CN1639317B - 益生菌唾液乳杆菌菌株 - Google Patents
益生菌唾液乳杆菌菌株 Download PDFInfo
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- CN1639317B CN1639317B CN028185803A CN02818580A CN1639317B CN 1639317 B CN1639317 B CN 1639317B CN 028185803 A CN028185803 A CN 028185803A CN 02818580 A CN02818580 A CN 02818580A CN 1639317 B CN1639317 B CN 1639317B
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- lactobacillus salivarius
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Abstract
一种唾液乳杆菌(Lactobacillus salivarius)菌株AH102,AH103,AH105,AH109或AH110或其突变体或变体,其可用于预防和/或治疗炎性,尤其非所希望的胃肠道炎性,如炎症性肠病或过敏性肠综合征。
Description
导言
本发明涉及唾液乳杆菌(Lactobacillus salivarius)菌株及其作为益生菌特别是作为免疫调节性生物治疗剂的应用。
保护人体胃肠道免于肠道细菌建群的防御机制非常复杂,包括免疫学和非免疫学两方面(1)。先天的防御机制包括胃液的低pH,胆盐,蠕动,粘液层和抗微生物化合物如溶菌酶(2)。免疫学机制包括在M细胞下面的特异的淋巴聚集,称为淋巴集结,其遍布于小肠和结肠(3)。在这些部位存在的腔抗原(luminal antigen)刺激合适的T和B细胞亚群,导致细胞因子网络建立及抗体分泌入胃肠道中(4)。另外,可以发生抗原呈递经上皮细胞至上皮内淋巴细胞及至下面的固有层免疫细胞(5)。因此,宿主在胃肠道免疫学防御作用中投入了许多。然而,由于胃肠道粘膜是宿主与外部环境相互作用的最大表面,必须存在特异的控制机制以调节对平均一生寿命中由胃肠道处理的100吨食物的免疫应答。另外,结肠肠道中定居有500个物种以上的1011-1012/g的细菌。因此,这些控制机制必须能将非病原性粘附细菌与对宿主造成明显伤害的侵染病原体加以区分。事实上,通过与新吸收的潜在病原微生物竞争,肠内菌群有助于宿主的防御作用。
存在于人体胃肠道中的细菌可以促进炎症。对土著微生物区系的异常应答与一些疾病状态相关,如炎症性肠病。与正常菌群相关的抗原通常产生免疫学耐受性,不能达到这种耐受性是粘膜炎症的主要机制(6)。在IBD患者中这种耐受性破坏的迹象包括针对肠道菌群的抗体水平提高。
本发明涉及唾液乳杆菌菌株,其示出通过调节细胞因子水平或者通过拮抗促炎微生物并将其从胃肠道中清除而具有免疫调节作用。
发明概述
根据本发明,提供了一种唾液乳杆菌菌株,其选自AH102,AH103,AH105,AH109或AH110及其突变体或变体中的任一个或多个。
所述突变体可以是遗传修饰的突变体。所述变体可以是唾液乳杆菌菌株的天然发生的变体。
在本发明的一个实施方案中,唾液乳杆菌菌株是活细胞形式。或者唾液乳杆菌菌株是非活细胞形式。
在本发明的一个实施方案中,所述菌株是生物学纯培养物形式。
在本发明的一个实施方案中,所述唾液乳杆菌菌株分离自切除并洗涤的人体胃肠道。优选地所述唾液乳杆菌菌株经口服由人体摄取后具有明显免疫调节作用。
本发明还提供了一种配方,其包含至少一种本发明的唾液乳杆菌菌株。该配方可以包含两或多种乳杆菌菌株。
在本发明的一个实施方案中,所述配方包括另一种益生菌材料。
在本发明的一个实施方案中,所述配方包括一种益生素材料。
优选地所述配方包括一种可摄食载体。所述可摄食载体可以是一种药物学合适的载体如胶囊,片剂或粉末。优选地所述可摄食载体是一种食品如酸奶(acidified milk),酸乳酪,冷冻酸乳酪,奶粉,浓缩奶,奶酪,调味品(dressings)或饮料。
在本发明的一个实施方案中,本发明的配方进一步包含一种蛋白质和/或肽,特别是有丰富谷氨酰胺/谷氨酸的蛋白质和/或肽,一种脂质,一种碳水化合物,一种维生素,矿物质和/或微量元素。
在本发明的一个实施方案中,配方中存在的唾液乳杆菌菌株超过106cfu/g输送系统。优选地所述配方包括佐剂,细菌成分,药物本体(drug entity)或生物学化合物中的任一或多种。
在本发明的一个实施方案中,所述配方用于免疫和接种方案。
