CN1312704A - 掺入口腔微生物区系的外源性乳酸菌 - Google Patents
掺入口腔微生物区系的外源性乳酸菌 Download PDFInfo
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- CN1312704A CN1312704A CN99809496A CN99809496A CN1312704A CN 1312704 A CN1312704 A CN 1312704A CN 99809496 A CN99809496 A CN 99809496A CN 99809496 A CN99809496 A CN 99809496A CN 1312704 A CN1312704 A CN 1312704A
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Abstract
用于制备预防或治疗龋齿、牙菌斑和牙周感染的组合物的乳酸菌以及用其制备的组合物的用途,其中所述乳酸菌不是口腔内定居微生物区系的组成部分,而且它低度酸化并能够直接粘附于牙表膜。
Description
本发明涉及掺入口腔微生物区系用以预防或治疗龋齿、牙菌斑和牙周感染的外源性乳酸菌(lactic bacteria)。
发明背景
口腔(口腔)含有定居和非定居的微生物区系。前者包括能够在口腔表面或多或少地建立永久定居的微生物。这些细菌主要集中于舌、颊粘膜和牙齿,而牙龈、口唇、面颊部、腭以及口腔底仅有非常稀少的微生物区系生长。
在舌和颊粘膜上,天然的定居微生物区系包括选自链球菌属(Streptococcus)、韦永氏球菌属(Veillonella)、类杆菌属(Bacteroides)和嗜血杆菌属(Haemophilus)的微生物。在牙齿上,链球菌属、乳酸杆菌属(Lactobacilli)和放线菌属(Actynomyces)占优势,但也可发现各种革兰氏阳性和阴性球菌和杆菌。
例如,Frandsen等证实血链球菌在颊粘膜上占优势但其初期栖息地却是牙表面,格氏链球菌在牙龈上成熟的菌斑中生长,口腔链球菌和缓症链球菌在初始牙菌斑中生长(Oral Microbiol.Immunol.,6,129-133,1991)。属于链球菌突变体族的菌株定居在牙齿上(大鼠链球菌、汗毛链球菌、野生链球菌、猕猴链球菌、变异链球菌(S.mutants)、鼠链球菌、表兄链球菌(S.sorbrinus))。属于米氏链球菌族的菌株在牙脓肿中占优势(咽峡炎链球菌(S.anginosus)、咽峡炎链球菌(S.constellatus)、中间链球菌;Bentley等,Iht.J.System.Bacter.1991,41,487-494;Wood等,乳酸菌的种类,Blackie Academic和Professional,Chapman & Hall,W.H.编辑,1995)。
这些微生物多数是无害的共生体,但已将其中的许多认为是一些十分少见的疾病的病原体(Hill,M.J.和Marsh,P.D.编辑HumanMicrobial Ecology,1990,CRC出版社,Boca Raton Florida,USA)。
所述牙菌斑是一层在牙齿表面形成的膜,由在胞外多糖和唾液产物的基质中在细菌细胞组成。牙齿萌出之后,立刻就被一层无定形的唾液覆盖,所获得的釉质膜(the acquired enamel pellicle)(ACE)厚约1.3μm并且不会被正常的刷牙除去。牙齿上细菌的沉积紧随AEP形成之后而菌斑在8-12小时后由于多层结构而变得明显。第一层含有通过特异性粘附素-受体的识别而主要贴附于牙齿的细菌(最早的定居细菌);它为通过相似的特异性结合或通过简单的并列而相互粘附的第二层定居细菌奠定了基础。菌斑的粘聚通过三个机理得到基本的保证:在细菌外层上唾液薄膜的存在、不同细菌种间的特殊的共聚集和由细菌合成的葡聚糖以及将其继续包埋于菌斑基质中(Skopek等,Oral Microbiol.Immunol.,9,19-24,1994;Kolenbrander等,Math.Enzymol.,253,385-397,1995;Hiroi等,FEMS Microbiol Lett.,96,193-198,1992;Gibbons等,Infect.Immun.,52,555-561,1986)。
在发酵过程中由口腔细菌产生的有机酸直接导致龋齿。这些酸侵蚀牙齿的坚硬组织,导致释出离子如钙、磷酸盐、碳酸盐、镁、氟化物、钠。当口腔内的pH再次升到中性附近时,唾液被钙饱和并因此可避免其从牙齿游离释出。
在口腔内发现的所有食物残渣中,由于口腔细菌的直接发酵作用,碳水化合物显示出最高的促进龋齿作用。
所有微生物发酵的糖都是生龋的潜在因素,但是牙冠和牙根龋齿的主要病原体却是突变的链球菌,因为它们是强酸产生菌;还涉及高度耐酸的乳酸杆菌。在人类中,变异链球菌和表兄链球菌是主要的生龋菌株,并且生活于牙齿上而不在整个牙列中建群。事实上已证实从磨牙到前牙其数量的逐渐减少(Lindquist等,Dent.Res.,69,1160-1166,1990)。因此在人类邻接的菌斑中,变异链球菌和表兄链球菌优先建群于接触区顶端的最容易生龋齿的部位(Ahmady等,Caries Res.,27,135-139,1993)。与变异链球菌相比,在磨牙部位还发现更占优势的表兄链球菌(Lindquist等,Caries.Res.,25,146-152,1991)。
已证实变异链球菌和表兄链球菌主要通过特异性粘附素-受体贴附于牙表膜(the pellicle of teeth)上。Gibbons等证实变异链球菌携有与所述表膜中的唾液成分结合的粘附素,而表兄链球菌细胞具有与所述表面中的葡聚糖结合的粘附素(Infect.Immun.,52,555-561,1986)。
