CN1694954A - 用于降低由螺杆菌引起炎症的乳酸菌的选择和应用 - Google Patents
用于降低由螺杆菌引起炎症的乳酸菌的选择和应用 Download PDFInfo
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- CN1694954A CN1694954A CNA2003801008000A CN200380100800A CN1694954A CN 1694954 A CN1694954 A CN 1694954A CN A2003801008000 A CNA2003801008000 A CN A2003801008000A CN 200380100800 A CN200380100800 A CN 200380100800A CN 1694954 A CN1694954 A CN 1694954A
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Abstract
本发明涉及具有降低胃肠炎症例如幽门螺杆菌炎症的能力经过选择的乳酸杆菌，和源自该菌株的产品，包括用于对人给药以治疗或预防与幽门螺杆菌有关炎症的试剂，和其中所选用菌株已经培育的调制培养基，以及该调制培养基含蛋白质的提取物。
Description
发明背景
发明领域
本发明涉及用于筛选非病原抗炎菌株方法的应用、和使用这类菌株用于治疗和预防由诸如幽门螺杆菌、其它螺杆菌种、和其它引起炎症的胃肠病原体之类胃肠细菌引起的炎症的产品和方法。
现有技术
幽门螺杆菌是一种螺旋形细菌，它定居在胃中，亦在其中通过其产生脲酶的能力以中和胃中的酸。脲酶转化尿素(它在胃中有丰富的供应)为碳酸氢盐和氨，它们是强碱。这将导致在幽门螺杆菌细胞周围存在着云状的酸中和碱，以保护它们不受胃酸的影响。幽门螺杆菌细胞渗入并穿过胃粘液层，附着到胃内膜的上皮细胞上。至少一部分的幽门螺杆菌菌株具有产生毒素的能力。幽门螺杆菌感染会刺激宿主的免疫系统，它会输送白血球、杀伤T细胞和其它抗感染剂到该区域，但是，人体免疫系统在胃的粘液内膜逆转幽门螺杆菌效果时不是有效的。幽门螺杆菌细胞仍存在于该内部中，免疫系统逐步增强其对细胞的响应，如果不存在有用的充分抗炎机制，就会引起炎症。在幽门螺杆菌感染过程中，由宿主上皮树状细胞产生的细胞分裂素(cytokine)细胞间信号蛋白、固有杀伤细胞、T细胞和其它免疫防御细胞，会传播免疫响应到侵袭的病原体。其结果是，宿主嗜中性白细胞被吸引到并渗透胃的上皮细胞，并在整个感染过程中存留在该处。除了别的因素以外，这些细胞会产生活性氧产物，如过氧化物自由基，它们会导致在该上皮细胞中发生氧化响应和随后的上皮细胞死亡、溃疡形成和最终癌发生。幽门螺杆菌还会诱发养分从宿主的泄漏流出胃的上皮细胞，以保持幽门螺杆菌提供养分源，并加剧感染和其后果。幽门螺杆菌能够躲避人体免疫系统，存活于胃中，尽管宿主的免疫响应和这种躲避机理是当前研究的目标。
当前治疗是基于通过抗生素和质子泵抑制剂消灭幽门螺杆菌，而不是企图消除宿主过度免疫响应对感染的影响，例如，使充分抗炎机理更有效，它是本发明的目的。
因此，幽门螺杆菌感染会引起发展中的胃炎、胃溃疡和十二指肠溃疡增加的危险，包括胃溃疡、胃癌、和胃粘膜相关的淋巴组织淋巴瘤。这些问题不是由幽门螺杆菌直接引起的，而是由胃内膜响应幽门螺杆菌的炎症引起的。业已使用多种治疗方法，用来改善胃溃疡和十二指肠溃疡的症状，例如，与抗生素结合，能减少胃中酸产生的治疗方法。新型的防幽门螺杆菌疫苗已经试过，但仅具有有限的成功。业已知道，其它幽门螺杆菌种、以及其它胃肠病原体，会引起胃肠炎症。
