CN1245994C - 唾液乳杆菌的应用 - Google Patents
唾液乳杆菌的应用 Download PDFInfo
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- CN1245994C CN1245994C CNB00802829XA CN00802829A CN1245994C CN 1245994 C CN1245994 C CN 1245994C CN B00802829X A CNB00802829X A CN B00802829XA CN 00802829 A CN00802829 A CN 00802829A CN 1245994 C CN1245994 C CN 1245994C
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Abstract
唾液乳杆菌在预防和治疗不希望的炎性活性,特别是胃肠道炎性活性如炎症性肠病或过敏性肠综合征中很有用。炎性活性也可以由癌症引起。唾液乳杆菌是人源的,分离自切除的并且冲洗过的人胃肠道。其中一株这样的菌株是在WO-A-98/35014中描述的UCC118菌株。
Description
导论
本发明涉及唾液乳杆菌(Lactobacillus salivarius)菌株的应用。
人保护胃肠道免受肠道细菌定居的防御机制是高度复杂的,并且涉及免疫学以及非免疫学方面(V.J.McCracken和H.R.Gaskins,“益生菌一个关键性评论”,地平线科学出版社,英国,1999年,第278页)。内在的防御机制包括胃中的低pH值、胆盐、蠕动、粘蛋白层和抗微生物化合物如溶菌酶(D.C.Savage,“消化道的微生物生态学”,学院出版社,伦敦,1997年,第278页)。免疫学机制包括专业的淋巴集结、隐伏M细胞、称做遍布在小肠或结肠的淋巴集结(M.F.Kagnoff,胃肠道学,1993,105,1275)。在这些位点呈递的腔抗原导致合适的T、B淋巴细胞亚群的激活,建立起细胞因子网络,并且向胃肠道分泌抗体(M.R.Neutra和J.P.Kraehenbuhl,“粘膜免疫的基本原理”,学院出版社,圣迭哥,1996年,第29页;M.E.Lamm,年度微生物学评论,1997,51,311)。此外,抗原也可经由上皮细胞呈递给表皮内的淋巴细胞或隐伏的腔Propria免疫细胞(S.Raychaudhuri等,自然生物工艺学,1998,16,1025)。因此,宿主在胃肠道的免疫学防御方面投入很多。但是,由于胃肠粘膜是宿主机体与外界环境相互作用的最大表面,在适当的位置必须有独特的控制机制以调控机体对胃肠道在平均一生的时间内所摄入的大约100吨食物的免疫反应(F.Shanahan,“胃肠道生理学”,雷文出版社,1994年,第643页)。而且,肠中定居有大约500多种细菌,在结肠中的数量为1011-1012/克。因此,这些控制机制必须能够将非致病性的附着菌与能够引起宿主显著损害的侵袭性致病菌区分开来。实际上,肠道菌群通过与新摄入的潜在致病性微生物竞争从而有助于宿主机体的防御。
服用非致病性细菌或益生菌可在健康志愿者体内引起免疫参数的增强。表1中列出了这些免疫调控效应的例子。
表1:口服益生菌的免疫增强效应
观察到的效应 | 参考文献 |
巨噬细胞吞噬作用增强自然杀伤细胞活性增强IFNγ血清水平升高B细胞和NK细胞数目增加促进IgA应答DTH应答增强 | 1011121211,13-1516 |
存在于人胃肠道中的细菌可以促进炎症。在某些疾病状况如肠炎中已经显示存在对土著微菌群的异常免疫应答(Brandzeag P等,Springer Semin.Immunopathol.,1997,18,555)。与正常菌群相关的抗原通常导致免疫耐受并且不能获得这种耐受是粘膜炎症的一个主要机制(Stallmach A等,今日免疫学,1998,19,438)。这种耐受破坏的证据包括IBD病人体内针对肠道菌群的抗体水平升高。