本发明还提供了本发明的唾液乳杆菌菌株或配方作为食品、药物的应用,及在预防和/或治疗非所希望的炎性(undesirable inflammatoryactivity)中的应用,在预防和/或治疗非所希望的胃肠道炎性如炎症性肠病如Crohns病或溃疡性结肠炎、过敏性肠综合征、囊炎(pouchitis)或感染后结肠炎中的应用,在预防和/或治疗胃肠道癌症中的应用,在预防和/或治疗全身性疾病如类风湿性关节炎中的应用,在预防和/或治疗由非所希望的炎性导致的自身免疫疾病中的应用,在预防和/或治疗由非所希望的炎性导致的癌症中的应用,在预防癌症中的应用,在预防和/或治疗由非所希望的炎性导致的腹泻疾病如艰难梭菌(Clostridium difficile)相关的腹泻、轮状病毒相关的腹泻或者感染后腹泻中的应用,在预防和/或治疗感染因子如大肠杆菌导致的腹泻疾病中的应用。
本发明还提供了唾液乳杆菌菌株或配方在制备一种用于预防和/或治疗非所希望的炎性的抗炎生物治疗剂中的应用,或者在制备多种用于预防和/或治疗非所希望的炎性的抗炎生物治疗剂中的应用。
在本发明的一个实施方案中,本发明的菌株通过拮抗促炎微生物并将其从胃肠道中清除而起作用。
本发明还提供了本发明的唾液乳杆菌菌株或配方在制备用于降低促炎细胞因子如IL8的水平的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌菌株在制备用于调节细胞因子水平如IL-8、IL-10、IL-12、TNFα或IFNγ的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌菌株在制备用于改变IFNγ水平的抗炎生物治疗剂中的应用。优选地,在这种情况中,所述菌株选自AH102、AH103或AH105中的任一种。
本发明还提供了唾液乳杆菌菌株在制备用于改变IL-10水平的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌菌株在制备用于改变IL-12水平的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌菌株在制备用于改变IL-8水平的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌AH110菌株在制备用于改变TNFα水平的抗炎生物治疗剂中的应用。
本发明还提供了唾液乳杆菌菌株由于其拮抗病原体生长的能力而作为抗感染益生菌菌株的应用。
我们已经发现特定的乳杆菌菌株在体外激发免疫调节作用。
本发明因此在预防或治疗免疫应答调节异常中具有重要的潜在治疗价值,所述免疫应答调节异常如非所希望的炎症反应,例如炎症性肠病。
所述菌株可以用作一组生物治疗剂,从中可以加以选择以改变IFNγ,TNFα,IL-8,IL-10和/或IL-12的水平。
本发明的菌株或配方可以用于预防和/或治疗炎症、免疫缺陷、炎症性肠病、过敏性肠综合征、癌症(特别是胃肠道和免疫系统癌症)、腹泻、抗生素相关的腹泻、儿童腹泻、阑尾炎、自身免疫疾病、多发性硬化、Alzheimer’s病、类风湿性关节炎、腹腔疾病、糖尿病、器官移植、细菌感染、病毒感染、真菌感染、牙周病、泌尿生殖系疾病、性传播疾病、HIV感染、HIV复制、HIV相关的腹泻、外科手术相关的损伤、外科手术诱导的转移性疾病、败血症、体重减轻、厌食、发热控制(fever control)、恶病质、伤口愈合、溃疡、肠屏障功能(gutbarrier function)、过敏反应、哮喘、呼吸系病变、循环系病变、冠心病、贫血、凝血系统病变、肾病、中枢神经系统病变、肝病、局部缺血、营养失调、骨质疏松、内分泌失调、表皮病变、银屑病和/或寻常痤疮。
所述乳杆菌菌株是共生微生物。它们已经从人胃肠道内的微生物菌群中分离。胃肠道内的免疫系统对这个菌群的成员不能具有明确的反应,因为所产生的炎性也会破坏宿主细胞和组织功能。
因此,存在一些机制,借此免疫系统可以识别与病原性生物体不同的胃肠道菌群的共生非病原性成员。这保证了对宿主组织破坏是有限的并且一种防御屏障仍被保留。
唾液乳杆菌菌株AH102于2000年4月20日保藏在国家工业和海洋细菌保藏中心(National Collections of Industrial and MarineBacteria Limited,NCIMB),保藏号NCIMB 41044。
唾液乳杆菌菌株AH103于2000年4月20日保藏在NCIMB,保藏号NCIMB 41045。
唾液乳杆菌菌株AH105于2000年4月20日保藏在NCIMB,保藏号NCIMB 41047。
唾液乳杆菌菌株AH109于2001年3月22日保藏在NCIMB,保藏号NCIMB 41093。
唾液乳杆菌菌株AH110于2001年3月22日保藏在NCIMB,保藏号NCIMB 41094。
唾液乳杆菌菌株可以是遗传修饰的突变体或者可以是其天然发生的变体。
优选地,唾液乳杆菌菌株是活细胞形式。或者,唾液乳杆菌菌株可以是非活细胞形式。
本发明的特异的唾液乳杆菌菌株可以以在常规制品中的口服可摄入形式给予动物(包括人),如胶囊,微胶囊,片剂,颗粒,粉末,锭剂,丸剂,栓剂,悬浮液及糖浆。合适的配方可以使用常规的有机和非有机添加剂通过常用方法制备。药物组合物中活性成分的量可以呈实现希望的治疗作用的水平。
所述配方还包括一种细菌成分,一种药物本体或一种生物学化合物。