暂居微生物区系包括可在口腔偶然出现、但却不能建立永久性定居(即便重复口服给予这些细菌)的外源性细菌。所有的食用细菌而且特别产乳酸菌可成为这种暂居微生物区系的一部分。尚未证实这些外源性乳酸菌能够直接粘附于牙表膜。然而外源性乳酸菌的重复给予可导致在整个口腔表面,例如舌、颊粘膜、牙龈、口唇、面颊部、腭、底部以及牙齿的口腔内定居。这种定居是通过与定居的微生物区系的细菌的特异结合(共聚集现象)、或包埋通过在定居细菌产生的多糖基质中、或通过粘附于唾液蛋白(特别是糖蛋白)的粘附引起的。
已有报道干酪鼠李糖乳杆菌(Lactobacillus casei rhamnosus)GG(ATCC53103)定居在口腔中,最可能定居在颊粘膜上皮上。该菌株也粘附于肠道上皮(US5032399,Gorbach等;Micr.Ecol.In Health andDis.,7,295-298,1994)。与此相比,鼠李糖乳杆菌(L.rhamnosus)不粘附于牙齿。
日本专利第4021633号(Cyconmedix KK)也报道嗜酸乳杆菌(Lactobacillus acidophilus)定居在口腔中,最可能定居在颊粘膜上皮上。已知许多嗜酸乳杆菌也粘附于肠道上皮上(EP577904;EP199535;Perdigon等;Medicina,46,751-754,1986;Perdigon等;Immunology,63,17-23,1988)。
外源性细菌也可产生抑制口腔内定居的微生物区系的生长的因子。例如,EP759469(Sociétédes Produits Nestlé)描述应用变异微球菌(Micrococcus varians)产生的细菌素抑制口腔病原菌表兄链球菌、血链球菌、变异链球菌和粘放线菌的生长。
已应用某些策略将口腔内的定居微生物区系生长减小到最低限度,即给予不引起龋齿的定居微生物区系的共生细菌如唾液链球菌和/或粘滑口腔球菌(Stomatococcus mucilaginosus),和/或重复给予外源性乳酸菌如干酪乳杆菌、发酵乳杆菌、嗜酸乳杆菌、卷曲乳杆菌、加氏乳杆菌、唾液乳杆菌、保加利亚乳杆菌(L bulgaricus)和唾液链球菌(Tanzer等,Iefect.and Immunity,48,44-50,1985;WO92/14475)。
细菌素的应用也是已提出用于减少龋齿的研究策略之一。这些分子作为未来的抗龋药和调节口腔内建群的重要因子颇具吸引力。应用某些细菌素的抗龋潜力得益于它们对与牙菌斑有关的变异链球菌和细菌的有效广谱抗菌活性,以及其被认为对从类是安全的细菌天然存在性(Colgate的US5368845,和Smithkline Beecham的WO94/12150)。
应用乳衍生物保持口腔健康也是使人感兴趣的。事实上,US5427769(Nestec S.A.)描述了另一可选择的方法,其中预防龋齿是通过使牙齿与含有足够量的微胶粒酪蛋白(micellar casein)的食用组合物接触以抑制表兄链球菌的定居。EP748591(Sociétédes ProduitsNestléS.A.)也报道了氟化微胶粒酪蛋白或其微胶粒亚单位在治疗龋齿或菌斑中的应用。US4992420(Nestec S.A.)描述了将乳衍生的K-酪蛋白-糖巨肽(kappa-caseino-glycomacro peptide)用于口腔治疗以消灭牙菌斑和龋齿。
从未证实不是口腔定居微生物区系的组成部分的乳酸菌确实能够直接粘附于牙表膜。因此,这些乳酸菌通过定居牙表膜将产生抗定居微生物区系包括口腔病原菌生长的抑制活性。
发明概述
本发明的目的是提供应用乳酸菌制备用于预防或治疗龋齿、牙菌斑和牙周感染的组合物,其中所述乳酸菌不是口腔定居微生物区系的组成部分,它是低度酸化的并且能够直接粘附于牙表膜。
另一个目的是以下这样的乳酸菌的应用:经遗传学改造以促进其通过粘附因子而可粘附于牙表膜和/或经遗传学改造使其更弱酸化,导致口腔内的pH大约为5.5-7的乳酸菌。
另一个目的应用不是口腔定居微生物区系组成部分的乳酸菌制备用于预防或治疗龋齿、牙菌斑和牙周感染的组合物,其中所述乳酸菌选自:
-可粘附于牙表膜并经遗传学改造因而是低度酸化的酸化乳酸菌;
-低度酸化的并经遗传学改造因而可粘附于牙表膜的非粘附性乳酸菌;
-经遗传学改造因而可粘附于牙表膜并经遗传学改造因而是低度酸化的非粘附性酸化乳酸菌。
另一个目的是提供包含以下乳酸菌的口腔保健组合物:该乳酸菌不是定居微生物区系组成部分,它低度酸化的而且能够直接粘附于牙表膜。
另一个目的是提供包含以下组分的口腔保健组合物:(1)至少一种这样的乳酸菌:不是口腔定居微生物区系组成部分、能够直接粘附于牙表膜而且使口腔pH高于5.5的乳酸菌;和(2)任何形式的酪蛋白糖巨肽、微胶粒酪蛋白、氟化微胶粒酪蛋白、粗制凝乳酶处理的乳或细菌素(renneted milk or bacteriocin)。
另一个目的是提供包含至少一种选自以下的乳酸菌菌株的口腔保健组合物:菌株CNCMI-1984、CNCMI-1985、CNCMI-1986、CNCMI-1987和LMG P18997。
另一个目的是提供包含至少一种选自以下的乳酸菌的口腔保健组合物:经遗传学改造以促进其通过粘附因子粘附于牙表膜和/或经遗传学改造而更低酸化并使口腔内pH大约为5.5-7的乳酸菌。
另一个目的是提供包含选自以下的乳酸菌的口腔保健组合物:
-可粘附于牙表膜并经遗传学改造因而是低度酸化的酸化乳酸菌;
-低度酸化并经遗传学改造因而可粘附于牙表膜的非粘附性乳酸菌;
-经遗传学改造因而可粘附于牙表膜并经遗传学改造因而是低度酸化的非粘附性酸化乳酸菌。
最后的再一个方面,本发明提供筛选能粘附于牙齿的乳酸菌的方法,该方法包括以下步骤:(1)制备识别能粘附于牙齿的乳酸菌菌株的特异性表面蛋白质的单克隆抗体,(2)应用能够粘附于牙齿的菌株的单克隆抗体,筛选任何乳酸菌菌株。发明详述
在下面的描述中,将所述的口腔限定为人或动物如宠物的口腔,包括口粘膜(牙龈、唇、颊、腭和口腔底)、舌和牙(包括人造结构)。