WO-A-98/35014中描述了从切除的并且冲洗过的人胃肠道中分离出的唾液乳杆菌,此菌能够抑制广谱的革兰氏阳性菌和革兰氏阴性菌,并且向无细胞的上清中分泌一种具有抗微生物活性的物质。
本发明的描述
免疫***主要保护宿主组织并且破坏侵入的病原体。一旦识别细菌细胞的存在,免疫***的细胞就会激活并且消除此细菌威胁。炎性介质的产生促进了细胞活化和破坏病原体。
另人惊奇的是,我们已经发现唾液乳杆菌菌株能够在体外和体内引发抗炎性反应。我们发现对唾液乳杆菌的免疫感受导致炎性活性受到抑制。有目的地服用大量的唾液乳杆菌抑制了炎性活性。因此,本发明在预防和治疗不希望的炎性反应如炎症性肠病中具有主要的潜在治疗价值。
唾液乳杆菌是一种最初分离自人胃肠道中微生物菌群的共栖微生物。胃肠道中的免疫***不能与此菌群的细菌发生显著反应,因为所产生的炎性活性也会破坏宿主细胞和组织功能。因此,存在某种(些)机制,凭借这种(这些)机制免疫***能够识别胃肠道菌群中与致病性微生物不同的共栖的非致病性微生物部分,这就确保对宿主组织的损害受到限制,并且仍然维持了防御屏障。
本发明提供了唾液乳杆菌菌株在预防和/或治疗不希望的炎性活性中的应用。
本发明中不希望的炎性活性可能是不希望的胃肠道炎性活性如肠炎,例如节段性回肠炎、溃疡性结肠炎、过敏性肠综合征、囊炎或传染病后结肠炎。
胃肠道炎性活性也可以是腹泻疾病。腹泻疾病可以是与艰难梭菌相关的或是与轮状病毒相关的腹泻。腹泻疾病也可以是传染病后腹泻病。
炎性活性也可能是由胃肠道癌症或全身性炎性活性如类风湿性关节炎所引起。
不希望的炎性活性的另外一个例子可能是由自身免疫紊乱引起。
不希望的炎性活性的又一个例子可能是由癌症引起。
在一个实施方案中,本发明提供了唾液乳杆菌菌株在预防癌症中的应用。
在另一个实施方案中,本发明提供了唾液乳杆菌菌株的应用,其中唾液乳杆菌被包含在一个配方中。
优选的配方包含另外一种益生菌物质。或者此配方包含一种益生素物质。
理想的配方包含一种可摄食的载体。此可摄食的载体可能是一种药物学可接受的载体如片剂、胶囊或粉末。
优选的可摄食载体是一种蛋白质和/或肽,特别是富含谷氨酰胺或谷氨酸的蛋白质和/或肽;一种脂类;一种碳水化合物;一种维生素;矿物质和/或微量元素。
最优选的可摄食载体是一种食品如发酵乳;酸乳酪;冻酸乳酪;奶粉;浓缩奶;涂在面包上的软质奶酪、调味品或饮料。
在一个实施方案中存在于配方中的唾液乳杆菌每克输送***大于106cfu。
在另外一个实施方案中配方中含有佐剂。此配方中也可以含有一种细菌成分。此配方可另外或额外含有一种药物本体。此配方也可以含有一种生物学化合物。
在一个实施方案中,本发明提供了唾液乳杆菌菌株的应用,其中此菌株或配方是施与动物的。优选的动物是哺乳动物,最优选人。
在另外一个实施方案中,本发明提供了唾液乳杆菌菌株的应用,其中当唾液乳杆菌菌株被引入到一个含有可与免疫***和免疫***中的细胞相互作用的细胞的***中时,可影响到免疫学标志的改变。
优选的能与免疫***相互作用的细胞是上皮细胞。最优选的免疫学标志是细胞因子特别是TNFα。
优选的能与免疫***相互作用的细胞和免疫***的细胞是来源匹配的。
在一个实施方案中与免疫***相互作用的细胞是胃肠、呼吸或泌尿生殖来源的。
在另外一个实施方案中免疫***的细胞是胃肠、呼吸或泌尿生殖来源的。
在另外一个实施方案中本发明提供了唾液乳杆菌菌株的应用,其中唾液乳杆菌菌株是唾液乳杆菌唾液亚种。优选的唾液乳杆菌是人源的,最优选来自切除的并且冲洗过的人胃肠道。
唾液乳杆菌优选抑制广谱的革兰氏阳性和革兰氏阴性微生物。最优选它向无细胞上清中分泌一种具有抗微生物活性的物质,上述活性仅由生长细胞所产生并且被蛋白酶K和链霉蛋白酶E所破坏。
一株特别优选的唾液乳杆菌菌株是唾液乳杆菌UCC118菌株或其突变株或变异株。
1996年11月27日唾液乳杆菌UCC118菌株被保藏在NCIMB,保藏号为NCIMB 40829。在WO-A-98/35014中描述了唾液乳杆菌的这株菌株。