另外,包含本发明一或多种菌株的疫苗可以使用任何合适的已知方法制备,并可以包括一种药物学可接受的载体或佐剂。
在本说明书中,术语突变体,变体及遗传修饰的突变体包括一种唾液乳杆菌菌株,其遗传和/或表型性质与亲代菌株相比发生变化。唾液乳杆菌菌株的天然发生的变体包括选择性分离的目标性质自发变化,而亲代菌株性质的预定变化可通过常规遗传处理方法实现,如基因破坏,接合转移等。
附图简述
图1是示出使用人胃肠道上皮细胞CaCo-2和HT-29,每20个上皮细胞粘附的细菌数的条形图。
图2是示出在与唾液乳杆菌菌株共温育后PBMC诱导的IFNγ水平的条形图。
图3是示出在与唾液乳杆菌菌株共温育后对PBMC产生IL-10(pg/m1)的水平的作用的条形图。
图4是示出唾液乳杆菌菌株对PBMC的IL-12产量(pg/ml)的作用的条形图。
图5是示出唾液乳杆菌菌株对PMBC的IL-8产量(pg/ml)的作用的条形图。
图6是示出唾液乳杆菌菌株调节促炎细胞因子产生的能力的条形图,以pg/ml测定。
详细描述
我们已经发现唾液乳杆菌菌株AH102,AH103,AH105,AH109和AH110不仅是酸和胆汁耐受的并附着于人小肠细胞系,而且令人惊讶地具有免疫调节作用,所述免疫调节作用通过调节细胞因子水平或通过拮抗及从胃肠道中排除促炎或免疫调节微生物而进行。
益生菌一般是以活细胞形式应用。然而,其还可以扩展为非活细胞如灭活培养物或含有由益生菌表达的有益因子的组合物。这可以包括加热灭活微生物或者通过改变pH或加压而灭活的微生物。非活细胞产物的制备较简便,细胞可以简易地掺入药物中,而且贮存要求比活细胞更不受限。Lactobacillus casei YIT 9018提供了有效应用热灭活的细胞治疗和/或预防肿瘤生长的方法实例,如美国专利No.US4347240所述。
目前还未知是否需要完整细菌发挥免疫调节作用或者本发明的各个活性成分是否能单独利用。已经鉴别了某些细菌菌株的促炎成分。革兰氏阴性菌的促炎作用是通过脂多糖(LPS)介导的。LPS单独能诱导一个促炎网络,部分是由于LPS与单核细胞上的CD14受体结合所致。推测益生菌的成分具有免疫调节活性是由于整个细胞的作用所致。在分离这些成分时采取药物级操作。
白细胞介素-8(IL-8)是包含巨噬细胞炎性蛋白(MIP)家族的细胞因子的一种。MIP-1和MIP-2家族代表一组蛋白质,其是白细胞和成纤维细胞的趋化因子。这个家族的蛋白质也称为intercrines,因为除了巨噬细胞之外的细胞也可合成它们。这些细胞包括T细胞和B细胞、成纤维细胞、内皮细胞、角质细胞、平滑肌细胞、滑膜细胞、嗜中性粒细胞、软骨细胞、肝细胞、血小板和肿瘤细胞。MIP-1α、MIP-1β、结缔组织激活蛋白(CTAP)、血小板因子4(PF4)和IL-8刺激嗜中性粒细胞趋化。单核细胞趋化蛋白(MCP-1)和RANTES是单核细胞趋化性的,IL-8是嗜中性粒细胞和淋巴细胞趋化性的,而PF4和CTAP是成纤维细胞趋化性的。针对这些家族成员中的一些已经描述了除了趋化性之外的作用。MCP-1刺激单核细胞细胞静止活性及超氧化物阴离子释放。CTAP和PF4提高成纤维细胞增殖,IL-8提高血管通透性,而MIP-1α和MIP-1β是热原性的。IL-8直接参与胃肠道内的炎性应答。刺激IL-8(及其它促炎细胞因子)易引起胃肠道损害发展,因此重要的是益生菌应不刺激这种细胞因子产生。
IL-10由T细胞,B细胞,单核细胞和巨噬细胞产生。这种细胞因子增加B细胞增殖及分化为分泌抗体的细胞。IL-10主要呈现抗炎活性。其通过正调节单核细胞表达IL-1RA,并抑制大多数单核细胞炎性。IL-10抑制单核细胞产生细胞因子、活性氧和氮中间体,MHCII类表达,杀灭寄生虫及通过反馈机制产生IL-10(7)。这种细胞因子还示出通过干扰PGE2-cAMP依赖性途径而阻断单核细胞产生肠胶原酶和IV型胶原酶,并因此可以是慢性炎症疾病中见到的结缔组织破坏的重要调节因子。
IL-12是一种70kD的异源二聚体蛋白,由两个共价连接的35kD和40kD的链组成。其在炎症级联早期主要由抗原呈递细胞产生,如巨噬细胞。胞内细菌刺激IL-12高水平产生。其是IFNγ产生的强力诱导物及是天然杀伤细胞的激活物。IL-12是产生细胞介导的或者Th1免疫应答所必需的关键细胞因子之一,主要通过其引发细胞高产IFNγ的能力而起作用(8)。IL-12诱导IL-10产生,其反馈抑制IL-12产生,因此限制不受控制的细胞因子产生。TGF-β也负调节IL-12产生。IL-4和IL-13对IL-12的产生可具有刺激或抑制作用。IL-12的体内抑制在治疗Th1相关的炎症如多发性硬化中可具有一些治疗价值(9)。
