CN100400645C - 益生菌的联合 - Google Patents
益生菌的联合 Download PDFInfo
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- CN100400645C CN100400645C CNB028041178A CN02804117A CN100400645C CN 100400645 C CN100400645 C CN 100400645C CN B028041178 A CNB028041178 A CN B028041178A CN 02804117 A CN02804117 A CN 02804117A CN 100400645 C CN100400645 C CN 100400645C
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- prebiotics
- associating
- bacterium
- probiotic
- product
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Abstract
本发明涉及益生菌的联合，其包含乳杆菌、丙酸杆菌和/或双歧杆菌的不同联合。优选益生菌与适合的益生元联合以形成合生素。本发明的联合可以就此使用，或与适合的食品或药品联合，并且其有治疗用途，例如用于刺激免疫系统和改善总体的健康。
Description
技术领域
本发明涉及益生菌的联合，该联合包括乳杆菌，丙酸菌杆和/或双歧杆菌的各种联合。优选益生菌与适宜的益生元联合以产生合生素(synbiotic)。本发明的联合可以就这样食用或可以与适宜的食品，如奶产品或饮料联合，并且其有治疗用途，例如刺激免疫系统和改善总体健康。
本发明的背景
益生菌是活微生物，当给人或动物施用它们时，其通过改善肠内微生物平衡促进宿主的健康(Fuller，R.人与动物的益生菌，1989，J.Appl.Microbiol.66：365-378)。文献很好地记载的益生菌包括鼠李糖乳杆菌(L.rhamnosus)LGG、约氏乳杆菌(L.johnsonii)LAI、干酪乳杆菌(L.casei)Shirota和乳双歧杆菌(Bifidobacterium lactis)BbI2。此外，在本领域的文献中还描述了许多其它益生菌(参见，例如M.E.Sanders & J.H.in’tVeld 1999.Antonie van Leeuwenhoek 76：293-315，Kluwer AcademicPublishers)。益生菌促进健康的作用包括肠内菌群的平衡和维持，免疫系统的刺激和抗致癌活性。益生菌在人肠道内的有益作用是基于活细菌细胞、它们的细胞结构和代谢产物引起的几个因素。通常在营养品中或作为胶囊施用益生菌。
如果一种细菌基本上满足下面的要求，那么该细菌可以称为益生菌：在消化道中普遍的苛刻条件下(胃的低pH，消化系统的酸性等)保持生活力；附着在肠壁上；在肠内代谢；技术上可应用(能承受处理)；显示了临床检验的和报告的健康作用；且食用安全(Lee，Y-K和Salminen，S.1995即将到来的益生菌时代，Trend Food Sci Technol，6：241-245)。
益生元是不易消化的食物组分，在结肠中其通过选择地刺激一个或一些益生细菌的生长和活性促进人类的健康(Gibson，G.R.和Roberfroid，M.B.1995.饮食调整人结肠微生物群-引入益生元概念J.Nutr.125：1401-1412)。益生元通常是不易消化的碳水化合物(寡糖或多糖)或在上消化道中不被降解或吸收的糖醇。用在商品中的已知益生元包括菊粉(果寡糖或FOS)和转半乳-寡糖(transgalacto-oligosaccharide)(GOS或TOS)。
合生素定义为益生元和益生菌的联合，其中益生元促进所添加的微生物的生活力和其对肠的粘附，由此促进健康(Gibson和Roberfroid 1995，上文)。当已通过小肠的不易消化的碳水化合物在结肠中发酵时，形成例如短链脂肪酸、其它有机酸、醇、氢和二氧化碳(Gibson和Roberfroid 1995，上文)。发酵中产生的主要脂肪酸是乙酸、丁酸和丙酸(Cummings，J.H.短链脂肪酸，《人结肠细菌：营养、生理和病理作用》(Human ColonicBacteria：Role in Nutrition，Physiology and Pathology)G.R.Gibson和G.T.Macfarlane(编辑)，101-130页，CRC Press，Boca Raton，1995)。短链脂肪酸数量的增加通常是有益的。尽管不易消化的碳水化合物也可能包括肠道发酵不利的化合物，但是，它们是结肠微生物的主要底物(Gibson和Roberfroid 1995，上文)。