在最近研究文章中，研究幽门螺杆菌感染的研究人员得出结论，幽门螺杆菌感染会引起胃粘膜唾液酸(sialylation)作为慢性炎症响应的一部分，并且许多有毒菌株从而更能连接到该发炎部位(Science18：573-578，2002)。
胃内和胃肠道的炎症，可通过称作细胞分裂素的细胞间信号蛋白而得到调节，该细胞分裂素是由上皮细胞中巨噬细胞和树状细胞响应抗原刺激诸如由幽门螺杆菌或其它病原体产生的刺激而产生的。当该上皮细胞与抗原诸如幽门螺杆菌或由其产生的内毒素如LPS接触时，该上皮细胞中的抗原递呈细胞(包括树状细胞)会传播该信号到自然巨噬细胞，它接着以所谓Th-1型响应进行响应，其中，包括TNFα、IL-1、IL-6、IL-12R前发炎细胞分裂素由巨噬细胞产生。这些细胞分裂素反过来刺激固有杀伤细胞、T-细胞和其它细胞产生干扰素γ(IFNγ)，它是炎症的关键培养基。IFNγ会导致发炎响应和上述导致细胞毒性反应的逐步升级。自然巨噬细胞还会以Th-2型响应对抗原进行响应。这种响应受到IFNγ的抑制。这些Th-2型细胞产生抗炎的细胞分裂素，诸如IL-4、IL-5、IL-9和IL-10。
已经知道IL-10能抑制产生IFNγ，从而能抑制免疫响应。Th-1和Th-2之间的平衡和它们各自细胞分裂素产生，决定了对于给定抗原的发炎响应的程度。Th-2型细胞还能经由免疫系统刺激免疫球蛋白的产生。在胃肠道中的抗炎活性，其中存在降低的TNFα水平，与提高的上皮细胞(肠壁内膜完整性)相关，从而，与由胃肠病原体和毒素引起的负作用降低相关联。
大量研究的结果表明，DNA能够对肠上皮细胞发挥抗炎作用，或者，能刺激免疫系统。(Madsen等和Rachmilewitz等各自在《消化疾病期刊(Digestive Disease Week)》，May 19-22，2002，The MosconeCenter，San Francisco的陈述)。
老鼠自发性产生慢性结肠炎，这在无病毒动物中不会发生。老鼠结肠炎与人的克罗恩氏病相似，它是一种慢性严重的胃肠道炎症。克罗恩氏病通常发生在肠内，但也可发生在胃肠道的任何地方。这些情形都需要存在肠道菌群，并且它们都是Th-1中介的-IL-12-依赖形结肠炎。由于起因和症状的相似性，结肠炎的老鼠模型和其它老鼠模型，被用来直接研究发炎响应的成分，并且，以应用于人体的相同机理，被接受用来研究开发对人体胃肠疾病的治疗。
罗伊乳酸杆菌是一种天然存在的动物胃肠道居民，它日常地发现在健康动物的肠内，尽管具有低的pH，有时也存在于人的胃中。已知它具有抗菌活性。例如，参见美国专利5,439,678、5,458,875、5,534,253、5,837,238和5,849,289。当罗伊乳酸杆菌细胞在甘油存在下于厌氧条件下生长时，它们会产生称作无蛋白菌质(reuterin)(β-羟基-丙醛)的抗菌物质。
棒状乳芽孢杆菌(Lactobacillus coryniformis)是一种鲜为人知的乳酸杆菌种，它是人体口腔常见居住者。它可在土壤、肥料和植物体中发现。它已经发现在青贮饲料中和当啤酒变坏时，而且，良好的乳酸生产以及抗真菌活性也有报导。此处所用棒状乳芽孢杆菌MM7分离物(ATCC PTA-4660)，发现存在于人体母乳中。
免疫调制活性还与多种乳酸杆菌有关。尽管一些乳酸杆菌的有效抗菌活性的可能性是已知的，但是，存在于菌株之间它们降低胃肠炎症的能力的实质性差异，以前还不是已知的，对这类菌株的选择也不是已知的。
因此，本发明一个目的是提供乳酸杆菌菌株，对于它们能降低胃肠炎症能力经过选择，例如归因于幽门螺杆菌的炎症。本发明另一个目的是提供含有所述菌株的产品，包括用于人体给药以治疗或预防与幽门螺杆菌有关炎症的试剂，包括调制培养基，其中所述菌株已经长成及其含蛋白质提取物。