干扰素γ(IFNγ)主要是激活的T淋巴细胞的产物,而且其大小由于可变糖基化而在20-25kD范围内。这种细胞因子与其它细胞因子协同导致更强力刺激单核细胞,巨噬细胞,嗜中性粒细胞和内皮细胞。IFNγ还通过增加细胞因子产生而增强单核细胞和巨噬细胞诱导脂多糖(LPS)(10),提高活性中间体释放,吞噬作用和胞毒性。IFNγ诱导或增强主要组织相容性复合物II类(MHC II类)抗原在单核细胞及上皮,内皮和结缔组织来源的细胞上的表达。这样使炎症组织内细胞的抗原更高地呈递给免疫系统。IFNγ也可以具有抗炎作用。这种细胞因子抑制磷脂酶A2,从而降低单核细胞产生PGE2和胶原酶(11)。IFNγ还可以调节TGFβ,TNFα和C5a的单核细胞和巨噬细胞受体表达(11),从而有助于这种细胞因子的抗炎性质。益生菌对这种细胞因子的刺激根据宿主的当前炎症状态、其它细胞因子的刺激及给药途径可在体内有不同作用。
TNFα是一种促炎细胞因子,其介导在炎症应答期间见到的许多局部和全身作用。这种细胞因子主要是单核细胞或巨噬细胞衍生的产物,但其它类型细胞包括淋巴细胞,嗜中性粒细胞,NK细胞,肥大细胞,星形胶质细胞,上皮细胞,内皮细胞和平滑肌细胞也可以合成TNFα。TNFα作为激素原合成并在加工之后观测到17.5kD的成熟产物。纯化的TNFα已经观测到呈二聚体,三聚体和五聚体形式,推测三聚体形式在体内是活性形式。已经鉴别了TNFα的三个受体,一个可溶受体似乎具有TNFα抑制剂功能(12),而另两个膜结合形式经鉴别分子大小分别为60和80kDa。在炎性部位局部产生TNFα可由内毒素诱导,而糖皮质激素地塞米松抑制细胞因子产生(13)。TNFα产生引起许多类型细胞的刺激。明显的抗病毒作用可在TNFα处理的细胞系中观测到(14),IFN与TNFα协同增强这种作用。内皮细胞受刺激产生前凝血剂活性,粘附分子、IL-1、造血生长因子、血小板激活因子(PAF)和花生四烯酸代谢物表达。TNFα刺激嗜中性粒细胞粘附,吞噬,脱粒(15),活性氧中间体产生,并可以影响细胞迁移。GM-CSF,TGFβ,IL-1,IL-6,PGE2及TNFα自身的白细胞合成均可在给予TNFα时被刺激(16,17)。编程性细胞死亡(细胞凋亡)在单核细胞中可被延迟(18),同时对成纤维细胞的作用包括促进趋化及IL-6,PGE2和胶原酶合成。尽管局部TNFα产生促进伤口愈合和免疫应答,但TNFα的未调节的全身释放可具有严重毒性作用如观测到恶病质,发热和急性期蛋白产生(19)。
通过以下实施例可以更清晰理解本发明。
实施例1:鉴定从切除并加以洗涤的人胃肠道中分离的细菌,表明益生菌性状
分离益生菌
对在重建手术期间获得的人阑尾和胃肠道(G.I.T)的大肠和小肠切片进行筛选以获得益生菌菌株。在手术后将所有样品立即贮存在-80℃无菌容器中。
将冷冻的组织解冻,称重并置于半胱氨酸化(0.05%)的1/4强度的Ringer’s溶液中。轻轻摇动样品以除去松散地粘附的微生物(称为洗涤“W”)。在移至另一Ringer’s溶液之后,将样品涡旋7分钟以除去紧密粘附的细菌(称为样品“S”)。为分离组织包埋的细菌,将样品356,176和A也在Braun搅拌机中均质(称为匀浆“H”)。将该溶液系列稀释并涂布(100μl)于以下琼脂培养基上:RCM(强化梭菌培养基)及用乙酸调节为pH5.5的RCM;TPY(类胰蛋白酶,蛋白胨和酵母膏);MRS(deMann,Roogosa和Shape);ROG(Rogosa的乙酸盐培养基(SL));LLA(Lapiere的肝乳糖琼脂);BHI(脑心浸液琼脂);LBS(乳杆菌选择性琼脂)及TSAYE(补加0.6%酵母膏的胰化蛋白胨大豆糖)。还使用了补加丙酸的TPY和MRS琼脂。除了TPY琼脂之外,所有琼脂培养基均由Oxoid Chemicals提供。将平板在厌氧瓶(BBL,Oxoid)中,使用C02产生试剂盒(Anaerocult A,Merck),在37℃温育2-5天。
将革兰氏阳性、过氧化氢酶阴性的杆状或二叉/多形细菌分离株在复合的非选择性培养基(MRS和TPY)上划线纯化。将分离株在MRS或TPY培养基(除非特别指定)中在37℃在厌氧条件下常规培养。将预测的乳杆菌在40%甘油中贮存于-20℃和-80℃。
对取自G.I.T.的7个组织切片筛选属于乳杆菌属的菌株的存在情况。在组织样品之间有一些变化。表1示出了组织样品的细菌计数,以菌落形成单位/g(cfu/ml)组织表示。
表1
ND:未测定
样品A(回肠)和316(阑尾)具有最低计数,大约为每克组织102个分离的细胞。相比之下,从其它样品中回收103cfu/g组织以上细胞。在“洗涤”和“样品”步骤期间分离相似数目的细菌,在433(回肠-盲肠)的“样品”溶液中计数略高。
发酵及生长特性
使用LKB Bromma,Aminex HPX-87H高效液相层析柱,检测碳水化合物葡萄糖的代谢及随后的有机酸终产物。将该柱保持在60℃,流速为0.6ml/分钟(恒压)。使用的HPLC缓冲液为0.01N H2SO4。在分析之前,将该柱用10mM柠檬酸盐,10mM葡萄糖,20mM乳酸盐和10mM乙酸盐作为标准校准。将培养物在修饰的MRS肉汤中(乳杆菌菌株),在37℃厌氧繁殖1-2天。在14000g离心10分钟后,将上清用HPLC缓冲液1∶5稀释,并取200μl在HPLC中分析。所有上清均以一式两份进行分析。
