抗菌用组合物中的用途,所述抗菌用组合物对选自阴沟肠杆菌(Enterobacter cloacea)、铜绿假单胞菌(Pseudomonasaeroginosa)、副溶血性弧菌(Vibrio parahaemolyticus)、产气肠杆菌(Enterobacteraerogenes)及变形梭杆菌(Fusobacterium varium)中的一种以上细菌具有抗菌性。
12.保藏编号为KCTC12754BP的丁酸梭菌S-45-5菌株在制备抗菌用组合物中的用途,所述抗菌用组合物对选自铜绿假单胞菌(Pseudomonas aeroginosa)、产气肠杆菌(Enterobacter aerogenes)及变形梭杆菌(Fusobacterium varium)中的一种以上细菌的具有抗菌性。
13.根据权利要求11或12所述的用途,其中所述抗菌用组合物为食品、食品添加剂、饲料或饲料添加剂形态。
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PCT/KR2016/002839 WO2016153247A1 (ko) | 2015-03-26 | 2016-03-22 | 면역 증진 및 항바이러스 활성을 가지는 클로스트리디움 부티리쿰 균주 및 이의 용도 |
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WO2018126026A1 (en) | 2016-12-28 | 2018-07-05 | Ascus Biosciences, Inc. | Methods, apparatuses, and systems for analyzing complete microorganism strains in complex heterogeneous communities, determining functional relationships and interactions thereof, and identifying and synthesizing bioreactive modificators based thereon |
US9938558B2 (en) | 2015-06-25 | 2018-04-10 | Ascus Biosciences, Inc. | Methods, apparatuses, and systems for analyzing microorganism strains from complex heterogeneous communities, predicting and identifying functional relationships and interactions thereof, and selecting and synthesizing microbial ensembles based thereon |
EP3314007B1 (en) | 2015-06-25 | 2024-01-24 | Native Microbials, Inc. | Methods, apparatuses, and systems for analyzing microorganism strains from complex heterogeneous communities, predicting and identifying functional relationships and interactions thereof, and selecting and synthesizing microbial ensembles based thereon |
RU2018128578A (ru) | 2016-01-07 | 2020-02-10 | Аскус Байосайенсиз, Инк. | Способы улучшения продукции молока путем введения микробных консорциумов |
CN106591195B (zh) * | 2016-12-29 | 2019-10-08 | 中国科学院水生生物研究所 | 一种适用于水产动物的微生物免疫增强剂及其应用 |
CA3057692A1 (en) | 2017-04-28 | 2018-11-01 | Ascus Biosciences, Inc. | Methods for supporting grain intensive and/or energy intensive diets in ruminants with a synthetic bioensemble of microbes |
WO2018204792A2 (en) | 2017-05-05 | 2018-11-08 | White Dog Labs, Inc. | Single cell protein products and an integrated method for the production of ethanol and single cell protein |
CN108478603B (zh) * | 2018-04-03 | 2020-09-04 | 潍坊华英生物科技有限公司 | 一种灭活丁酸梭菌注射剂 |
CN108342345A (zh) * | 2018-04-27 | 2018-07-31 | 江南大学 | 一种唾液乳杆菌特异性培养基及其应用 |
KR20190127156A (ko) * | 2018-05-03 | 2019-11-13 | 씨제이제일제당 (주) | 항바이러스 및 면역조절 효능을 가지는 락토바실러스 플란타럼 cjlp17 및 이를 포함하는 조성물 |
KR102249897B1 (ko) * | 2019-12-13 | 2021-05-10 | 옥민 | 부티르산 생산능, 유해세균에 대한 항균 활성, 혈전분해 활성, 리폭시게나아제 억제 활성 및 지질과산화물 생성 억제 활성을 가지는 클로스트리디움 부티리쿰 obl_1 균주 및 이의 용도 |
CN115666604A (zh) * | 2020-05-21 | 2023-01-31 | 超级酿造食品公司 | 治疗或预防感染的方法 |
US20240066076A1 (en) * | 2021-03-11 | 2024-02-29 | Miyarisan Pharmaceutical Co., Ltd. | Interferon production promoter |
CN113308396B (zh) * | 2021-05-18 | 2023-03-21 | 上海市公共卫生临床中心 | 一种植物乳杆菌及在制备新冠疫苗免疫增强剂中的应用 |
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