唾液乳杆菌可以是一个基因受到修饰的突变株或是唾液乳杆菌的一天然变异株。
唾液乳杆菌菌株优选采用活细胞的形式。另外唾液乳杆菌也可以采用非活细胞的形式。
附图的简要描述
图1表示与服用安慰剂组的小鼠相比,服用UCC118菌株的小鼠中的产气荚膜梭菌水平(p<0.05)。结果是用每一组小鼠的平均对数值±标准误差绘制曲线表示的。
图2表示与对照组小鼠相比,服用UCC118菌株的小鼠的炎性分值的条形图。结果是用每一组小鼠的平均值±标准误差表示的。
图3表示服用UCC118菌株6周后患者体内的TNFα水平。结果是用每一时间点上平均的TNFα水平pg/ml绘制曲线表示的(n=22)。
图4表示服用UCC118菌株的患者在饲喂益生菌后的CDAI得分图。CDAI分数从平均180下降到平均160。
图5表示体外暴露至UCC118后的细胞因子分泌情况,结果用pg/ml表示。
图6是表示暴露至唾液乳杆菌UCC118之后细胞外TNFα、IL-1RA、IL-6、sIL-6R和IFNγ水平的条形图。
图7表示用268种细胞因子以及相关分子的特定基因序列进行基因矩阵分析以检测对UCC118的免疫应答。上面的图表示对照培养,下面的图表示暴露至UCC118之后PBMCs中的细胞因子表达情况。
图8表示在各种不同的细菌菌株存在的情况下TNFα水平的条形图。
详细描述
我们已经发展出体外选择能够反映宿主体内某些效应的益生菌的标准,例如调节GIT微菌群和调节粘膜免疫应答导致针对服用菌株的特异性分泌性抗体的产生。我们已经发现唾液乳杆菌唾液亚种UCC118不仅能够在胃肠道中存活并且粘附到人肠细胞系上,而且它们另人惊奇地具有抗炎性效应。
普遍应用活细胞形式的益生菌。但是,也可以应用非活细胞形式的益生菌如灭活的培养物或含有由益生菌所表达的有益因子的组合物。这可能包括热灭活的微生物或暴露至改变的pH值或压力而灭活的微生物。使用非活细胞的产品制备更简单一些,细胞可以很容易地掺入到药物中并且贮存要求要比活细胞受到的限制更少一些。正如在美国专利No.US4347240中所描述的那样,干酪乳杆菌YIT9018菌株提供了一个有效应用热灭活的细胞作为治疗和/或预防肿瘤生长的方法的例子。
现在尚不清楚是否施加抗炎性效应需要完整的细菌或是否本发明的个别活性成分可以单独应用。已经鉴定出了某些细菌菌株的促炎成分。革兰氏阴性细菌的促炎效应是由脂多糖(LPS)所介导的。脂多糖单独就可以诱发产生促炎网络,这可能是部分由于脂多糖与单核细胞表面的CD14受体结合的原因。由于整个细胞的效应,据推测益生菌成分具有抗炎性活性。一旦分离出这些成分,就可以实现药物学等级的操作。
从下面的实施例中我们可以更清楚地理解本发明。
实施例1:对唾液乳杆菌特别是唾液亚种UCC118菌株体内抗炎性效应的详细描述。
胃肠道炎症的小鼠模型
在某些疾病状况如肠炎中已经显示存在对土著微菌群的异常免疫应答(Brandzeag P等,Springer Semin.Immunopathol.,1997,18,555)。与正常菌群相关的抗原通常导致免疫耐受并且不能获得这种耐受是粘膜炎症的一个主要机制(Stallmach A等,今日免疫学,1998,19,438)。这种耐受破坏的证据包括IBD病人体内针对肠道菌群的抗体水平升高。此外,当在无菌条件下饲养或用抗生素处理时,某些预先在胃肠道造成炎性损伤的小鼠模型仍然维持无疾病状态(Kuhn R,等,细胞,1993,75,263;Panwala C.M.,等,免疫学期刊,1998,161,5733)。
C57BL6白细胞介素基敲除小鼠在存在肠道细菌菌群的情况下被预先发展成为结肠炎。当在无菌条件下饲养时,IL-10基因敲除小鼠并不发病(Kuhn R,等,细胞,1993,75,263)。由于这种疾病的致病性与肠道菌群相关,消除这种菌群的特异性成分可能有助于缓解疾病的严重性。