确定细菌分离株的生物化学和生理性状以助于鉴别。分析硝酸盐还原作用,吲哚形成及β-半乳糖苷酶活性表达情况。确定在15℃和45℃这两个温度下的生长状况,在存在浓度增加直至5.0%的NaCl的情况下的生长状况及在明胶上的蛋白酶活性。对菌株在石蕊牛奶中的生长特性也加以确定。
从不同的样品中选择大约1500个过氧化氢酶阴性细菌分离株,根据其革兰氏反应,细胞大小和形态,在15℃和45℃下的生长状况及从葡萄糖发酵的终产物加以鉴定(数据未示出)。测试的分离株中有60%以上是革兰氏阳性的以四个一组、链或分叉形式排列的同型发酵球菌(HOMO-)。18%的分离株是革兰氏阴性杆菌和异型发酵球杆菌(HETERO-)。剩余的分离株(22%)主要是同型发酵球杆菌。对38个菌株加以更详尽鉴定,其中样品433鉴定13株,样品423鉴定4株,样品312鉴定8株,样品356鉴定9株,样品176鉴定3株及样品316鉴定1株。所有测试的38个分离株的硝酸盐还原作用及从色氨酸中产生吲哚均是阴性的。记录在不同温度,NaCl浓度下的生长和明胶水解,如下表2所示。
表2
HOMO-,同型发酵;HETERO-,异型发酵;-,反应/生长阴性;+,反应/生长阳性;+(s),缓慢生长;REDn,还原;NR,无反应;Rp,部分还原;Cp,部分凝固;
*所述菌株能生长的NaCl最大浓度
**在37℃于石蕊牛奶中温育24小时后的pH
菌种鉴别
使用API 50CHL(BioMerieux SA,法国)通过乳杆菌的碳水化合物发酵分布图试验性鉴别乳杆菌菌种。离心收获过夜MRS培养物并再悬浮于所述试剂盒提供的悬浮培养基中。根据厂商指导接种API条带并加以分析(在24和48小时后)。然后通过总细胞蛋白的SDS-聚丙烯酰胺凝胶电泳分析(SDS-PAGE)检测乳杆菌菌种(Bruno Pot,Ghent大学,Belgium,私人交流)。最后,使用16s RNA分析及ribotyping证实菌株身份。
API 50CHL可以快速鉴别乳杆菌分离株。通过SDS-PAGE,16sRNA分析及ribotyping对乳杆菌菌种的总细胞蛋白进行的分析揭示了所述特异菌种的进一步信息(Bruno Pot,个人信息)。下表3示出通过4种不同的方法对五个乳杆菌菌株的鉴别。
表3
酶活性谱
使用API ZYM系统(BioMerieux,法国)半定量测定乳杆菌分离株产生的组成型酶。得自晚期对数生长期的细菌细胞通过在14000g离心10分钟而收获。洗涤沉淀的细胞并再悬浮于50mM磷酸盐缓冲液(pH6.8)中至相同的光密度。根据厂商指导接种该条带,在37℃温育4小时并记录颜色产生情况。
5个菌株AH102,AH103,AH105,AH109和AH110的酶活性谱示于下表4。无一菌株呈现脂酶,胰蛋白酶,胰凝乳蛋白酶,α-葡糖醛酸糖苷酶,α-甘露糖苷酶或α-岩藻糖苷酶活性。
表4
抗生素敏感性谱(profile)
所述分离株的抗生素敏感性谱使用“圆盘敏感性”分析确定。将培养物在合适的肉汤培养基中生长24-48小时,涂布(100μl)于琼脂培养基上,并将含有已知浓度抗生素的圆盘置于该琼脂上。在厌氧条件下在37℃温育1-2天后,检测菌株的抗生素敏感性。如果观测到1mm或更大的抑制圈,则认为菌株是敏感的。
使用人体临床重要的抗生素确定5个乳杆菌菌株的抗生素敏感性(μg/ml)谱。测试的每种乳杆菌均对氨苄青霉素,阿莫西林(amoxacillin),ceftaxime,头孢曲松(ceftriaxone),环丙沙星(ciprofloxacin),头孢拉定(cephradine),利福平和氯霉素敏感。唾液乳杆菌AH102,AH103,AH105,AH109和AH110的抗生素敏感性(μg/ml)如下表5所示。
表5
R,抗性;S,敏感的;ND,未测定
乳杆菌在低pH情况下的生长
通过经鼻饲胃管(Mercy医院,Cork,Ireland)抽吸从健康人体中获得胃液。将其在13000g立即离心30分钟以除去所有固体颗粒,通过0.45μm和0.2μm滤膜过滤灭菌,分成40ml等份贮存在4℃和-20℃。
在实验应用之前,测定样品的pH和胃蛋白酶活性。胃蛋白酶活性使用定量血红蛋白分析测定。简而言之,将等份胃液(1ml)加入5ml底物(0.7M脲,0.4%(w/v)牛血红蛋白(Sigma Chemical Co.),0.25M KCl-HCl缓冲液,pH2.0)中,在25℃温育。以0,2,4,6,8,10,20和30分钟间隔取出样品。加入5%三氯乙酸(TCA)终止反应及不搅动静止30分钟。然后将分析混合物过滤(Whatman,no.113),在14000g离心15分钟,测定在280nm的吸光度。1单位的胃蛋白酶活性是指使用血红蛋白作为底物,测定TCA可溶产物在pH2.0每分钟提高A280nm 0.001单位所需要的酶的量。
为确定乳杆菌菌株在低pH值的生长状况与在胃中发现的那些生长状况是否相等,将过夜培养物接种于(1%)新鲜MRS肉汤中,并用1N HCl将pH调节为4.0,3.0,2.0和1.0。在定期间隔取等份(1.5ml),测定在600nm的光密度(OD600),并使用平板计数方法计算菌落形成单位/ml(cfu/ml)。在24-48小时期间监测生长。