人消化道容纳了大量与宿主共生生活的细菌。在消化道的不同部分之间微生物的内容有很大差异，所有肠道细菌中有大约95％出现在结肠中，结肠是肠的最重要部分。估计在结肠中旺盛地生长着400多种细菌物种。除了这些以外，肠道中还包含称为暂居微生物的微生物(G.R.Gibson和M.B.Roberfroid(编辑)《结肠微生群：营养和健康》(Colonic Microbiota；Nutrition and Health.)Kluwer Academic Publisher，Dordrecht，1999)。优势物种如下：拟杆菌属(Bacteroides)、双歧杆菌属(Bifidobacterium)、粪球菌属(Coprococcus)、消化链球菌属(Peptostreptococcus)、真杆菌属(Eubacterium)和瘤胃球菌属(Ruminococcus)。乳杆菌属(Lactobacillus)、链球菌属(Streptococcus)、梭杆菌属(Fusobacterium)、韦荣氏球菌属(Veillonella)、丙酸杆菌属(Propionibacterium)和肠杆菌科(Enterobacteriaceae)物种的数量稍微少些。其中一些物种是有用的微生物，而其它物种甚至可能是有害的。在粪便中平均微生物含量是1012cfu/g(每干物质)。细菌在结肠中降解和发酵小肠中不吸收的那些食物组分，身体可以利用肠道所吸收的发酵终产物。除了营养外，结肠内的微生物平衡对人的健康状况有重要意义(Tannock，G.W.1998.肠道微生物群的研究：研发益生菌的先决条件Int.Dairy J.8：527-533)。肠内菌群组成的改变或其数量的突然减少(由于严重腹泻，抗生素治疗等)将增加潜在病原物种的感染性，这可能造成严重的后果(过敏的发作，肠道疾病，癌症)。
例如，认为肠细菌产生的β-葡糖醛酸酶有利于致癌化合物的形成。类固醇和其它致癌化合物在肝中代谢，然后与葡糖醛酸缀合。胆汁将缀合的葡糖醛酸内脂化合物递送到小肠，化合物进一步经过小肠到达结肠，在结肠中葡糖醛酸酶能水解这些化合物，由此释放毒性化合物进入结肠(Rowland，I.R.1995.结肠毒理学：肠道微生物群的作用，《人结肠细菌：营养、生理和病理作用》编者：Gibson，G.R.和Macfarlane，G.T.155-174页，Boca Raton：CRC Press)。真杆菌属、拟杆菌属和梭菌属种被认为比双歧杆菌属和乳杆菌属代表物种可以释放更大量的这些有害酶进入肠。因此，这提供了为什么由双歧杆菌和乳杆菌组成的肠内菌群是有益的一个原因。
此外，例如来源于蔬菜和茶的糖苷在小肠中不被吸收，其经过小肠到达结肠，在结肠它们可以通过β-葡糖苷酶作用水解，形成有毒或致诱变的苷元化合物(Goldin，B.R.1990.肠道微生物群：药物和致癌剂的代谢Annalsof Medicine 22：43-48)。
而且，肠内菌群产生降解脲为氨的脲酶。高数量的氨对肠上皮细胞有毒(Mobley，H.L.T.和Hausinger，R.P.1989.微生物脲酶：意义、调节和分子表征Microbiological Review 53：85-108)。
人的肠内菌群是在生命的早期形成的，此后其组成不会发生较大的变化。仅可能发生物种内的微小变化(例如，在双歧杆菌内)。
随着对肠内菌群重要性的日益增加理解，研究已经活跃地集中于发现可以通过加强有益细菌物种而减少有害细菌物种用于影响菌群组成及菌群活动(生活力)的因子。促进有益细菌的益生元被认为可以影响微生物的活动。对半乳寡糖(GOS)已经进行广泛的研究，其是二、三、四、五和六糖，而且其主要含有半乳糖单元。它们是从乳糖酶促制备的，而且终产物的内容取决于所用的酶(Matsumoto，K等，1993.半乳寡糖，《寡糖：制备，性质和应用》(Oligosaccharides.Production，properties andapplication.)编辑Nakakuki，T.Japanese Technology Reviews.3卷，2号，90-116页，Gordon and Breach Science Publishers，瑞士，澳大利亚)。较早已经证明GOS显示了例如双歧因子(bifidogenic)特性，即促进双歧杆菌生长的特性(Ito，M等，1990.施用半乳寡糖对人排泄物中微生物群、粪便重量和腹部感觉的影响Microb.Ecol Health Dis.3：285-292)。