其它目的和优点将从下述说明和随后权利要求书变得更加清楚明了。
发明概述
本发明包括对于能降低胃肠炎症能力经过选择的乳酸杆菌菌株，例如这种炎症归因于幽门螺杆菌，和源自所述菌株的产品，包括用于人体给药以治疗或预防与幽门螺杆菌有关炎症的试剂，并包括调制培养基，其中所述菌株已经长成和该调制培养基的含蛋白质提取物。
本发明其它目的和特征将从下述说明和随后权利要求书变得更加清楚明了。
附图简要说明
图1为表示乳酸杆菌调制培养基对由LPS活化巨噬细胞产生的TNFα影响的条形图。45种乳酸杆菌菌株得到测试。
图2为表示在调制培养基存在下各种不同乳酸杆菌株和LPS的巨噬细胞TNFα表达与仅有LPS的巨噬细胞比较的折叠变化的条形图。
发明详细说明及其优选实施例
本发明包括对于能降低胃肠炎症能力经过选择的乳酸杆菌菌株，例如这种炎症归因于幽门螺杆菌。这类菌株包括棒状乳芽孢杆菌MM7、ATCC PTA-4660和罗伊乳酸杆菌MM2-3、ATCC PTA-4659。诸如食品、营养添加剂和配方、医药品或含有源自这些菌株的全部细胞或成分的医疗器械的产品，可按本领域已知方法进行配制，通常包括已知的可吸收载体和乳酸杆菌菌株、或其衍生成分。先前已知的菌株，现在确认具有良好TNFα降低能力，诸如鼠李糖乳酸杆菌GGATCC 53103、罗伊乳酸杆菌ATCC 55730和其它菌株，也可用于上述配方。这些产品是用于人体给药以治疗或预防与幽门螺杆菌有关炎症的试剂。
使用合适细胞分裂素的模型系统，用来确定能降低或提高炎症的因素。在本申请提供的实施例中，一种老鼠巨噬细胞化验，它使用RAW 264.7巨噬细胞(ATCC，Rockville，MD，ATCC # TIB-71)，用来筛选细菌菌株主要是乳酸杆菌，以确定它们对于发炎途径的影响。IL-10用于此化验中作为正控制，采用IL-10的治疗对于前炎性细胞分裂素如TNFα(肿瘤坏死因子α)具有抑制作用。当筛选的乳酸杆菌株在实验室培养基中经过单独培育后，通过过滤除去活的细菌细胞，在巨噬细胞化验中对上清液(本申请中也称作“调制培养基”)进行测试。巨噬细胞先采用前炎性抗原进行刺激，例如，纯化的LPS(大肠杆菌衍生的脂多糖)、金黄色葡萄球菌衍生的脂磷壁质酸(LTA)或不含大肠杆菌或螺杆菌调制培养基的细胞，以产生含TNFα的前炎性细胞分裂素。源自乳酸杆菌菌株的调制培养基，含有源自筛选细菌的假定免疫调制物质，与抗原活化的巨噬细胞一起被培养。调制培养基对调制巨噬细胞免疫响应的能力，可通过改变该细胞的TNFα产生而进行监测。自该化验的TNFα轮廓，能保证选择的菌株在降低巨噬细胞的TNFα产生方面是最有效的。在该化验体系中采用pH调节的对照实验，消除了变化的pH会引起观察影响的可能性。
令人惊奇地，明显相似的细菌分离物和乳酸杆菌菌株，甚至来自非常相似的人体来源，都显示变化的且广泛不同的能力都影响在响应前炎性抗原时由巨噬细胞的TNFα的产生。这些菌株甚至不能通过遗传指纹而被确认，因为它们可高达98％的遗传相似，但是，对于免疫细胞仍具有非常不同的影响。经此筛选且发现对于防止巨噬细胞的受激前炎性细胞分裂素生产具有强的抑制效果的菌株，对于治疗人体胃肠道炎症是非常有效的，包括幽门螺杆菌引起的胃部炎症。
本发明特征借助于下述实施例将变得更加清楚明了，但是，这些实施例不能理解为是对本发明的限制。
实施例1 选择抗炎菌株