使用两种分析研究菌株在体外在低pH下的存活力:
(a)从新鲜过夜培养物中收集细胞,在磷酸盐缓冲液(pH6.5)中洗涤两次并再悬浮于MRS肉汤中,用1N HCl将pH调节为3.5,3.0,2.5和2.0,至乳杆菌终浓度为大约108cfu/ml。在37℃温育并在5,30,60和120分钟间隔使用平板计数方法测定存活力。
(b)将乳杆菌在缓冲的MRS肉汤(pH6.0)中繁殖5天。收获细胞,洗涤并再悬浮于pH经调节的MRS肉汤中,使用平板计数方法在2小时的时间测定存活力。
为确定乳杆菌菌株在经过胃后的存活力,使用人胃液进行源于体内的分析。从新鲜过夜培养物中收获细胞,在缓冲液(pH6.5)中洗涤两次并再悬浮于人胃液中,终浓度根据菌株为106-108cfu/ml。在37℃温育30-60分钟期间监测存活力。使用pH≈1.2(未调节的)和pH2.0和pH2.5(用1N NaOH调节)的胃液进行试验。
每种乳杆菌菌株在pH6.8和pH4.5均正常生长,在8小时后达到稳定期,倍增时间为80-100分钟。在pH3.5生长受限,倍增时间提高至6-8小时。在pH2.5或更低值观测无生长,因此检测该菌株在低pH的存活力。
每种乳杆菌菌株对pH3.5,3.0和2.5均有抗性,唾液乳杆菌AH102和AH105在pH2.0也呈现抗性(数据未示出)。
为确定乳杆菌菌株在人胃中遇到的条件下的存活力,在pH1.2和pH2.5的人胃液中测试5个菌株的存活能力,如表6所示。存活力以log10cfu/ml表示(nd=未确定)。
表6
培养物在存在胆汁的条件下的生长
将新鲜培养物在补加牛胆汁(B-8381,Sigma Chemical有限公司,Poole)和猪胆汁(B-8631,Sigma Chemical有限公司,Poole)的MRS琼脂平板上划线,所述牛胆汁的浓度为0.3,1.0,1.5,5.0和7.5%(w/v),所述猪胆汁浓度为0.3,0.5,1.0,1.5,5.0和7.5%(w/v)。将平板在37℃在厌氧条件下温育,并记录24-48小时后生长状况。
将从一些人胆囊中分离的胆汁样品在使用之前贮存在-80℃。为进行实验研究,将样品解冻,集合并在80℃灭菌10分钟。人胆汁的胆汁酸组分使用反相高效液相层析(HPLC)组合Dekker等所述方法(20)的脉冲电流检测仪确定。将人胆汁以0.3%(w/v)浓度加入MRS/TPY琼脂培养基中。在24和48小时后检测新鲜划线培养物的生长。
人胆囊胆汁的胆汁酸浓度为50-100mM,在小肠中稀释后浓度降低至5-10mM。另外,在生理条件下,胆汁酸以钠盐形式存在。因此,筛选培养物在含有以下每种胆汁酸的钠盐(Sigma Chemical有限公司,Poole)的MRS琼脂平板上的生长:
(a)缀合形式:牛磺胆酸(TCA);甘氨胆酸(GCA);牛磺脱氧胆酸(TDCA);甘氨脱氧胆酸(GDCA);牛磺鹅脱氧胆酸(TCDCA)和甘氨鹅脱氧胆酸(GCDCA);
(b)早期解离(deconjugated)形式:石胆酸(LCA);鹅脱氧胆酸(CDCA);脱氧胆酸(DCA)和胆酸(CA)。针对每种胆汁酸,使用浓度为1,3和5mM。在厌氧温育24和48小时后,记录生长状况。
使用定性(琼脂平板)和定量(HPLC)这两种分析确定每个菌株的早期解离活性。
平板分析:将所有培养物在补加(a)0.3%(w/v)猪胆汁,(b)3mM TDCA或者(c)3mM GDCA的MRS琼脂平板上划线培养。在集落周围出现不透明的沉淀物作为观测到早期解离的标示。
高效液相层析(HPLC):使用HPLC进行人胆汁早期解离的体外分析。简而言之,将过夜培养物接种于(5%)补加0.3%(w/v)人胆汁的MRS肉汤中,在37℃厌氧温育。在24小时温育期间以不同间隔取样品(1ml),在14000rpm离心10分钟。然后将未稀释的无细胞上清(30μl)通过HPLC进行分析。
唾液乳杆菌AH102,AH103,AH105,AH109和AH110能在所使用的三种来源的胆汁中生长(胆汁酸抗性)。观测到对牛胆汁的抗性大大高于对猪胆汁的抗性。每种乳杆菌菌株对浓度直至并包括5.0%的牛胆汁有抗性(数据未示出)。
猪胆汁更具抑制性,如下表7所示。
表7
菌株 | %(w/v)猪胆汁 |
乳杆菌AH102AH103AH105AH109AH110 | 0.0 0.3 0.5 1.0 1.5 5.0 7.5+ + - - - - -+ + + - - - -+ + - - - - -+ + - - - - -+ + - - - - - |
不管在存在牛和猪这两种胆汁的情况下胆汁抗性谱如何,每个乳杆菌菌株在0.3%(v/v)生理浓度的人胆汁中均生长至铺满(数据未示出)。
当特异性分析对各种胆汁酸的抗性时,每个乳杆菌菌株在存在牛磺酸缀合的胆汁酸的情况下均生长良好,在含有直至并包括5mM牛磺酸缀合物TCA,TDCA和TCDCA的琼脂培养基上,每个乳杆菌分离株均生长至铺满。测试的甘氨酸缀合物中,GCDCA一般是最具抑制性的。在三种甘氨酸缀合物中GDCA抑制性略低,GCA抑制性最低。每个菌株在补加5mM GCA的琼脂培养基上均生长,如下表8所示。