所述口腔定居微生物区系包括生活口腔内的所有天然微生物,因为它们可在口腔表面建立永久性定居。所述口腔定居微生物区系也包括生长于牙的坚硬组织和软组织之间的交界区(牙齿-牙龈结合部)的细菌,尽管认为在健康的口腔内不存在牙龈沟和牙周袋(periodontalpocket)。这种微生物区系包括选自以下的微生物:链球菌属、葡萄球菌属(Staphylococcus)、肠球菌属(Enterococcus)、微球菌属(Micrococcus)、消化链球菌属(Peptostreptococcus)、消化球菌属(Peptococcus)、乳杆菌属、棒杆菌属(Corynebacterium)、放线菌属、蛛菌属(Aracnia)、罗氏菌属(Rothia)、产硷杆菌属(Alcaligenes)、优杆菌属(Eubacterium)、丙酸菌属(Propionibacterium)、双歧杆菌属(Bifidobacterium)、芽孢杆菌属(Bacillus)、梭状芽孢杆菌属(Clostridium)、奈瑟氏菌属(Neisseria)/布兰汉氏球菌属(Branhamella)、韦永氏球菌属(Veillonella)、肠杆菌科(Enterobacteriaceae)、弯曲杆菌属(Campylobacter)、艾肯氏菌属(Eikenella)、放线杆菌属(Actinobacillus)、二氧化碳嗜纤维菌属(Capnocytophga)、嗜血杆菌属(Haemophilus)、西蒙斯氏菌属(Simonsiella)、拟杆菌属(Bacteroides)、梭形杆菌属(Fusobacterium)、卟啉单胞菌属(Porphyromonas)、普雷沃氏菌属(Prevotella)、纤毛菌属(Leptotrichia)、沃林氏菌属(Wolinella)/月形单胞菌属(Selenomonas)、支原菌属(Mycoplasma)、念珠菌属(Candida)、螺旋体属(Spirochaetes)、原生动物门。
暂居微生物区系包括可偶而在口腔内出现、但不建立永久定居的外源性细菌。这种暂居微生物区系可包括所有的食用微生物如双歧杆菌类(婴儿双歧杆菌、青春双歧杆菌、短双歧杆菌和长双歧杆菌);乳球菌类(乳酸乳球菌乳亚种(Lactococcus lactis subsp.lactis)(乳链球菌)、乳酸乳球菌乳脂亚种(Lactococcus lactis subsp.cremoris)(酪链球菌)和Lactococcus lactis subsp.lactic biovar diacetylactis);链球菌类(嗜热链球菌(Streptococcus thermophilus)、乳链球菌(Lactococcus lactis)、酪链球菌(S.lactis cremoris)和乳酸乳球菌双乙酰亚种(S.lactisdiacetylactis));乳杆菌类(德氏乳杆菌保加利亚亚种、瑞士乳杆菌、香肠乳杆菌、消化乳杆菌、干酪乳杆菌干酪亚种、德氏乳杆菌乳亚种、清酒乳杆菌、弯曲乳杆菌、发酵乳杆菌和包括约氏乳杆菌的嗜酸菌群;参见Fujisawa等,Int.J.Syst.Bact.,42,487-491,1992);片球菌类(戊糖片球菌(Pediococcus pentosaceus)、乳酸片球菌和嗜盐片球菌);肠球菌类;葡萄球菌类(木糖葡萄球菌和肉葡萄球菌);微球菌类(变异微球菌);属于德巴利酵母属(Debaromyces)、念珠菌属(Candida)、毕赤酵母属(Pichia)、球拟酵母属(Torulopsis)和酵母属(Saccharomyces)的酵母菌;以及属于曲霉属(Aspergillus)、酒曲菌属(Rhizopus)、白霉属(Mucor)和青霉属(Penicillium)的霉菌。
与本发明的第一个目的是应用乳酸菌制备用于预防或治疗龋齿、牙菌斑和牙周感染的组合物,其中所述乳酸菌不是口腔内的定居微生物区系的组成部分,而且它低度酸化并且能够直接粘附于牙表膜。
根据本发明的乳酸菌是低度酸化的且其能直接粘附于牙表膜,因此用这些乳酸菌制备的组合物是用于排除牙齿的病原菌或预防它们的粘附。根据本发明的乳酸菌是“低度酸化的”,这意味着它们比病原菌株的酸性低。因此,它们使口腔的pH大约为5.5-7。它们最好是乳源性的。
根据本发明的乳酸菌通过特异性或非特异性的相互作用和/或粘附因子粘附于牙表膜。所述特异性粘附因子是蛋白质或多糖。
至少一种乳酸菌是选自嗜热链球菌、乳酸乳球菌乳亚种和Lactococcus lactis subsp.lactic biovar diacetylactis并且特别选自菌株CNCMI-1984、CNCMI-1985、CNCMI-1986、CNCMI-1987和LMGP-18997。
所选定的这些菌株属于可粘附于牙表膜、其最佳生长温度大约为37℃(为口腔温度)的乳酸菌菌株。此外它们能够发酵葡萄糖和蔗糖并且不合成葡聚糖,葡聚糖是生龋菌株的致病性因素。
根据本发明的另一个目的是考虑对乳酸菌进行遗传学改造以使其通过粘附因子粘附于牙表膜。对于已经粘附于牙表膜的乳酸菌,这种改造的目的是使所述菌株更牢地粘附于牙的表面。同样,任何非粘附性乳酸菌(不是乳杆菌)可经遗传学改造而可粘附于牙表膜。
例如,可通过插入基因X17390、X14490或X53657(GenBank注册号)而实现乳酸菌进行这样的改造。这些基因在变异链球菌中表达介导粘附于唾液糖蛋白的抗原Ⅰ/Ⅱ。
根据本发明,对乳酸菌进行遗传学改造以使其成为低度酸化菌也是可能的。对于已经是低度酸化的乳酸菌,这种改造的目的是通过降低其乳酸的产生而增强所述效应。
许多方法并优选根据下述文件中所述方案之一可实现这种改造:Boumerdassi等,Appl.Environ.Microbiol.,63,2293-2299,1997;Platteeuw等,Appl.Environ.Microbiol.,61,3967-3971,1995;Ito等,Biosci.Biotechnol.Biochem.,58,1569-1573,1994。