乳酸杆菌[例如，包括鼠李糖乳酸杆菌GG ATCC 53103，约氏乳酸杆菌(L.Johnsonii)ATCC 33200，罗伊乳酸杆菌MM2-3ATCCPTA-4659，棒状乳芽孢杆菌菌株，MM7，ATCC PTA-4660]和大肠杆菌Nissle，分别在de Man，Rogosa，Sharpe(MRS)和Luria-Bertani(LB)培养基(Difco，Sparks，MD)培育。过夜，乳酸杆菌培养物稀释到OD600为1.0(大约表示109细胞/ml)，进一步以1∶10进行稀释，并另外培育4、8和24小时。幽门螺杆菌、(悉尼菌株SS1)和肝螺杆菌381(ATCC 51449)在补充有10％牛胎儿血清(FBS)的布鲁氏肉汤(Difco)中培养48小时。培养物以1∶10进行稀释，并培育另外24和48小时。在4℃于8500rpm周速通过离心分离10分钟，收集不含细菌细胞的调制培养基。调制培养基与该细胞小球分离，接着过滤流过0.22μm孔过滤装置(Millipore，Bedford，Mass)。
老鼠单核细胞/巨噬细胞细胞系，RAW 264.7(ATCC TIB-71)和RAW 264.7γNO(-)(ATCC CRL-2278)，用作研究炎症反应途径的报道细胞。RAW 264.7细胞是在补充有10％FBS和2％抗生素(5000单位/ml青霉素和5mg/ml链霉素，Sigma)的Dulbecco’s改性鹰培养基(野生型)或RPMI培养基1640(γNO-)(Gibco-InvitrogenCarlsbad，CA)中于5％ CO237℃下进行培育，直到80-90％融合。大约5×104细胞播种到96孔细胞培养物簇中，并在脂多糖(LPS)活化和添加调制培养基之前，使之粘合2小时。自然RAW 264.7细胞暴露于自大肠杆菌血清型O127:B8(Sigma)的纯化LPS。活化培养通过每孔添加2ng LPS到20μl调制培养基进行。巨噬细胞既可预培养，或者可与不含细胞的乳酸杆菌调制培养基一起共培养。重组体mIL-10(R&D体系，Minneapolis，Min.)用作正控制。细胞存活率通过台盼蓝(Invitrogen)排除进行评价。在细胞培养物上清液中TNF-α的存在，采用夹心酶免疫测定进行测量，Quantikine M老鼠TNF-α免疫测定(R&D体系)。
乳酸杆菌调制培养基对LPS活化巨噬细胞的TNF-α产生的影响，如图1所示，它表明，在测试的45种菌株中，多种不同菌株具有降低活化巨噬细胞的TNF-α产生的能力。图2表示各种不同乳酸杆菌株的TNFα表达与单独LPS相比的折叠变化。这些研究结果接着可用来选择最有效的菌株。在附图中有提及但在文本中没有特别提及的菌株，是已经测试的乳酸杆菌主要是罗伊乳酸杆菌的各种菌株。
在这个实施例中，棒状乳芽孢杆菌MM7，ATCC PTA-4660，通过使用上述方法进行选择，用于添加到标准酸奶中。通过使用乳品加工业培育乳酸杆菌的标准方法，使棒状乳芽孢杆菌菌株培育并使之冻干。这种培养物接着添加到先前发酵牛奶中，使用传统酸奶培养物，以10E+7CFU/克酸奶的水平，该酸奶为人所用，作为预防由幽门螺杆菌引起的胃炎。
实施例2使用调制培养基
使用上述方法，在此实施例中，源自一种有效TNF-α降低菌株的调制培养基是选择源自罗伊乳酸杆菌ATCC PTA-4659的培养基。这种培养基通过使该菌株在de Man，Rogosa，Sharpe(MRS)(Difco，Sparks，MD)培育而大规模地制备。过夜，乳酸杆菌培养物稀释到OD600为1.0(大约表示109细胞/ml)，进一步以1∶10进行稀释，并另外培育24小时。在4℃于8500rpm转速通过离心分离10分钟，收集不含细菌细胞的调制培养基。调制培养基与该细胞小球分离，接着过滤流过0.22μm孔过滤装置(Millipore，Bedford，Mass)。该调制培养基接着进行冻干，并使用标准方法进行配制以制得片剂。这种片剂被人作为药物用来治疗由幽门螺杆菌引起的溃疡。