背景技术描述
在本领域文献中已经大量描述了含有单个益生菌株系的产品和大量不同益生菌的联合。在本领域的文献中也已经描述了合生素。
例如EP 904784公开(N.V.Nutricia)描述了含有双歧杆菌、屎肠球菌(Enterococcus faecium)和乳杆菌的益生菌产品。此外，该产品可以含有益生元(如多糖和非降解性淀粉)和免疫球蛋白、维生素等。根据该公开，因为该产品可以例如刺激免疫系统，所以其有促进健康的作用。然而，该作用没有在临床试验中被证实，也没有任何其它生物学活性的研究。
WO 00/33854，(N.VNutricia)描述了包含益生菌和寡糖的产品。尽管也提到了片球菌属(Pediococcus)、丙酸杆菌属、明串珠菌属(leuconostoc)和酵母属(Saccharomyecs)，但是此益生菌特别指乳杆菌属和双歧杆菌属。涉及的益生元包括转半乳寡糖(TOS)和果寡糖(FOS)。根据该公开，特别有益的联合包括鼠李糖乳杆菌和转半乳寡糖或马铃薯半乳聚糖的水解产物，在实施例中也示例了这种联合和其制备。根据该公开，产品有促进健康的作用，而且在肠道失调治疗方面特别有用。然而，没有以任何方式证明其活性。
WO 97/34615(University of New South Wales)描述了益生菌组合物，其除了含有一种或多种益生菌外还含有耐受性(非降解性)淀粉和寡糖，在这三种成分间获得了协同效应。所提到的益生菌是酵母属，双歧杆菌属，拟杆菌属，梭菌属(Clostridium)，梭杆菌属，丙酸杆菌属，乳球菌属，链球菌属，肠球菌属，葡萄球菌属(Staphylococcus)，消化链球菌属和乳杆菌属；寡糖尤其包括果寡糖和半乳寡糖。实施例表明了双歧杆菌、玉米淀粉和果寡糖对双歧杆菌数量有协同效应。然而，没有描述任何治疗效果。
US 5,895,648(Sitia-Yomo S.p.A.)描述了益生菌组合物，其包含冻干形式的活细菌，即至少两种双歧杆菌和至少两种乳杆菌或链球菌，它们与一个或多个寡糖相联合。组合物包含一共4到20重量份的益生菌和5到22重量份的寡糖，其中所提及的寡糖是例如半乳寡糖和果寡糖，特别提到了菊粉。提到的益生菌包括短双歧杆菌(Bifidobacterium breve)、婴儿双歧杆菌(Bifidobacterium infantis)、长双歧杆菌(Bifidobacterium longum)、两歧双歧杆菌(Bifidobacterium bifidum)、嗜酸乳杆菌(Lactobacillusacidophilus)、保加利亚乳杆菌(Lactobacillus bulgaricus)、干酪乳杆菌、植物乳杆菌(Lactobacillus plantarum)、嗜热链球菌(Streptococcusthermophilus)和屎链球菌(Streptococcus faecium)。根据该公开，含有益生菌和益生元的混合物可以加到基于奶的甜食、奶或汁中以平衡肠的功能。然而，没有描述该联合的任何生物活性。
出版物Milchwissenschaft(1998)，53卷，11号，603-605页描述了含有三种细菌株系：费氏丙酸杆菌舍氏亚种(Propionibacterium freudenreichiisubsp.shermanii)MTCC 1371、嗜酸乳杆菌R.和两歧双歧杆菌NDRI的PAB奶。该产品中没有加益生元。根据该公开，PAB奶适于婴儿和儿童，也适合患有乳糖不耐受症的人。
WO 99/10476描述了特定细菌株系，即鼠李糖乳杆菌HN001(NM97/09514)和HN067(NM97/01915)及嗜酸乳杆菌HN017(NM97/09515)和乳双歧杆菌HN019(NM97/09513)对免疫系统的刺激作用，该刺激作用经测定为增强的吞噬作用。这些株系可以单独使用，或加入到奶产品或药物制剂中。
US 5,902,578(Abbott Laboratories)涉及用罗伊氏乳杆菌(lactobacillus reuterii)、嗜酸乳杆菌和婴儿双歧杆菌混合物预防和治疗腹泻的方法，该混合物制备为粉末、液体或丸剂。