唾液乳杆菌唾液亚种UCC118是一种分离自一个健康人回肠的益生菌。由于它符合益生菌菌株挑选的许多标准,因此它适于在胃肠道中定居。这其中包括如下特征如胆汁耐受、抗酸性和体外粘附至人结肠细胞系上。已经在健康人体上进行了摄食试验,并且观察到胃肠道菌群的明显改变。此外,粘膜免疫***感知UCC118从而导致针对UCC118的特异性IgA的产生和分泌。
因此,UCC118在胃肠道中存活,调节肠道菌群并且被粘膜免疫***所感知。使用结肠炎小鼠模型检测这种益生菌在胃肠道中对调控炎性应答的影响。此外,我们检测了在胃肠道中唾液乳杆菌唾液亚种菌株在降低致瘤性改变比率中的作用。
20只IL-10基因敲除小鼠(10只饲喂含有益生菌微生物的牛奶,10只饲喂未处理的牛奶)被研究了16周。每周进行粪便微生物分析以对排出的乳杆菌、产气荚膜梭菌、拟杆菌、大肠菌、双歧杆菌和肠球菌进行计数。在处死小鼠时,对小鼠的大肠和小肠进行微生物学和组织学评价。
与对照组动物相比,试验组动物粪便中大肠菌和肠球菌水平显著下降。在处死小鼠时,在试验组小鼠中观测到产气荚膜梭菌细菌数目明显减少(图1)。与对照组中两只死于暴发性结肠炎的小鼠相比,试验组中并没有什么致命因素。与对照组肿只小鼠相比,试验组动物中仅有一只小鼠发展成为结肠腺癌。所测试动物的粘膜炎症记分持续低于对照组(图2)。服用UCC118后肿瘤发生率的降低可能与胃肠道炎症的降低有关,或可能是因为消除了胃肠道菌群的致病原成分(Rumney C.J等,致癌作用,1993。14,79;RowlandI.R(1995),在Gibson G.R(编):人结肠炎细菌:在营养中的作用,生理学和病理学,第155-174页,Boca Raton CRC出版社;Darveau D,自然生物工艺学,1999,17,19),
总之,服用唾液乳杆菌UCC118菌株导致肠道菌群的明显改变,并且在死亡率、癌症发生率和疾病记分方面有所改善。
实施例2:在具有活性节段性回肠炎的患者体内用UCC118进行的人体试验
炎症性肠病(IBD)包含许多胃肠道的炎性紊乱,包括节段性回炎症性肠病和溃疡性结肠炎。
已经用UCC118对正患活性节段性回肠炎的患者进行了治疗。简言之,22个患者服用含有UCC118的发酵牛奶产品6周。在第0、1、3和6周进行微生物学和免疫学测定。未进行安慰剂对照试验。
在摄食过程中测量了许多种身体组织细胞因子水平,特别是肿瘤坏死因子α(TNFα),一种与许多炎性疾病状态包括炎症性肠病的致病性有关的促炎性细胞因子。目前对炎症性肠病的治疗特异性旨在降低TNFα水平(Present D.H等,新英格兰医学期刊,1999,340,1398)。在这个实验中,服用UCC118后身体组织的TNFα水平下降(图3)。
此外,在6周的实验期内评价患者的节段性回肠炎指数(CDAI)。这个指数评价了每个患者的一般健康情况和福利安宁情况(图4)。全面地说,对于试验中的大多数个体来说这个疾病活性指数增加不大。这些患者患有适度活性的疾病,并且预期他们的CDAI记分会增加。但是,用UCC118治疗后,CDAI记分并未增加,并且实际上它们从平均180下降到平均160。
实施例3:体外显示唾液乳杆菌特别是唾液亚种UCC118抗炎性效应机制的详细描述
许多方法学已经被用于这些研究包括ELISAs(测定细胞外蛋白质)、流式细胞术(测定细胞内蛋白质)和cDNA表达矩阵(mRNA表达)。特别是检测肿瘤坏死因子α的表达由于其临床重要性已经被作为靶目标,并且利用所有的三种方法已经观察到暴露至UCC118之后这种细胞因子的产生受到抑制。
应用一种转孔分析***,上皮细胞和外周血单核细胞,用ELISAs方法检测细胞外细胞因子水平。与UCC118工孵育之后,与对照培养相比,所产生的TNFα的量显著减少。而且,IL-1RA和IFNγ水平下降,而IL-6和可溶性IL-6受体水平升高(图5)。细胞内TNFα染色证实了与对照相比TNFα水平低于UCC118刺激样品水平这一ELISA结果。