根据本发明,至少将一种经遗传学改造或未经改造的乳酸菌以“有效量”用于制备预防或治疗人类或动物如宠物的龋齿、牙菌斑和牙周感染的组合物。所述有效量最好在104到109cfu/g之间。
也可以至少一种乳酸菌结合使用乳衍生物,例如乳或发酵乳或乳衍生物(如选自任何形式的酪蛋白-糖巨肽、微胶粒酪蛋白、氟化微胶粒酪蛋白、粗制凝乳酶处理的乳或细菌素)。所选定菌株的生化特性发酵模式:用api 50 CH bioMerieux条带测试法(bioMérieux SA,69280 Marcy-l’Etoile,法国)对49种单糖进行测试,结果见表1。酸化曲线:按下述条件在37℃下确定酸化曲线:-表兄链球菌OMZ 176:FUM蔗糖1%和FUM葡萄糖1%-嗜热链球菌CNCM I-1985:Belliker蔗糖1%和Belliker葡萄糖1%接种始终是5%;每20分钟记录一次pH。
在蔗糖发酵中,嗜热链球菌CNCM I-1985将pH降低至4.5,而表兄链球菌OMZ 176将pH降低至4。表1.乳酸乳球菌CNCM I-1987、乳酸乳球菌CNCM I-1986、嗜热链球菌CNCM I-1984、嗜热链球菌CNCMI-1985和嗜热链球菌LMG
P-18997的糖发酵。
+,++,+++,++++表示在3、6、24或48小时后开始发酵。
糖福寿糖醇七叶甙苦杏仁甙D-阿拉伯糖L-阿拉伯糖D-阿拉伯糖醇L-阿拉伯糖醇熊果甙纤维二糖 | 乳酸乳球菌CNCM I-1987++++++++++++++++++ | 乳酸乳球菌CNCMI-1986+++++++++++ | 嗜热链球菌CNCMI-1984 | 嗜热链球菌CNCM I-1985 | 嗜热链球菌LMGP-18997 |
半乳糖醇赤藓醇D-果糖D-岩藻糖L-岩藻糖半乳糖β-糊精糖葡萄糖酸盐2-酮-葡萄糖酸盐5-酮-葡萄糖酸盐GlcNAcD-葡萄糖甘油糖原肌醇阿兰粉乳糖D-来苏糖麦芽糖甘露糖醇D-甘露糖松三糖蜜二糖α-甲基-D-葡萄糖苷α-甲基-D-甘露糖苷D-棉子糖鼠李糖核糖水杨苷山梨醇L-山梨糖淀粉蔗糖D-塔格糖海藻糖D-松二糖木糖醇D-木糖L-木糖β-甲基-木糖苷 | ++++++++-+++++++++++++++ | ++++++++++++++++++++++++++++++++++ | +++++++ | ++++++++++ | +++++++++ |
本发明的第二个主要目的与含有乳酸菌的口腔保健组合物有关,该乳酸菌不是口腔内的定居微生物区系的组成部分,它是低度酸化的并能直接粘附于牙表膜。
这类组合物特别用于预防或治疗龋齿、牙菌斑和牙周感染。
所述乳酸菌菌株选自嗜热链球菌、乳酸乳球菌乳亚种、Lactococcus lactis subsp.lactic biovar diacetylactis并优选选自菌株CNCMI-1984、CNCMI-1985、LMG P-18997、CNCMI-1986和CNCMI-1987。
在这类用于口腔保健的组合物中,乳酸菌菌株可如上述一样经过遗传学改造。
所述乳酸菌菌株可包含于例如食品、宠物食品、美容或药用组合物中。
因此,这类组合物优选为例如牙膏、漱口液、口香糖、喷雾剂、饮料、糖果、婴儿配方、冰淇淋、冷冻甜食、甜沙拉调味品(sweet saladdressing)、奶制品、乳酪、夸克(quark)、酸乳、酸化奶、咖啡稀奶油或搅打起泡的稀奶油(whipped cream)。
在这类组合物中,例如可只含有乳酸菌菌株或使其与乳衍生物结合以获取协同作用的制剂。因此,这类口腔保健组合物含有:
-非口腔内定居微生物区系组成部分、能直接粘附于牙表膜的乳酸菌。
-任何形式的乳糖肽(lactic glycopeptide)、粗制凝乳酶处理的乳或细菌素。
所述乳糖肽优选为酪蛋白-糖巨肽(CGMP),也可加入氟化或非氟化的微胶粒酪蛋白(可按专利EP 0 604 802和EP 0 748 591所述获得)或粗制凝乳酶处理的乳。加入酪蛋白-糖巨肽的最小量优选为约0.1%。另外还证实该酪蛋白-糖巨肽不能妨碍所述乳酸菌粘附于牙表膜(图2和图3)。
也可加入至少一种细菌素制备协同作用的组合物,所述细菌素具有抗口腔革兰氏阳性菌活性。假使这样,则所述口腔保健组合物可含有占组合物重量的0.00001到50%,优选0.00001到15%的纯细菌素。所述细菌素优选为variacin(EP 0 759 469)。
为防止组合物降解,也可包含油溶性的抗氧化剂。合适的抗氧化剂包括“生育酚”、丁基-羟茴香醚(BHA)、丁基-羟甲苯(BHT)和棕榈酸抗坏血酸酯。所述油溶性抗氧化剂可以占组合物重量的0.005%到0.5%,优选0.005%到0.01%的量存在。
在本发明牙粉组合物中应用的合适的摩擦剂包括碳酸钙、铝硅酸钙、氧化铝、水合氧化铝、正磷酸锌、塑胶颗粒和二氧化硅,其中二氧化硅是优选的摩擦剂。
根据本发明的组合物将具备口腔可接受的pH并且在此pH下所述乳酸菌的活性未遭损害。该pH可在3.0-9.5的范围内,优选在3.5-6.5的范围内。
可用常规方法制备这类组合物,该方法包括将所述成分以适当的成比例的量混合在一起,最后如果需要,将pH调至需要值。
根据本发明的最后一个方面是关于筛选能粘附于牙齿的乳酸菌的方法。该方法包括下述步骤:
(1)制备能特异性识别可粘附于牙齿的乳酸菌菌株的表面蛋白
质的单克隆抗体,和
(2)通过应用能粘附于牙齿的菌株的单克隆抗体,筛选任何乳
酸菌菌株。
在邻近生长的其它菌株中,可将该单克隆抗体用作工具以检测所述乳酸菌菌株。
本发明并不局限于本文所述的具体的实施方案的范围内。事实上除本文所述的那些之外,本领域技术人员可根据前面的描述和附图清楚明白对本发明进行的各种修改。这些修改属于所述权利要求范围。本文引用了多种公开出版物,其公开内容以理解本发明必须的程度整体引用结合到本文中。除非另有说明,按照Sambrook等(Sambrook等,分子克隆,实验室手册,Cold Spring Harbor LaboratoryPress,U.S.A.,1989)的教科书进行细菌细胞的DNA操作、克隆和转化。在描述实施例之前,先简述所用的质粒、菌株和多种培养基以及产生单克隆抗体的方法。