在背景技术中也已经描述了上述类型的益生菌和合生素的生物学与治疗作用。作为例子可以提到Gallagher，D.等，Journal of Nutrition(1996)，126卷，5号，1362-1371页，其中描述了在大鼠中双歧杆菌和嗜酸乳杆菌对结肠癌的作用，并指出通过联合使用细菌和果寡糖获得了最好结果；而且，Kirjavainen，P.等，Clinical and Diagnostic LaboratoryImmunology(Nov 1999)，6卷，6号，799-802页描述了两个单独研究的乳酸株系，鼠李糖乳杆菌GG和费氏丙酸杆菌舍氏亚种JS对小鼠淋巴细胞水平和由此的免疫应答的积极效果。但没有描述或研究这两个细菌的联合。
在本领域的文献中也已经描述了益生菌和有治疗效果的其它物质的联合。例如，WO 97/29762和WO 97/29763(Procter & Gamble Company)描述了与半乳寡糖或果寡糖联合的乳杆菌和双歧杆菌和石南科(Ericaceae)植物或其提取物一起在尿道感染和肠失调治疗中的用途，而且，WO 00/29007(Reddy)描述了益生菌，如乳球菌属、乳杆菌属、片球菌属、链球菌属、丙酸杆菌属、短杆菌属(Brevibacterium)、青霉属(Penicillium)和酵母属与基于草本植物的天然产品和药样物质的联合。
尽管已经广泛研究了益生菌和合生素，但是在相当大程度上尚未得到好的和多种多样的商品。因此，存在给消费者提供新产品的继续而明显的需要，所述新产品有清楚证实的益生菌效果，并且可以制备成使其能作为例如每日饮食的方便部分或增补物使用的形式。
发明概述
因此，本发明的目的是提供新的含益生菌的产品，其益生菌作用已经清楚证明，其使用起来舒适而且对消费者是健康的。
用包含多种益生菌的本发明新联合达到了这些目的。因此本发明是基于新的联合，其包含两种乳杆菌株系、一种丙酸杆菌和/或一种双歧杆菌。此外，优选此联合还包含支持上述微生物生长的益生元。
根据本发明，主要利用两个乳杆菌株系，即鼠李糖乳杆菌LGG(ATCC53103)和鼠李糖乳杆菌LC705(DSM 7061)。丙酸杆菌通常是费氏丙酸杆菌舍氏亚种PJS(DMS 7067)。双歧杆菌可以是有益生菌作用的任何双歧杆菌，通常使用属于短双歧杆菌、婴儿双歧杆菌、长双歧杆菌、两歧双歧杆菌和青春双歧杆菌(Bifidobacterium adolescentis)的株系。
通常至少包含这些细菌中的三种，并且优选所述联合包含鼠李糖乳杆菌LGG和/或费氏丙酸杆菌舍氏亚种PJS。
最优选的联合是四种株系，即鼠李糖乳杆菌LGG(ATCC 53103)、鼠李糖乳杆菌LC705(DSM 7061)、费氏丙酸杆菌舍氏亚种PJS(DMS 7067)和婴儿双歧杆菌Bbi99(DSM 13692)的联合。然而，如果期望，联合中可以包含任何双歧杆菌(如BbI2)。所用益生元优选半乳寡糖(GOS)。
另一个优选的组合物是双歧杆菌和丙酸杆菌的联合，其中可以与费氏丙酸杆菌舍氏亚种PJS(DMS 7067)一起使用任何双歧杆菌。
可以就此使用此新的联合，或将其用作另一个产品(如药品或食品)的一部分。本发明的联合对人肠内平衡有有益的效果，因为它增加了肠内酯(entero-lactone)的产生并降低了不利的高pH值。该联合通过增加淋巴细胞和γ-干扰素(IFN)的量及通过降低致癌物质的形成也影响了免疫应答。因此，本发明的联合对于肠失调、过敏和癌症的预防和治疗及促进总体健康是有用的。
因此根据本发明，此联合也适用作治疗物质和用于治疗物质的制备中。
本发明的详述
在现有技术中已经描述了本发明所用的株系，鼠李糖乳杆菌GG(LGG)、干酪乳杆菌鼠李糖亚种(Lactobacillus casei ssp.rhamnosus)LC705和费氏丙酸杆菌舍氏亚种JS(PJS)。可以包含在该联合中的婴儿双歧杆菌Bbi99是一种新的株系，在下面将对其作更详细描述。
例如，在美国专利5,032,399，(Gorbach & Goldin)中描述了鼠李糖乳杆菌GG(LGG)。该株系是从人粪便中分离的，它在pH3中能很好生长，并且在甚至更低pH及高胆汁酸含量中也能存活。该株系对粘膜和上皮细胞都显示了优良的粘附作用。其从葡萄糖可以得到很好的乳酸产量：当在MRS肉汤中生长时，该株系产生了1.5-2％的乳酸。该株系不发酵乳糖，因此不从乳糖产生乳酸。该株系利用下面的碳水化合物：D-阿拉伯糖，核糖，半乳糖，D-葡萄糖，D-果糖，D-甘露糖，鼠李糖，半乳糖醇，肌醇，甘露醇，山梨糖醇，N-乙酰氨基葡萄糖，苦杏仁苷，对苯二酚葡萄糖苷，七叶苷，水杨苷，纤维二糖，麦芽糖，蔗糖，海藻糖，松三糖，龙胆二糖，D-塔格糖，L-岩藻糖和葡糖酸。该株系在+15℃-45℃生长良好，最适温度是30-37℃。鼠李糖乳杆菌GG保藏在保藏单位：美国典型培养物保藏中心(ATCC)，保藏号ATCC 53103。