图6显示了所发生的三细胞信号。PBMCs和唾液乳杆菌UCC118菌株共孵育导致对TNFα产生的刺激。但是,PBMCs、唾液乳杆菌UCC118菌株和上皮细胞(CaCo-2细胞)共孵育导致对TNFα产生的显著抑制。因此,与单独用细菌和PBMCs相比,在三细胞模型中存在显著不同的信号特征。
使用基因矩阵的方法检测一群细胞的mRNA数量。我们利用UCC118菌株刺激外周血单核细胞24小时并且测量其对细胞因子基因表达的效应(图7)。观察到细胞因子基因表达的明显改变。例如,编码促炎性细胞因子IL-1β和TNFα的基因表达逆转,而编码Th2类细胞因子如IL-6的基因表达被增强。
体外模型表明UCC118能够诱发Th2类细胞因子(即IL-6和可溶性IL-6受体),与此同时抑制促炎性细胞因子如TNFα和IL-1β的产生。因此,这些结果表明服用UCC118对患有炎性疾病如IBD的患者有益。
实施例4:抗炎性细菌菌株的检测
在这个新型的分析***中我们检测了许多分离自人胃肠道的乳酸细菌的抗炎性效应。所有的细菌菌株取自-20摄氏度甘油冻存的菌种并且在MRS肉汤中过夜培养,并用含有抗生素的培养基洗涤。在加入PBMCs和细菌细胞之前上皮细胞单层生长6周。
这些刺激的结果见图8。与对照培养相比,两种细菌菌株抑制TNFα产生。这两种抑制TNFα表达的菌株中唾液乳杆菌UCC118菌株是WO-A-9835014的主题。长婴儿双歧杆菌(Bifidobacteriumlongum infantis)UCC35624菌株是与本申请同时递交的PCT申请的主题。
炎症
炎症是用于描述液体、胞浆蛋白和白血球在已经造成身体损伤、感染的某一部位或正发生免疫应答的部位局部积聚的属于。可在许多水平上控制炎性反应(见Henderson B和Wilson M,1998年的评论,在“健康和疾病中细菌与细胞因子的相互作用”,波特兰出版社,79-130)。控制因素包括细胞因子、激素(例如氢化可的松)、***素、反应性中间物和白细胞三烯。细胞因子是低分子量的生物活性蛋白质,其参与免疫学应答和炎性应答的产生和控制,同时也调控发育、组织修复和血细胞生成。它们提供了一种在白细胞之间以及与其它类型的细胞通讯的方法。许多细胞因子是多效的,并且表达多重生物学上重叠的活性。细胞因子级联和网络控制了炎性应答而不是某一种特别的细胞因子对某一种特别细胞类型作用的结果(Arai KI等,年度生物化学评论,1990,59:783-836)。炎性应答的降低导致较低浓度的合适的激活信号和其它炎性介质,最终造成炎性应答的停止。TNFα是一种关键的促炎性细胞因子,因为它起始造成炎性状态的细胞因子级联和生物学效应。因此,抑制TNFα的试剂现被用于治疗炎性疾病,例如Infliximab。
据认为促炎性细胞因子在许多炎性疾病包括炎症性肠病(IBD)中起主要作用。目前对IBD的治疗旨在降低这些促炎性细胞因子包括IL-8和TNFα的水平。这些治疗也可能在治疗全身性炎性疾病如类风湿性关节炎中起显著作用。
由于唾液乳杆菌的抗炎性特性,我们已经发现这些菌株可能在治疗广泛范围的炎性疾病中具有潜在的应用价值,特别是与其它抗炎性治疗例如非类固醇抗炎性药物(NSAIDs)或Infliximab一起组合使用时。
腹泻疾病
在精神紧张(乙酰胆碱)和免疫(组胺)介导的分泌时,肠上皮的屏障作用可能被破坏。某些细菌毒素也可以诱导Ca2+和PKC依赖的分泌,因此也能破坏上皮屏障(Ganguly UK和Kaur T,印度医学研究期刊,1996,104:28-37;Groot JA,Vet Q,1998,20(s3):45-9)。一些研究已经检测到用益生菌可以预防和治疗腹泻。前瞻性研究已经表明在幼儿、新生儿、儿童中应用乳酸细菌预防和治疗腹泻(Isolauri E等,Dig Dis Sci,1994,12月,39(12):2595-600)和在治疗抗生素相关的腹泻(Siitonen S等,Ann Med,1990,2月,22(1):57-9)和旅行者腹泻(Oksanen PJ等,Ann Med,1990,2月,22(1):53-6)中的效率。