实施例3罗伊乳酸杆菌菌株的DNA指纹识别
使用Lupski等的美国专利5,523,217和5,691,136的方法，来进行罗伊乳酸杆菌菌株的染色体组指纹识别。这种方法利用通过添加一对外表定向的引物到细菌样品中的细菌DNA的放大。在放大后，所得杂交作用的延伸产物按尺寸进行分离，细菌菌株通过测量分级的延伸产物图案对其进行表征。通过使用Upriime E引物(一种引物)，对于Bacterial Barcodes，Inc.(Houston，TX)的82种罗伊乳酸杆菌菌株，获得二倍凝胶图象。这些数据的二倍组是可比的。共有11个相互不同的簇，和8个看起来独特的异常值。
已经发现对于降低TNF-α有效的(参见图1和2)菌株，使用这种方法没有集合在一起，表明使用DNA指纹识别这种方法以发现具有TNF-α的多种菌株，是不充分的。
实施例4 表征由有效乳酸杆菌菌株产生的蛋白质
采用多种变性化合物，对不同的有效乳酸杆菌调制培养基包括罗伊乳酸杆菌菌株MM2-3调制的培养基，进行处理，以确定源自该细菌的假定免疫模量的性质。这样，调制培养基进行重复的冻融、热处理、采用DNA消化酶、蛋白酶和灭活蛋白酶的消化。这样，假定免疫模量实质上被确定为一种或多种蛋白质或肽。为了确定贫富蛋白质免疫模量的大小，通过过滤对该调制培养基进行分离，并测试滤液的疗效。这样，发现有效乳酸杆菌的调制培养基的活性成分，大小约为5kDa或更小。
尽管本发明业已借助具体实施方式对其进行了说明，但是，应该理解多种变化、改进、和实施方式是可能的，因此，所有这些变化、改进和实施方式可被认为是处于本发明精神和范围之内。
Claims (23)
1、一种棒状乳芽孢杆菌菌株MM7，ATCC PTA-4660的生物纯培养物。
2、一种罗伊乳酸杆菌菌株MM2-3，ATCC PTA-4659的生物纯培养物。
3、一种乳酸杆菌菌株的生物纯培养物，是通过使用老鼠巨噬细胞化验TNFα活性、对于其具有降低与哺乳动物胃肠道中幽门螺杆菌感染有关的胃肠炎症的能力进行选择的。
4、一种降低与幽门螺杆菌相关炎症的成分，源自乳酸杆菌菌株的生物纯培养物，所述成分是在所述菌株培育后从不含细胞的培养物上清液中获得的，并具有降低TNFα数量的能力。
5、权利要求4所述降低与幽门螺杆菌相关炎症的成分，其中，所述成分是蛋白质或其组成部分。
6、权利要求5所述成分，其中，所述蛋白质、或其组成部分特征在于小于5kDa。
7、一种自罗伊乳酸杆菌菌株MM2-3，ATCC PTA-4659的生物纯培养物分离得到的不含细胞的培养物上清液。
8、一种自棒状乳芽孢杆菌菌株MM7，ATCC PTA-4660的生物纯培养物分离得到的不含细胞的培养物上清液。
9、一种食品组合物，包括一种可消化载体和一种降低与幽门螺杆菌相关炎症的成分，该成分源自一种乳酸杆菌菌株，其选自由棒状乳芽孢杆菌菌株MM7，ATCC PTA-4660和罗伊乳酸杆菌菌株MM2-3，ATCC PTA-4659组成的组。
10、权利要求9所述食品组合物，其中，所述成分含有所述乳酸杆菌菌株的生物纯培养物的细胞。
11、一种药物组合物，包括一种药物载体和一种降低与幽门螺杆菌相关炎症的成分，该成分源自一种乳酸杆菌菌株，其选自由棒状乳芽孢杆菌菌株MM7，ATCC PTA-4660和罗伊乳酸杆菌菌株MM2-3，ATCC PTA-4659组成的组。
12、权利要求11所述药物组合物，其中，所述成分含有所述乳酸杆菌菌株的生物纯培养物的细胞。
13、一种营养补剂，包括一种可消化载体和一种降低与幽门螺杆菌相关炎症的成分，该成分源自一种乳酸杆菌菌株，其选自由棒状乳芽孢杆菌菌株MM7，ATCC PTA-4660和罗伊乳酸杆菌菌株MM2-3，ATCC PTA-4659组成的组。