在F1专利92498(Valio Oy)中较详细地描述了干酪乳杆菌鼠李糖亚种LC705。LC705是以链的形式存在的革兰氏阳性短杆菌；它是同型发酵细菌；弱蛋白水解；在+15℃-45℃生长良好；不从精氨酸产生氨；过氧化氢酶阴性；当在MRS肉汤(LAB M)中生长时，该株系产生1.6％有L(+)构型旋光活性的乳酸；该株系分解柠檬酸(0.169％)，因此产生双乙酰和3-羟基丁酮；该株系可以发酵至少下列碳水化合物(糖，糖醇)：核糖，半乳糖，D-葡萄糖，D-果糖，D-甘露糖，L-山梨糖，鼠李糖，甘露醇，山梨糖醇，甲基-D-糖苷，N-乙酰氨基葡萄糖，苦杏仁苷，对苯二酚葡萄糖苷，七叶苷，水杨苷，纤维二糖，麦芽糖，乳糖，蔗糖，海藻糖，松三糖，龙胆二糖，D-松二糖和D-塔格糖。LC705弱粘附于粘膜细胞，但是适度地粘附于上皮细胞。在低pH值和高胆汁酸含量中，该株系的生活力良好。在5％盐浓度中该株系很好地存活，在10％盐浓度中该株系相当好地存活。干酪乳杆菌鼠李糖亚种LC705保藏在德意志微生物保藏中心GmbH(DSM)，保藏号DSM 7061。
在F1专利92498(Valio Oy)中也较详细地描述了费氏丙酸杆菌舍氏亚种JS(PJS)。PJS为革兰氏阳性短杆菌；它可以发酵葡萄糖，果糖，半乳糖和乳糖；它能很好地发酵乳酸；它的最适生长温度是32℃。在低pH值和高胆汁酸含量中，该株系的生活力是优良的。费氏丙酸杆菌舍氏亚种JS保藏在德意志微生物保藏中心GmbH(DSM)，保藏号DSM 7067。
从健康新生儿的粪便中分离了婴儿双歧杆菌Bbi99。婴儿双歧杆菌Bbi99是革兰氏阳性多形杆菌。该株系是过氧化氢酶阴性，果糖-6-磷酸-磷酸转酮酶阳性(F6PPK)及α-和β-半乳糖苷酶与α-和β-葡糖苷酶阳性。婴儿双歧杆菌Bbi发酵下列碳水化合物：核糖，半乳糖，D-葡萄糖，D-果糖，D-甘露糖，甲基-D-甘露糖，N-乙酰氨基葡萄糖，七叶苷，水杨苷，纤维二糖，麦芽糖，乳糖，蜜二糖和龙胆二糖。最适的生长温度是30-40℃而最适pH6.5-7.0。当在含有己糖的肉汤中生长时，该株系产生L-乳酸和乙酸(以2∶3的比率)。DNA的G+C含量是55-67mol％。根据布达佩斯条约，婴儿双歧杆菌Bbi99在2000年8月28日保藏在德意志微生物保藏中心GmbH(DSM)，保藏号DSM 13692。
本发明的联合也可以包含其它微生物，如奶品工业所用引子中含有的微生物和益生菌。存在很多文献很好记载的引子株系，从生产商如HansenA/S，(丹麦)和Danisco/Wiesby GmbH(德国)可以商购得到该引子株系。
为了制备本发明的联合，用本领域常规的方法培养微生物。它们可以作为纯培养物或作为不同混合的培养物培养。培养物可以就此使用，或可以如期望地例如通过纯化、浓缩、冻干或精加工进行处理以生产各种制品。
在联合中使用足够量的益生菌以产生期望的益生菌效果。因此，每种益生菌的量根据例如所用的株系和它们的数量、益生菌细胞总数、总的日剂量及产品的其它特性和组分可以在宽的范围内变化。此联合的日剂量通常包含约106-1010cfu的益生菌。
优选向联合中加入一个或多个益生元以形成合生素。根据涉及的联合中含有的微生物选择益生元，以便其能支持微生物的生长。适宜的益生元可以包括例如寡糖，特别是半乳寡糖(GOS)，低聚异麦芽酮糖(palatinoseoligosaccharide)，大豆寡糖，龙胆寡糖，低聚木糖，非降解性淀粉，乳蔗糖，乳果糖，乳糖醇，麦芽糖醇，聚右旋糖或类似物。向合生素加入足够量的益生元以产生益生元效果。可以根据例如涉及的株系、包含的益生元的量及产品的其它内容物和应用，确定什么是足够量。因此，该量也在宽的范围内变化；例如在日剂量中它可以是0.5到5g。
益生元不一定需要包含在联合中。根据终产品和应用的目的，尽管益生元可以几乎与益生菌联合同时使用，但是单独地食用益生元可能更好。在一些情况下，可能仅消耗益生菌联合就足够了，因此根本不需要益生元。当宿主肠内条件不需要添加益生元就适合益生菌生长时以及当正常饮食中含有益生元时(例如，如果它在麦片粥或黑麦面包中提供时)即是这种情况的例子。