由于抗炎性效应我们已经发现唾液乳杆菌也可能产生抗腹泻效应,很可能是通过cAMP调控介导的。环化AMP依赖的CI分泌是人肠道中的主要分泌途径(Brzuszczak IM等,胃肠道学和肝病学期刊,1996,11(9):804-10)。这种抗腹泻效应可能不仅仅局限于胃肠道炎症导致的腹泻,也可应用于腹泻疾病的通常治疗。
自身免疫疾病
免疫***具有一个大的由T和B细胞表达的特异性成分库。在这些特异性中有一部分是针对自身成分的。自身识别通常受到克隆耗竭和自身反应性淋巴细胞的控制。但是,存在持续性的背景自身免疫,其抗体针对血清中发现的许多蛋白质。自我-非自我识别***的破坏导致自身免疫。当发生自身免疫疾病时,所产生的免疫应答损害了带有攻击抗原的组织。免疫复合物沉积、II型超敏反应和细胞介导的应答是免疫病理损害的最主要机制。自身免疫性疾病的例子包括但不局限于全身性***红斑狼疮、类风湿性关节炎、胰岛素依赖的糖尿病mellitus、重症肌无力和恶性贫血。我们已经发现唾液乳杆菌是一种免疫调节细菌。因此,自身免疫疾病患者服用单一成分或与其它细胞组合服用可能限制器官损害并且帮助恢复正常的机体血细胞生成。
炎症和癌症
广谱类型的肿瘤产生多功能的细胞因子表明在癌症患者体内正在发生显著的炎性应答。现在尚不清楚这种应答对体内肿瘤细胞的生长和发育具有什么保护性效应。但是,这种炎性应答可能对肿瘤依附于宿主具有不利影响。在肿瘤和正常组织中复杂的细胞因子相互作用包括到细胞因子产生的调控和细胞增殖(McGee DW等,免疫学,1995年9月,86(1):6-11;Wu S等,Gynecol Oncol 1994,4月,53(1):59-63)。很久以来就已经认识到体重降低(恶病质)是癌症病人死亡的单一最常见原因(Inagaki等,癌症,1974,2月,33(2):568-73),并且起初的营养不良预示着预后较差(Van Eys,J.Nutr.Rev,1982,12月,40(12):353-9)。对于肿瘤来说,它要生长和扩展就必须诱导新血管生成并且降解细胞外基质。炎性应答可能在参与上述机制中具有显著作用,因此有助于宿主死亡和肿瘤发展。由于唾液乳杆菌的抗炎性效应,这些细菌菌株可能降低恶性细胞转化率。而且,肠细菌能够利用营养化合物产生具有基因毒性、致癌性和促肿瘤活性的物质,并且肠细菌能够激活致癌原成为DNA反应性介质(Rowland IR(1995),结肠的毒理学:肠微菌群的作用,在Gibson G.R(编):人结肠炎细菌:在营养中的作用,生理学和病理学,第155-174页,Boca Raton CRC出版社)。通常来说,与肠中的其它菌群如类菌体、真细菌和梭菌相比,乳杆菌的异生素代谢酶活性较低(Saito Y等,微生物生态学健康疾病,1992,5,105-110)。因此,增加肠中乳杆菌数量有益于改变这些酶的水平。
益生素
益生菌有机物的引入是通过摄食合适载体中的微生物完成的。提供一种能够促进这些益生菌在大肠中生长的培养基很有利。加入一种或多种寡糖、多糖或其它益生素促进了乳酸细菌在胃肠道中的生长(Gibson GR,英国营养学期刊,1998,80(4):S209-12)。益生素指在结肠中被据信具有有益价值的土著细菌如双歧杆菌、乳杆菌特异性发酵的任何非活的食物成分。益生素的类型可能包含那些含有果糖、木糖、大豆、半乳糖、葡萄糖和甘露糖的类型。益生菌与一种或多种益生素化合物组合施与可能促进所施与的益生菌在体内的生长,最终导致更明显的健康益处,被称做synbiotic。
其它活性成分
如上所述,唾液乳杆菌可以预防性施与或作为一种治疗方法单独施与或与其它益生菌和/或益生素物质一起应用。此外,此细菌可被用做使用其它活性物质如用于治疗炎症或其它紊乱特别是肠道炎症和紊乱的预防和治疗策略的一部分。这些组合可在一个单一的配方中施与或作为另外的配方在相同或不同的时间使用相同或不同的接种途径而施与。
本发明不限于此前所描述的实施方案,在细节上可能会做些改动。