1998年3月3日,根据布达佩斯条约将菌株嗜热链球菌S118(NCC 1529)、S123(NCC 1561)、乳酸乳球菌乳亚种29(NCC 2211)、L.lactis subsp.lactic biovar diacetylactis 69(NCC 2225)保藏于法国国立微生物保藏中心(Collection Nationale de Culture deMicroorganismes,25 reu du docteur Roux,75724 Paris,France)(分别是CNCM I-1984、CNCM I-1985、CNCM I-1986和CNCM I-1987)。1999年7月5日,根据布达佩斯条约将菌株嗜热链球菌BF11116(CNBL 1177)保藏于比利时微生物协调保藏中心(Belgian CoordinatedCollection of Micro-organismes,K.L.Ledeganckstraat 35,B-9000 Gent,Belgium)(LMG P-18997)。关于获得这些保藏物的所有限制在首次公开本申请或要求本申请优先权利益的另一申请后立即失效。
附图-图1a、1b和1c分别代表表兄链球菌OMZ 176、乳酸乳球菌NCC 2211和嗜热链球菌NCC 1561的粘附饱和曲线。-图2代表结合细胞数对逐渐增加量的CGMP作图获取的三种菌株的曲线。-图3代表结合细胞数对数量逐渐增加的As-CGMP作图获得的三种菌株的曲线。
实施例1:菌株和培养条件
筛选100多种菌株(属于Nestléculture collection)粘附于唾液-包被的羟基磷灰石珠的能力,特别是下述23种菌株:嗜热链球菌YS4(NCC 2284)、嗜热链球菌Sfi6(NCC 1971)、嗜热链球菌Sfi13(NCC2008)、嗜热链球菌Sfi21(NCC 2038)、嗜热链球菌Sfi39(NCC 2130)、嗜热链球菌Sfi42(NCC 2145)、嗜热链球菌Sfi47(NCC 2172)、嗜热链球菌S118(NCC 1529)、嗜热链球菌S119(NCC 1536)、嗜热链球菌S122(NCC 1554)、嗜热链球菌S123(NCC 1561)、嗜热链球菌S126(NCC 1587)、乳酸乳球菌乳脂亚种15(NCC 92)、乳酸乳球菌乳脂亚种25(NCC 1932)、乳酸乳球菌乳脂亚种136(NCC 2419)、L.lactissubsp.diacetylactis 8(NCC 1970)、L.lactis subsp.diacetylactis 28(NCC2057)、L.lactis subsp.diacetulactis 69(NCC 2225)、Lactococcus lactissubsp.lactic biovar diacetylactis 80(NCC 2272)、乳酸乳球菌乳亚种29(NCC 2211)、乳酸乳球菌乳亚种50(NCC 2224)、乳酸乳球菌乳亚种54(NCC 2228)、S.macedonicus 216(NCC 2484)。
5种口腔菌株表兄链球菌OMZ 176、口腔链球菌OMZ 607、A.naeslundii OMZ 745、V.dispar OMZ 493和F.nucleatum OMZ 596获自Institute für Orale Mikrobiologie und Allgemeine Immunologie,University of Zürich,并将其在厌氧条件、38℃下培养于FUM培养基(GasPackSystem,BBL)中。
将所有菌株在-20℃下保存于甘油中并于使用前将它们预培养于其特殊的最适温度下14小时;表兄链球菌OMZ 176生长于FUM培养基中(Gmür等),而乳球菌和链球菌生长于M17(Difco)中,但是嗜热链球菌NCC1529、S119、S122、NCC1561和S126生长于Belliker(通过将20g胰蛋白胨、5g酵母提取物、2.5g明胶、5g葡萄糖、5g蔗糖、5g乳糖、4g氯化钠、0.5g维生素C、10g牛肉提取物溶于11水中而制备)中。
平板计数:将表兄链球菌OMZ 176培养于Mitis-Salivarius琼脂(Difco)中、将嗜热链球菌NCC1529、S119、S122、NCC1561、BF11116和S126培养于Belliker琼脂(通过向Bellliker液体中加入15g Bacto琼脂(Difco)而制备)中,其余乳酸菌菌株培养于M17琼脂(Oxoid)中。实施例2:单克隆抗体的制备
将单克隆抗体用作工具在5种口腔菌株中检测乳酸乳球菌乳亚种NCC2211,该5种菌株一起生长于S-HA盘上并形成模拟牙菌斑的生物膜。因此,对这些菌株测试所述单克隆抗体以证实它们之间无交叉反应。
为此,按照Granato等“抗-乳乳球蛋白的小鼠单克隆IgE抗体在胃肠道变态反应中的研究”(Clin.Exp.Immunol.,63,703-710,1986)所述制备该单克隆抗体。实施例3:粘附性乳酸菌的筛选对唾液-包被的羟基磷灰石珠(S-HA)的粘附
为了在乳酸菌乳品菌株中筛选能粘附于唾液-包被的羟基磷灰石珠(S-HA)上的乳酸菌菌株,应用经过稍许修改的Neeser等以前描述的方法:用150μl体积洗涤珠子并用Benzethonium hydroxide(Sigma)代替Hyamine hydroxide。
简要地说,除了嗜热链球菌NCC1529、S119、S122、NCC 1561和S126生长于Belliker中之外,将所有菌株生长于FUM中至对数生长期末。表兄链球菌OMZ 176、乳酸乳球菌乳亚种NCC 2211、50和54、嗜热链球菌NCC1529、S119、S122、NCC1561和S126生长于37℃,其它乳球菌生长于30℃而其它链球菌生长于42℃。