本发明已证明所用微生物满足设定的益生菌标准：它们在消化道的苛刻条件下很好地生存，很好地粘附于肠道细胞并在肠内很好地繁殖。也已证明它们显示了优良的生物学作用；例如，它们可以增加从健康观点考虑的期望微生物的数量而降低肠内有害微生物的数量，它们可以降低有害酶的活性并由此降低有害或甚至致癌物质的形成，而且它们可以对免疫应答产生刺激作用。
本发明的联合可以就此或以例如在制备药品的常规方法中制造的胶囊，丸剂或片剂形式使用。也可以向各种可食用产品，如食品、饮料或糖果工业产品、促进健康的产品、天然产品等中加入本发明的联合。在本发明上下文中，优选含有本发明联合的产品，如奶产品，特别是酸奶和其它发酵的奶产品；奶酪和糊；儿童食品；汁和汤；和胶囊。胶囊形式的产品通常仅含有益生菌联合，而益生元单独服用。
可以以常规方法制备终产品，本发明联合可以在制备时加入，或者此后在终产品精加工期间加入。
参考下面的实施例更详细地描述本发明，实施例仅意指示例本发明，其不以任何方式限制本发明的范围。
实施例1
本发明联合的制备
从细菌混合物中制备本发明联合，当期望时，添加半乳寡糖(GOS)作为益生元。从四个株系，即鼠李糖乳杆菌LGG(ATCC 53103)、鼠李糖乳杆菌LC705(DSM 7061)、费氏丙酸杆菌舍氏亚种PJS(DSM 7067)和婴儿双歧杆菌Bbi99(DSM 13692)的细菌培养物(浓缩物或冷冻干燥的粉末)形成所述细菌混合物。
单独地培养LGG和双歧杆菌
在包含5.0％低蛋白乳清粉(Valio Oy)，0.5％酪蛋白水解产物(ValioOy)，0.5％工业酵母和0.0015％ MnSO4xH2O的培养基中培养LGG。在水中溶解培养基成分，灭菌培养基(在120℃，20分钟)。在37℃的温度和pH5.8(用NH4OH调节)下及在100rpm的混合速率下培养约18小时。培养后，用10％(v/v)保护剂补料(如46％的蔗糖肉汤或本领域技术人员已知的类似替代物)浓缩、洗涤和冷冻干燥细菌细胞。培养物中最终细菌含量＞1×109cfu/ml，浓缩物中＞1×109cfu/g，冻干粉末中＞1×1011cfu/g。
双歧杆菌的生长培养基的组成如下：低蛋白乳清粉(Valio Ltd.)4％，酪蛋白水解产物(Valio Ltd.)1.0％，工业酵母(LAB M)1.0％，半胱氨酸-HCl(Merck，Darmstadt，德国)0.03％。将培养基的其它组分最先溶解在水中，然后加入半胱氨酸-HCl，灭菌培养基(在120℃，20分钟)。在37℃的温度和pH6.7(用NH4OH调节)下及在100rpm的混合速率下培养约18-20小时。培养物中的细菌含量＞1×109cfu/ml。培养后，用10％(v/v)保护剂补料(如46％的蔗糖肉汤或本领域技术人员已知的类似替代物)浓缩、洗涤和冷冻干燥细菌细胞。浓缩物中细菌含量＞1×1010cfu/g，冻干粉末中＞1×1011cfu/g。
通过以1∶2的比率接种细菌细胞到基于乳清的生长肉汤中，一起培养LC705和PJS。基于乳清的生长培养基含有3.5-5％低蛋白乳清粉(ValioOy)，1.0％酪蛋白水解产物，1.0％酵母提取物(Valio Oy)。在30℃培养所述株系3天，其中通过自动pH调整方法维持pH在4.5。培养后，每个细菌株系的含量＞1×109cfu/ml。培养后，用10％(v/v)保护剂补料，如46％的蔗糖肉汤或本领域技术人员已知的类似替代物浓缩，洗涤和冷冻干燥细菌细胞。浓缩物中每种细菌的含量＞1×1010cfu/g，冻干粉末中＞1×10cfu/g。
也可以单独培养所述的株系。在此情况下，LC705按上述与共同培养有关的方法进行培养，但在30℃培养时间仅是1天。PJS在包含2％低蛋白乳清粉、1.0％酪蛋白水解产物和1％酵母提取物的基于乳清的生长培养基中培养。在pH6.3中，在30℃培养该株系3天，之后，执行上述过程。
以1∶1∶1的比率混合浓缩物或粉末。当LC 705和PJS单独培养时，混合的比率是1∶1∶1∶1。将获得的浓缩物或冻干粉末混合物用作本联合的不同产品施用物中的益生菌部分。向产品施用物中加入混合物以在产品中获得下列最终细菌含量：
LGG ＞106cfu/g产品
LC 705 ＞106cfu/g产品
PJS ＞106cfu/g产品
双歧杆菌 ＞106cfu/g产品
当期望时，GOS(Valio Oy)作为单独产物加入到产品施用物中以在产品中获得约0.5-5g/剂的GOS浓度。
实施例2
株系的粘附特性和它们在肠内条件下的耐受性
根据Ouweland等(Ouwehand，A.C.Kirjavainen，P.V.