表8
-:无生长;+:铺满生长
对在存在早期解离的胆汁酸的情况下的生长状况也进行测试。每个菌株均对5mM LCA抗性。对在存在CA的情况下的生长状况也进行测试。如下表9所示,5个菌株中有3个,即AH102,AH105和AH109在存在1mM CA的情况下生长。在存在1mM CDCA的情况下没有菌株可以生长(数据未示出)。
表9
检测抗微生物活性
使用指定方法检测抗微生物活性(21)。在初始筛选中使用的指示微生物是L.innocua,L.fermentum KLD,P.flourescens和大肠杆菌V157。简而言之,将乳杆菌(MRS)分别温育12-16小时和36-48小时。将10倍系列稀释液涂布于(100μl)MRS/TRY琼脂培养基上。在过夜温育后,将具有独特菌落的平板用指示菌覆盖。指示菌菌苔通过用2%(v/v)过夜指示菌培养物接种一层熔融覆盖物而制备,所述接种的熔融覆盖物倾注于接种的MRS平板表面上。将该平板在适于指示菌生长的条件下再温育过夜。观测到半径大于1mm的抑制带的指示菌培养物被认为对测试细菌敏感。
由于噬菌体活性所致的抑制通过上下翻转接种的MRS/TPY琼脂平板及用指示菌覆盖而除去。噬菌体不通过琼脂扩散。
筛选唾液乳杆菌AH102,AH103,AH105,AH109和AH110菌株的抑制活性,使用Ls.innocua,L.fermentum KLD,P.flourescens和大肠杆菌作为指示微生物。当测试菌株接种于未缓冲的MRS上时,观测四个指示菌的抑制情况。测定大小为1mm-5mm的条带。每个乳杆菌对Ls.innocua的抑制均产生最大的条带。
实施例2:益生菌与胃肠道上皮细胞的粘附
粘附分析
使用对前述方法加以修改的形式进行益生菌菌株粘附(22)。在无菌22m2玻璃盖片上制备单层的HT-29和Caco-2细胞,浓度为4×104个细胞/ml,将玻璃盖片置于Corning组织培养皿中。将细胞每两天补充一次新鲜培养基。在大约10天及发生单层分化后,将该单层用磷酸盐缓冲盐水(PBS)洗涤两次。在每个培养皿中加入无抗生素的DMEM(2ml)及2ml含有109cfu/ml的约18小时乳杆菌悬浮液,并将细胞在含有5%CO2的潮湿大气下在37℃温育2小时。在温育之后,将该单层用PBS洗涤5次,在甲醇(BDH实验室提供,Poole,UK)中固定3分钟,进行革兰氏染色(Gram Stain Set,Merck)并在油浸下经显微镜检测。针对每个玻璃盖片单层,在10个显微镜视野计数每20个上皮细胞粘附的细菌数目。计算每20个上皮细胞粘附的细菌的平均值和标准误差。一式两份进行每个粘附分析。
在另一种方法中,在PBS中洗涤5次后,通过将细胞单层在冷却的无菌水中剧烈涡旋以除去粘附的细菌。将细菌细胞通过在1/4强度的Ringer’s溶液(Oxoid)中系列稀释及在MRS(乳杆菌)上温育而计数。
五个乳杆菌AH102,AH103,AH105,AH109和AH110均粘附于胃肠道上皮细胞(图1)。这些益生菌菌株适用作疫苗/药物输送载体,因为它们粘附于胃肠道上皮并因此与相关的宿主组织相互作用。实施例3:确定乳杆菌菌株对PBMC产生细胞因子的作用
通过密度梯度离心从健康供体(19名)中分离周围血单核细胞。在37℃将PBMC用益生菌菌株刺激72小时。在此时收集培养上清,离心,等份并贮存于-70℃直至使用ELISA(Boehringer Mannheim)确定IL-8,IL-10,IL-12和IFNγ水平。
AH102,AH103和AH105刺激PBMC产生IFNγ(图2)。
AH102,AH103,AH109和AH11共温育不明显改变IL-10水平(图3)。用AH105刺激明显降低PBMC分泌IL-10。
AH102,AH105,AH109和AH110共同温育明显正调节PBMC产生IL-12(图4)。AH103对IL-12产生无明显作用。
5个乳杆菌菌株中无一刺激分离自健康供体的PBMC体外产生IL-8。在每种情况中,IL-8水平实际上降低(图5)。
实施例4:确定在与AH103和AH110温育后在上皮/PBMC共培养模型中的细胞因子水平
与肠道生理学相关的合适的体外模型是一个掺入上皮细胞,T细胞,B细胞,单核细胞和细菌菌株的培养系统。为此,将人Caco-2上皮细胞以5×105个细胞/m1种植于孔大小为3μm的25mm transwell插入物(Costar)顶端表面上。将这些细胞在补加10%胎牛血清,谷氨酰胺,青霉素和链霉素的RPMI-1640中,在37℃在5%CO2环境中培养4周。每三天更换一次培养基。当上皮细胞完全分化时,通过密度梯度离心分离人周围血单核细胞(PBMC)。将1×106个洗涤的PBMC在上皮细胞基底外侧温育,并与1×107个益生菌一起培养。对照组只含有培养基。在这个模型系统中PBMC和上皮细胞之间无直接细胞-细胞接触是可能的,而且细胞通讯只由可溶因子介导。
在与AH103或AH110温育72小时后,取细胞培养上清,等份并贮存在-70℃。使用标准ELISA试剂盒(R&D系统)测定TNFα胞外细胞因子水平。使用来自3个健康志愿者的PBMC一式两份测定TNFα和IL-8水平。