Claims (31)
1.唾液乳杆菌(Lactobacillus salivarius)在制备用于预防和/或治疗炎症性肠病的药物中的应用。
2.唾液乳杆菌在制备用于预防和/或治疗节段性回肠炎的药物中的应用。
3.如权利要求1的应用,其中唾液乳杆菌被包含在一配制品中。
4.如权利要求2的应用,其中唾液乳杆菌被包含在一配制品中。
5.如权利要求3或4的应用,其中配制品包含另外一种益生菌物质。
6.如权利要求3或4的应用,其中配制品包含一种益生素物质。
7.如权利要求3至4的应用,其中配制品包含一种可摄食的载体。
8.如权利要求7的应用,其中可摄食的载体是片剂、胶囊或粉末形式的药物学可接受的载体。
9.如权利要求8的应用,其中可摄食的载体是蛋白质和/或肽,脂类,碳水化合物,维生素,矿物质和/或微量元素。
10.如权利要求9的应用,其中所述蛋白质和/或肽富含谷氨酰胺/谷氨酸。
11.如权利要求7的应用,其中可摄食的载体是选自以下一组的食品:发酵乳,酸乳酪,冻酸乳酪,奶粉,浓缩奶,涂在面包上的软质奶酪、调味品和饮料。
12.如权利要求3或4的应用,其中唾液乳杆菌以每克输送***大于106菌落形成单位的量存在。
13.如权利要求3或4的应用,其中配制品包含一种佐剂。
14.如权利要求3或4的应用,其中配制品包含细菌成分。
15.权利要求1的应用,其中当唾液乳杆菌菌株被引入到一个包含与免疫***相互作用的细胞和免疫***的细胞的***中时,其实现免疫学标志的改变。
16.如权利要求15的应用,其中与免疫***相互作用的细胞是上皮细胞。
17.权利要求15或16的应用,其中免疫学标志是细胞因子。
18.如权利要求17的应用,其中细胞因子是TNFα。
19.如权利要求15或16的应用,其中能与免疫***相互作用的细胞和免疫***的细胞是来源匹配的。
20.如权利要求15或16的应用,其中与免疫***相互作用的细胞是胃肠道、呼吸道或泌尿生殖道来源的。
21.如权利要求15或16的应用,其中免疫***的细胞是胃肠道、呼吸道或泌尿生殖道来源的。
22.如权利要求1或2的应用,其中唾液乳杆菌菌株是唾液乳杆菌唾液亚种。
23.如权利要求1或2的应用,其中唾液乳杆菌是人源的。
24.如权利要求1或2的应用,其中唾液乳杆菌分离自切除的并且冲洗过的人胃肠道。
25.如权利要求1或2的应用,其中唾液乳杆菌抑制广谱的革兰氏阳性和革兰氏阴性微生物。
26.如权利要求1或2的应用,其中唾液乳杆菌向无细胞上清中分泌一种具有抗微生物活性的产物,所述活性仅由生长细胞所产生并且被蛋白酶K和链霉蛋白酶E所破坏,其中所述抗微生物活性拮抗革兰氏阳性和革兰氏阴性微生物的生长。
27.如权利要求1或2的应用,其中唾液乳杆菌菌株是UCC118或其突变株或变异株。
28.如权利要求1或2的应用,其中唾液乳杆菌是基因修饰的突变株。
29.如权利要求1或2的应用,其中唾液乳杆菌是唾液乳杆菌的天然变异株。
30.如权利要求1或2的应用,其中唾液乳杆菌以活细胞的形式存在。
31.如权利要求1或2的应用,其中唾液乳杆菌以非活细胞的形式存在。
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IE990033A IE990033A1 (en) | 1999-01-15 | 1999-01-15 | Bifidobacterium longum infantis in the treatment of inflammatory bowel disease |
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CNB00802829XA Expired - Fee Related CN1245994C (zh) | 1999-01-15 | 2000-01-17 | 唾液乳杆菌的应用 |
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