M.-M.Isolauri，E.和Salminen，S.J.1999.益生微生物对肠粘膜的粘附Dairy J.9：623-630)，检测这些益生菌株系对粘膜的粘附性。LGG和益生菌PJS极好地粘附于肠粘膜上，Bbi99中度粘附，LC705弱粘附。粘附是微生物在肠内产生有益效果的先决条件。另一方面，已知LC705可以很好地粘附上皮细胞，这与LGG类似(Lehto，E.和Salminen S.1997.两种乳杆菌、一种乳球菌和一种丙酸杆菌对培养的人肠CaCO-2细胞系的粘附，Bioscience Microflora 16：13-17)。当肠内失去平衡和保护性粘膜弱化时，该特性是有益的。
表1益生菌株系的粘附特性
体外试验表明所述株系耐受生理胆汁盐含量和胃的低pH。
在MRS肉汤中，在不同pH值下检测所述株系，其中pH用乳酸调到数值pH4，pH3和pH2。在pH肉汤中接种1％的待研究的株系(新鲜的培养物)，在37℃生长3小时，之后，用适宜所述株系的琼脂测定活细胞的含量(见表5)。在pH3中，在3小时过程中，所述株系很好地保持了它们的生活力。丙酸杆菌即使在pH2中也保持了生活力。在试验中，细菌不受食物带有的成分(如脂肪)的保护，因此，我们认为，当它们与食物一起体内消耗时可以保存得甚至更好。
表2在调整pH的MRS肉汤中培养的株系的细胞含量
关于胆汁盐的耐受性，通过接种1％新鲜培养物到待研究的胆汁盐MRS肉汤中，在含有0.3％和0.5％Oxgal(Sigma)胆汁盐的MRS肉汤中检验所述株系。
在37℃，在肉汤中培养所述株系3小时，之后，用适宜该株系的琼脂测定活细胞的含量(见表5)。所有株系均经受住了处理而极好地存活下来。
表3在0.3％和0.5％胆汁盐含量中培养的株系的细胞含量
实施例3
筛选适宜本联合的益生元
通过在添加有1％待研究益生元的无糖MRS肉汤中培养每个株系，研究对于每个株系可选择使用的益生元。将每个株系在其最适温度下培养1-2天。在试验期间，通过用分光光度法测定培养物的浊度观察细菌生长。如表4所示，对于所有四株株系的生长而言最好的促进剂是1％半乳-寡糖(GOS)增补物。
表4益生元对细菌生长的作用
实施例4
终产物的制备
用功能饮料(Finnish‘tehojuoma’中；Valio Oy)作为制备汁(剂量65ml/天)的基础，其中所述每剂量(＝65ml)汁中添加0.1g冻干的细菌混合物和70％GOS糖浆3.8g。用没有添加GOS糖浆或细菌混合物的相应汁作为对照。
成品汁的细菌含量如下：
LGG ＞107cfu/ml
LC705 ＞107cfu/ml
PJS ＞108cfu/ml
Bbi99 ＞107cfu/ml
产品用于下面的临床试验中，其中pro＝汁+益生菌增补物和syn＝汁+益生菌+益生元增补物。
实施例5
本发明联合的临床效果
对20位男性临床试验实施例4所述的饮料，该饮料包含上述益生菌联合(Pro)或益生菌联合和益生元(Syn)。根据研究计划，受试者每日饮用饮料，而且在研究期间，不允许他们消费任何其它含有益生菌的产品。研究方案是，试验开始于安慰剂导入期(run-in period)，接着进入两周的益生菌期和随后的合生素期，然后结束于所谓的安慰剂洗脱期(wash-outperiod)。
研究方案和进度表
每一期的最后，受试者提供了粪便样品和血液样品(＝N)。
从粪便样品分析微生物和酶，从血液分析肠内酯含量和免疫应答。
5.1微生物
微生物的数量
用本领域已知的方法和表5中的参数确定总乳酸菌的含量(LGG、LC705)，总丙酸杆菌含量(PJS)和总双歧杆菌的含量。
表5测定微生物的方法
| 测定 | 琼脂 | 培养温度/时间 | |
| 乳杆菌 | MRS | 37℃/3天 | 厌氧的 |
| LGG | MRS+0.005％万古霉素(Sigam) | 37℃/3天 | |
| LC705 | MRS+0.005％万古霉素 | 37℃/3天 | |
| 丙酸杆菌 | Mod.YEL | 30℃/7天 | 厌氧的 |
| PJS | Mod.YEL | 30℃/7天 | 厌氧的 |
| 双歧杆菌 | 棉子糖琼脂(RB) | 37℃/2天 | 厌氧的 |
对体内肠细菌细胞含量的影响
在受试者使用含有益生菌产品的期间，在受试者的样品中LGG，LC705和PJS的含量显著增加(表6)。因为从最开始试验时双歧杆菌含量就高，所以推测改变仅发生在种内。
表6细菌含量(log，cfu/g粪便；±标准差)
向摄取试验中消费的产品中添加合生素改善了所加入的益生菌在肠内的生活力。例如，这已通过合生素期间LGG含量的增加得到了证明。
对pH的影响
在服用益生菌混合物和合生素的组中，有最初高于7的pH水平的人的pH水平降低了，而在最初pH值低于7的人中没有观察到降低(表7)。
表7益生菌和合生素补充后pH的变化
| 对照 | 单独的益生菌 | 合生素 | |
| pH＞7 | 7.2 | 6.9 | 6.7 |
| pH＜7 | 6.6 | 6.7 | 6.6 |
5.2酶
如Ling等(Ling，W-H.Korpela，R.