将获自实验室志愿者并按以前所述(Neeser等,1994)制备的澄清唾液70μl包被5mg羟基磷灰石珠(BDH Chemicals Ltd,Poole,England)。将唾液包被珠在4℃下过夜,然后洗涤(第一次用蒸馏水而以后用HEPES缓冲液),最后用100μl代谢标记的细菌悬浮物(已将细菌培养于其附加有10μCi/ml 14C乙酸的培养基中)接种。在37℃下45分钟内发生粘附,然后将未结合的细菌洗涤除去并在LKB闪烁计数仪(Rackbeta 1219型)直接计数粘附的细胞。
粘附百分率以结合到所述珠子上的放射活性相对于加入每孔的总放射活性表示。所有的检测作三个复孔。表2报告了从几株筛选的菌株和表兄链球菌OMZ 176(参比菌株)获得的粘附于唾液-包被的羟基磷灰石珠的百分率。
表2:从筛选的几株菌株中获得的粘附于唾液-包被的
羟基磷灰石珠的百分率。
菌株 | 粘附率%(+/-SD) |
表兄链球菌OMZ 176嗜热链球菌Sfi42(NCC 2145)嗜热链球菌Sfi47(NCC 2172)嗜热链球菌NCC1529嗜热链球菌S119(NCC 1536)嗜热链球菌S122(NCC 1554)嗜热链球菌NCC1561嗜热链球菌S126(NCC 1587)乳酸乳球菌双乙酰亚种28(NCC 2057)乳酸乳球菌双乙酰亚种NCC2225乳酸乳球菌双乙酰亚种80(NCC 2272)乳酸乳球菌乳亚种NCC2211 | 2.23+/-0.490.08+/-0.020.14+/-0.042.89+/-0.600.15+/-0.040.93+/-0.172.19+/-0.501.19+/-0.561.59+/-0.171.96+/-0.401.20+/-0.352.85+/-0.85 |
嗜热链球菌NCC1529(CNCM I-1984)、嗜热链球菌NCC1561(CNCM I-1985)、乳酸乳球菌乳亚种NCC2211(CNCM I-1986)(在下文中为乳酸乳球菌NCC2211)以及乳酸乳球菌双乙酰亚种NCC2225(CNCMI-1987)四种菌株显示的值与表兄链球菌OMZ 176的接近。
由于乳酸乳球菌NCC2211和嗜热链球菌NCC1561在37℃即口腔内温度下生长良好,因此将它们选作更有希望的侯选者,而乳酸乳球菌双乙酰亚种NCC2225的最适生长温度是30℃。特别是乳酸乳球菌NCC2211不能在蔗糖中生长,但它能发酵较宽范围的糖,而且,其它口腔菌株能通过它们的转化酶提供葡萄糖。粘附饱和曲线
检测结合的菌落形成单位与接种到该孔中的菌落形成单位的曲线以证实珠子可获得的饱和度。从获得的曲线的弯曲点(bending point)直接画出50%饱和度。测定表兄链球菌OMZ 176、乳酸乳球菌NCC2211和嗜热链球菌NCC1561的粘附饱和曲线。将它们示于图1中。
对于所述三种菌株,接种在孔中以获得50%珠子饱和度的菌落形成单位数和相应的结合菌落形成单位的数可根据该曲线的弯曲点直接推断出,并在表3中给出其结果。
表3:接种到每孔以获得50%珠子
饱和度的菌落形成单位数。
实施例4:酪蛋白糖巨肽的作用
表兄链球菌OMZ 176乳酸乳球菌NCC2211嗜热链球菌NCC1561 | 菌落形成单位/孔 | 结合的菌落形成单位 | 粘附率% |
4.00E+071.00E+073.00E+07 | 4.00E+069.00E+052.00E+06 | 10%9%7% |
研究CGMP对乳酸乳球菌NCC2211和嗜热链球菌NCC1561的粘附的影响以证实应用CGMP促进该两种菌株之一成为相对于致病性菌株(即表兄链球菌OMZ 176)的优势菌株的可能性。酪蛋白-糖肽(CGMP)及其去唾液酸衍生物(As-CGMP)获自Nestec S.A.,Lausanne(关于其制备参见Neeser等,1994)。
通过将含有不同浓度的CGMP或As-CGMP的细菌悬浮液(相当于前面计算的50%珠子饱和度的菌落形成单位/m1)100μl接种到所述孔中,然后按照常规进行粘附检测,研究粘附于S-HA珠子上的剂量-反应作用。测试的浓度范围为0.05-3mg/ml。所述细菌培养先前的培养是在没有CGMP或As-CGMP存在下进行的。
图2为结合细胞数对数量逐渐增加的CGMP作图获得的三种菌株的曲线,接种细胞数量相当于前面计算的每种菌株的50%珠子饱和度的细菌细胞数。在表兄链球菌OMZ 176观察到的强抑制作用证实了以前由Neeser等(1994)和Schüpbach等(J.Dent.Res.,75,1779-1788,1996)获得的结果。
如图2所证实的一样,0.25mg/ml CGMP对表兄链球菌OMZ 176产生50%的粘附抑制,而对嗜热链球菌NCC1561则必需高于2mg/ml才具有相同抑制效果。CGMP能稍许增强乳酸乳球菌NCC2211的粘附。
与CGMP一样,去唾液酸衍生物抑制表兄链球菌OMZ 176的粘附;仅需0.05 mg/ml就导致粘附百分率降低50%。As-CGMP不影响乳酸乳球菌NCC2211的粘附,然而稍许促进嗜热链球菌NCC1561的粘附(图3)。
实施例5:牙膏
通过在含有以下成分的混合物加入105菌落形成单位/ml至少一种冻干形式的乳酸菌菌株CNCM I-1984、CNCM I-1985、CNCM I-1986、CNCMI-1987或LMG P-18997制备牙膏:十六烷基氯化吡啶鎓 1.65%山梨醇(70%soln) 33.0%甘油 25.0%羧甲基纤维素钠 2.0%氟化钠 0.25%二氧化硅(RP 93) 26.3%稠化二氧化硅(Sident 22) 8.1%糖精钠 0.5%聚羟体(poloxamer)(Pluronic F108) 3.2%
这种牙膏用于预防或治疗龋齿、牙菌斑和牙周感染。
实施例6:冰淇淋