14、权利要求13所述营养补剂，其中，所述成分含有所述乳酸杆菌菌株的生物纯培养物的细胞。
15、一种制备食品组合物的方法，包括：
a.选择一种权利要求3的乳酸杆菌菌株；
b.从所述菌株得到一种抗炎成分；和
c.添加所述成分到一种可消化载体中得到食品。
16、一种制备药物组合物的方法，包括：
a.选择一种权利要求3的乳酸杆菌菌株；
b.从所述菌株得到一种抗炎成分；和
c.添加所述成分到药物载体中得到一种药物组合物。
17、一种制备营养补剂的方法，包括：
a.选择一种权利要求3的乳酸杆菌菌株；
b.从所述菌株得到一种抗炎成分；和
c.添加所述成分到一种可消化载体中得到一种营养补剂。
18、一种用于治疗或预防与幽门杆菌有关炎症的试剂，含有一种源自权利要求1、2或3的乳酸杆菌菌株的抗炎成分。
19、一种用于治疗或预防与幽门杆菌有关炎症的方法，包括：选择至少一种乳酸杆菌菌株，所述至少一种菌株其特征在于它能够降低胃肠炎症；和将所述至少一种菌株的细胞对人给药。
20、权利要求19所述方法，其中，所述细胞是口服给药。
21、权利要求19所述方法，其中，所述细胞是直肠给药。
22、权利要求19所述方法，其中，所述菌株在调制培养基中产生一种与降低炎性细胞分裂素活性有关的蛋白质。
23、权利要求22所述方法，其中，所述蛋白质其特征在于小于5kDa。
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| PCT/SE2003/001552 WO2004031368A1 (en) | 2002-10-07 | 2003-10-06 | Selection and use of lactic acid bacteria for reducing inflammation caused by helicobacter |
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| CN102115721B (zh) * | 2008-05-08 | 2012-09-26 | 景岳生物科技股份有限公司 | 具有抗炎活性的乳杆菌分离株及其用途 |
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| CN1694954B (zh) | 2010-05-12 |
| US20060251636A1 (en) | 2006-11-09 |
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| US7960137B2 (en) | 2011-06-14 |
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| KR101064058B1 (ko) | 2011-09-08 |
| US7105336B2 (en) | 2006-09-12 |
| EP1551952B1 (en) | 2016-08-17 |
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| AU2003269756B2 (en) | 2007-08-09 |
| KR101107453B1 (ko) | 2012-01-19 |
| US20100129337A1 (en) | 2010-05-27 |
| AU2003269756A1 (en) | 2004-04-23 |
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