H.Salminen，S.和
O.1994补充乳杆菌GG减少健康成年女性的结肠水解和还原活性Journal of Nutrition 124，18-24)所述处理粪便样品。
如Freeman(Freeman，H.J.1986.在1，2-二甲基肼诱导的大鼠结肠癌发生中不同纯化的纤维素果胶和半纤维素纤维对粪便中酶的影响Cancer Research 46：5529-5532)所述测定β-葡糖醛酸酶和β-葡糖苷酶，根据制造商(Boehringer Mannheim cat no.542946)的说明书测定脲酶。
在试验过程中，在益生菌摄取和合生素摄取期间，β-葡糖醛酸酶、脲酶和β-葡糖苷酶的含量减少了(表8)。摄取后，酶的水平恢复到正常。合生素比益生菌混合物对酶的水平有更强的降低作用。
表8酶含量的变化(nmol/分钟/g粪便)
葡糖苷酶和葡糖醛酸酶的代谢产生了致癌化合物。通过本发明的益生菌和合生素联合产生的酶活性的显著降低清楚地证明了与致癌物质形成降低有关的积极效果。
5.3肠内酯的含量
用Adlercreutz等的方法(Adlercreutz，H.Fostis T.Lampe，J.
K.
T.Brunow，G.和Hase，T.1993.通过同位素稀释气相色谱质谱定量测定杂食和素食女性血浆中的木脂体和异黄酮类化合物Scan J.Clin Lab Invest 53：5-18)测定肠内酯的含量。
作为合生素摄取的结果，最初肠内酯水平＜10nmol/l的受试者的肠内酯水平显著增加了(达到11.2的水平)。
在试验期间，没有观察到在试验开始时血清肠内酯水平已经正常(10＜x＞30)的人的肠内酯水平有变化。结果如表9所示。
表9试验期间肠内酯含量(根据最初的水平分组)
| 10＜x＞30nmol/l | ＜10nmol/l | |
| 最初的水平益生菌合生素 | 24.419.823.9 | 3.22.611.2 |
已经证明肠内酯含量与患癌症的风险明显相关：含量越高，风险越低。因此，该结果也表明本发明的益生菌和合生素联合对降低癌症风险具有有益的效果。
5.4免疫学研究
对淋巴细胞功能的影响
开始合生素产品摄取前和已经开始摄取后4周后研究淋巴细胞功能。
按如下研究淋巴细胞的功能：
用Ficoll梯度从外周血分离淋巴细胞。在RPMI培养肉汤(NationalPublic Health Institute；department of nutrient broth)中用PHA促细胞分裂剂(Sigma)刺激淋巴细胞，该培养肉汤含有5％灭活的AB+血清(FinnishRed Cross)和L-谷氨酰胺。48小时后，从4个相邻的培养孔中收集细胞培养基用于细胞因子测定，在所述培养孔的为每个孔中细胞浓度为每200μl培养肉汤有200000个细胞并且孔中有或无促细胞分裂剂。加入胸腺嘧啶核苷16小时后收集细胞，测定掺入DNA的放射性胸腺嘧啶核苷(cpm)。通过用ELISA方法，从细胞培养肉汤测定细胞因子IL-4，IL-5，TGF-β1和IFN-γ的含量。
在跟踪调查期间，没有检测到淋巴细胞分泌的IL-4，IL-5和TGF-β1含量的变化。在跟踪调查期间，由PHA刺激的淋巴细胞分泌的IFN-γ含量显著增加(p＝0.009，Wilcoxon检验，参见图1)。在跟踪调查期间，淋巴细胞的自发和PHA刺激的增殖均增加(两种情况p＝0.0002，wilcoxon检验，图1和2)。
根据研究的结果，因此，合生素产品的应用促进了受试者淋巴细胞的增殖和IFN-γ细胞因子的分泌。IFN-γ属于所谓的Th1细胞因子，其增强细胞毒性淋巴细胞的功能，是IL-4和TGF-β1细胞因子的拮抗剂。据报告，易于过敏的人的IFN-γ分泌低下。此外，据推测有特应性和过敏反应易感性的儿童在IFN-γ分泌上成熟缓慢。因此，本发明联合对IFN-γ分泌的显著刺激作用证明了它们在过敏症的预防和治疗中的效力。
Claims (11)
1.一种组合物，其特征在于：它包含微生物鼠李糖乳杆菌LGG、鼠李糖乳杆菌LC705、费氏丙酸杆菌舍氏亚种PJS和双歧杆菌。
2.根据权利要求1所述的组合物，其特征在于：双歧杆菌是婴儿双歧杆菌Bbi99(DSM 13692)。
3.根据权利要求1所述的组合物，其特征在于：它进一步包含常规的引子微生物。
4.根据权利要求1到3任一项所述的组合物，其特征在于：它还包含益生元或与益生元一起使用。
5.根据权利要求4所述的组合物，其特征在于：益生元是寡糖。
6.根据权利要求5所述的组合物，其特征在于：寡糖是半乳寡糖(GOS)。
7.权利要求1到6任一项所述的组合物在制备治疗物质中的用途。
8.权利要求1到6任一项所述的组合物在食品工业、制药工业、或健康促进产品或天然产品的生产中的用途。
9.根据权利要求8所述的用途，其特征在于：将所述组合物添加到奶产品、饮料、汁、汤或儿童食品中。
10.根据权利要求8所述的用途，其特征在于：以单剂量的形式制备所述组合物。
11.根据权利要求10的用途，其特征在于：所述单剂量形式是胶囊。
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