制备含有10.8%乳脂、13.5%乳固体(非脂肪性)、0.3%EmulstabSE30 et 0.3%Emulstab泡沫剂(Grindsted,DK)的奶油,然后在105℃下用巴氏法灭菌20秒,在75℃和300 bar下使其匀化,冷至38℃并接种预先培养于MRS培养基中的处于对数生长期的培养物,接种率为107-108菌落形成单位/ml的至少一种以下乳酸菌菌株:CNCM I-1984、CNCM I-1985、CNCMI-1986、CNCMI-1987或LMG P-18997。然后将该奶油在38℃下发酵10小时至pH约为4.5。在发酵结束时,加入蔗糖和葡萄糖糖浆。该奶油的组成示于下面的表4中。
然后搅打所述混合物,冷却至4℃,贮存于4℃,使其冷却至体积膨胀95℃(chilled to a degree of expansion of 95℃ by volume)。
表4
实施例7:酸乳
成分 | 构成(kg) | 脂肪(%) | 非-脂肪固体(%) | 蔗糖(%) | 固体含量(%) |
奶油(35%) | 30,83 | 10,79 | 1,54 | 12,33 | |
脱脂奶粉 | 12,45 | 11,95 | 11,95 | ||
EmulstabSE30 | 0,41 | 0,37 | |||
Emulstab泡沫剂 | 0,41 | 0,36 | |||
水 | 55,91 | ||||
总计:奶油基质 | 100,00 | 10,79 | 13,49 | - | 25,01 |
奶油基质 | 74,14 | 8,00 | 10,00 | - | 18,54 |
蔗糖 | 22,06 | 15,00 | 15,00 | ||
葡萄糖糖浆 | 3,80 | 3,00 | |||
发酵的冰淇淋 | 100,00 | 8,00 | 10,00 | 15,00 | 36,54 |
将51 MRS培养基在121℃下灭菌15分钟,随后接种5%体积、含有大约109菌落形成单位/ml的嗜热链球菌菌株CNCM I-1984、CNCM I-1985或LMG P-18997中的至少一种的活性培养物。在41℃下培养8小时后,获得的起子培养物含有4.5.108菌落形成单位/ml。
将含有10%干性物质(其中加入了0.1%的酵母提取物)的51复制脱脂乳在121℃下灭菌15分钟,然后接种2%体积含有大约109细胞/ml的商用增稠的嗜热链球菌的活性培养物。于41℃培养4小时后,获得的起子培养物含有4.5.108细胞/ml。
用2%(体积)的至少一种菌株CNCM I-1984、CNCM I-1985或LMG P-18997的起子培养物和3%(体积)增稠的嗜热链球菌起子培养物接种一批全乳,该全乳含有3.7%脂肪并用2.5%脱脂奶粉强化,然后于90℃用巴氏法灭菌30分钟。将该接种的乳搅拌、注入到发酵罐中并在41℃下培养4小时。
获得的酸奶具有良好的坚实而平滑的口感(texture)并将其用于口腔保健。
实施例8:口香糖
用于预防或治疗龋齿、牙菌斑或牙周感染的口香糖可通过在以下常规组分中加入嗜热链球菌CNCM I-1984、CNCM I-1985或LMGP-18997菌株中的至少一种的活性培养物而制备,所以它含有大约104-109菌落形成单位/g,所述常规组分为:
木糖醇 67.5%
胶基质 20%
碳酸钙 5%
甘油 3%
Pluronic F127 2%
纤维素胶 1%
Balast化合物 0.5%
调味品 1%实施例9:宠物食品组合物
通过制备由玉米、玉米麸质的鸡肉和鱼肉(comgluten chicken andfish meal)、盐、维生素和矿物质组成的饲料混合物获得用于口腔保健的宠物食品。将该饲料混合物送入预处理器(preconditioner)并使其湿润。然后将离开预处理器的潮湿饲料送入挤压机-蒸煮机(extruder-cooker)并使其成凝胶状。从挤压机将凝胶基质压入模中并挤压成形。将该挤压品切成适合给狗喂饲的片状,在约110℃下干燥大约20分钟并冷却成具有约0.6水分活性的颗粒饲料。
用3种包被混合物喷洒颗粒饲料。每种包被混合物含有嗜热链球菌CNCM I-1984、CNCM I-1985或LMG P-18997菌株中的至少一种的活性培养物,但是其中一种包被混合物应用氢化大豆脂作为包被底物、一种包被混合物应用水作为包被底物而一种包被混合物应用蛋白消化产物作为包被底物。该颗粒饲料含有大约104到109菌落形成单位/g的所述菌株。
Claims (24)
1.用于制备用以预防或治疗龋齿、牙菌斑和牙周感染的组合物的乳酸菌的用途,其中所述乳酸菌不是口腔内定居微生物区系的组成部分,而且它低度酸化并能够直接粘附于牙表膜。
2.根据权利要求1的用途,其中所述组合物用于替换牙齿的致病菌或防止其粘附。
3.根据权利要求1或2的用途,其中所述乳酸菌的酸化比致病性菌株低,从而使口腔pH约5.5-7。
4.根据任何前述权利要求的用途,其中所述乳酸菌是乳源性的。
5.根据任何前述权利要求的用途,其中至少一种乳酸菌选自嗜热链球菌、乳酸乳球菌乳亚种和Lactococcus lactis subsp.lactic biovardiacetylactis。
6.根据任何前述权利要求的用途,其中至少一种乳酸菌选自菌株CNCMI-1984、CNCM I-1985、CNCMI-1986、CNCMI-1987和LMGP-18997。
7.根据任何前述权利要求的用途,其中所述乳酸菌通过粘附因子粘附于牙表膜。
8.根据任何前述权利要求的用途,其中所述乳酸菌已经过遗传学改造以增强其对牙表膜的粘附和/或经遗传学改造以使其酸化更弱。
9.用于制备用以预防或治疗龋齿、牙菌斑和牙周感染的组合物的乳酸菌的用途,所述乳酸菌不是口腔内定居微生物区系的组成部分,其中所述乳酸菌选自:
-可粘附于牙表膜并经遗传学改造因而是低度酸化的酸化乳酸菌;
-低度酸化并经遗传学改造因而可粘附于牙表膜的非粘附性乳酸菌;
-经遗传学改造因而可粘附于牙表膜并经遗传学改造因而是低度酸化的非粘附性酸化乳酸菌。
10.根据权利要求8和9的用途,其中所述乳酸菌经遗传学改造因而可通过粘附因子粘附于牙表膜并使口腔pH约5.5-7。
11.根据任何前述权利要求的用途,其中所述组合物是含有用于预防或治疗龋齿、牙菌斑和牙周感染的有效量乳酸菌的食用组合物。
12.根据任何前述权利要求的用途,其中所述组合物含有至少104-109cfu/g的乳酸菌。
13.根据任何前述权利要求的用途,其中所述乳酸菌与乳、发酵乳、乳衍生物或细菌素联合应用。
14.根据权利要求13的用途,其中所述乳衍生物选自任何形式的酪蛋白-糖巨肽、微胶粒酪蛋白、氟化微胶粒酪蛋白或粗制凝乳酶处理的乳。
15.含有乳酸菌的口腔保健组合物,其中所述乳酸菌不是口腔内定居微生物区系的组成部分,而且它低度酸化并能够直接粘附于牙表膜。
16.根据权利要求15的口腔保健组合物,其中所述乳酸菌已经过遗传学改造以增强其对牙表膜的粘附和/或经遗传学改造使其成为更弱酸化的乳酸菌。
17.根据权利要求15或16的口腔保健组合物,其中所述乳酸菌选自:
-可粘附于牙表膜并经遗传学改造因而是低度酸化的酸化乳酸菌;
-低度酸化并经遗传学改造因而可粘附于牙表膜的非粘附性乳酸菌;
-经遗传学改造因而可粘附于牙表膜并经遗传学改造因而是低度酸化的非粘附性酸化乳酸菌。
18.根据任何前述权利要求的口腔保健组合物,其中所述乳酸菌已经过遗传学改造因而可通过粘附因子粘附于牙表膜并使口腔pH约5.5-7。
19.根据任何前述权利要求的口腔保健组合物,它含有用于预防或治疗龋齿、牙菌斑和牙周感染的有效量乳酸菌。
20.根据任何前述权利要求的口腔保健组合物,它含有至少104-109cfu/g的乳酸菌。
21.一种口腔保健组合物,它含有:
(1)一种乳酸菌,该乳酸菌为不是口腔内定居微生物区系的组成部分,它能直接粘附于牙表膜并使口腔pH约5.5-7;
(2)任何形式的酪蛋白-糖巨肽、微胶粒酪蛋白、氟化微胶粒酪蛋白或粗制凝乳酶处理的乳或细菌素。
22.根据任何前述权利要求的口腔保健组合物,它含有至少一种选自嗜热链球菌、乳酸乳球菌乳亚种和Lactococcus lactis subsp.lacticbiovar diacetylactis的乳酸菌菌株。
23.根据任何前述权利要求的口腔保健组合物,它含有至少一种选自CNCMI-1984、CNCMI-1985、CNCMI-1986、CNCMI-1987和LMG P-18997的乳酸菌菌株。
24.用于筛选能粘附于牙齿的乳酸菌的方法,该方法包括以下步骤:
(1)制备能特异性识别可粘附于牙齿的乳酸菌菌株的表面蛋白质的单克隆抗体,和
(2)通过应用能粘附于牙齿的菌株的单克隆抗体,筛选任何乳酸菌菌株。
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- 1999-07-26 RO ROA200100152A patent/RO121005B1/ro unknown
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- 1999-07-26 WO PCT/EP1999/005473 patent/WO2000009080A1/en not_active Application Discontinuation
- 1999-07-26 ES ES99940086T patent/ES2363201T3/es not_active Expired - Lifetime
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- 1999-08-12 TW TW088113807A patent/TW552142B/zh not_active IP Right Cessation
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2001
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- 2001-01-11 PL PL345890A patent/PL201312B1/pl not_active IP Right Cessation
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- 2001-02-08 ZA ZA200101110A patent/ZA200101110B/en unknown
- 2001-02-09 US US09/779,596 patent/US6942849B2/en not_active Expired - Fee Related
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2005
- 2005-03-23 US US11/087,523 patent/US20050186148A1/en not_active Abandoned
- 2005-06-23 US US11/166,605 patent/US20050238590A1/en not_active Abandoned
Cited By (4)
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CN102352324A (zh) * | 2003-01-29 | 2012-02-15 | 生命大地女神有限公司 | 乳酸杆菌在减少龋齿和细菌引发龋齿中的用途 |
CN102352324B (zh) * | 2003-01-29 | 2013-10-30 | 生命大地女神有限公司 | 乳酸杆菌在减少龋齿和细菌引发龋齿中的用途 |
CN101056972B (zh) * | 2004-09-10 | 2012-07-04 | 巴斯夫欧洲公司 | 用于预防和/或治疗龋齿的手段和方法 |
CN102123604A (zh) * | 2008-06-24 | 2011-07-13 | Wm.雷格利Jr.公司 | 益生菌口香糖的制造方法 |
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