在用益生菌温育上皮细胞-PBMC共培养物之后,通过ELISA检测TNFα和IL-8细胞因子水平(图6)。AH103明显降低由这些细胞释放的IL-8水平。AH110降低由这些细胞释放的TNFα和IL-8水平。
免疫调节
人免疫系统在许多人疾病的病原学和病理学方面发挥明显作用。超免疫和低免疫应答导致或者是大多数疾病状态的一个成分。一个生物学实体家族,称为细胞因子,对控制免疫过程特别重要。这些精密的细胞因子网的紊乱与许多疾病越来越多地相关联。这些疾病包括但非限于炎症,免疫缺陷,炎症性肠病,过敏性肠综合征,癌症(特别是胃肠道和免疫系统癌症),腹泻,抗生素相关的腹泻,儿童腹泻,阑尾炎,自身免疫疾病,多发性硬化,Alzheimer’s病,类风湿性关节炎,腹腔疾病,糖尿病,器官移植,细菌感染,病毒感染,真菌感染,牙周病,泌尿生殖系疾病,性传播疾病,HIV感染,HIV复制,HIV相关的腹泻,外科手术相关的损伤,外科手术诱导的转移性疾病,败血症,体重减轻,厌食,发热控制,恶病质,伤口愈合,溃疡,肠屏障功能,过敏反应,哮喘,呼吸系病变,循环系病变,冠心病,贫血,凝血系统病变,肾病,中枢神经系统病变,肝病,局部缺血,营养失调,骨质疏松,内分泌失调,表皮病变,银屑病和寻常痤疮。每个测试的益生菌菌株对细胞因子产生的作用是特异性的。因此,可选择特异性益生菌以特别针对特异类型疾病而校正单纯的细胞因子不均衡。疾病特异治疗可使用选择上述益生菌菌株而实现。
免疫训练
肠道菌群对肠道免疫系统的发育和正确发挥功能很重要。在没有肠道菌群的情况下,如在无微生物的动物模型中表明的那样,肠道免疫系统发育不全,而且一些功能参数降低,如巨噬细胞吞噬及免疫球蛋白产生的能力降低(23)。肠道菌群在刺激非损害性免疫应答中的重要性变得更明显。在西方世界中过敏反应的影响范围和严重程度的增加与卫生学和卫生设施的增加相关联,伴随宿主遭遇的感染性攻击的数量和范围降低。这种免疫刺激的缺乏使宿主与非病原性但抗原性因子反应而产生过敏或自身免疫性。慎重应用一系列非病原性免疫调节细菌可为宿主提供必需的及合适的训练刺激,以正确发育及控制免疫功能。
炎症
炎症是一个术语,用于描述液体,血浆蛋白和白细胞在一个部位的局部积聚,所述部位具有持续的物理损害,感染或者在此有正在进行的免疫应答。炎症应答的控制在各种水平上发挥(24)。控制因子包括细胞因子,激素(例如氢化可的松),前列腺素,活性中间体及白三烯。细胞因子是低分子量的生物活性蛋白,其参与免疫应答和炎性应答的产生和控制,而且还调节发育,组织修复和血细胞生成。它们提供了白细胞自身及与其它类型细胞之间通讯的一种方式。大多数细胞因子是多效的并表达多种生物学重叠活性。细胞因子级联和网络控制炎性应答而不是特定细胞因子针对特定类型细胞起作用(25)。炎症应答的衰退产生较低浓度的合适的激活信号及其它炎症介质,引起炎性应答停止。TNFα是一种关键的促炎细胞因子,因为其发起导致炎性状态的细胞因子级联及生物作用。因此,抑制TNFα的因子,例如infliximab,通常用于治疗炎性疾病。
现在认为促炎细胞因子在许多炎症疾病包括炎症性肠病(IBD)的发病机理中起主要作用。目前治疗IBD的方法是针对降低这些促炎细胞因子包括IL-8和TNFα的水平而进行。这种治疗方法在治疗全身性炎症疾病如类风湿性关节炎中也发挥明显作用。
过敏性肠综合征(IBS)是一种常见的胃肠道病变,在人的一生当中的一些阶段影响将近15-20%的人群。最常见的症状包括腹痛,肠道习性紊乱,出现腹泻或便秘,肠胃胀气及腹胀。没有简便的试验证实诊断,如果出现这些症状而未发现其它器官病变,则通常诊断为IBS。胃肠病学家见到的患者中有多如25-50%的患者患有IBS。
认为许多因子参与症状的发作,例如胃肠炎,腹部或盆部手术,也许由抗生素摄取所致的肠道细菌菌群失调,及情绪压力所引起的症状。与一般人群相对比,IBS患者的生命质量明显下降,更可能失去工作并使用更多的健康关怀资源。目前没有有效的医学处理方法,推荐的治疗方法包括镇痉剂,止泻剂,膳食纤维补充剂,改变结肠内脏感觉阈值的药物,止痛剂及抗抑郁剂。
本发明的每种菌株均具有关于细胞因子调节和抗微生物的独特性质,预期可以选择特异性菌株基于这些性质用于特异疾病状态中。还预期将具有合适的细胞因子调节性质和抗微生物性质的这组菌株组合将会增强治疗效力。
本发明的菌株可潜在应用于治疗一系列炎症疾病,特别是如果与其它抗炎治疗如非类固醇抗炎药物(NSAID)或Infliximab组合使用则更有效。
细胞因子与癌症
广谱类型肿瘤产生多功能的细胞因子提示在患有癌症的患者中存在明显的炎症应答。目前还不清楚为什么这种应答的保护性作用在体内对抗肿瘤细胞的生长和发育。然而,这些炎症应答能逆转地影响具有肿瘤的宿主。复杂的细胞因子相互作用在肿瘤和正常组织内参与调节细胞因子的产生和细胞增殖(26,27)。长期以来意识到体重丧失(恶病质)是癌症患者最常见的单一致死因素,而且最初的营养不良表明不良预后。就肿瘤的生长和扩散而言,其必须诱导新血管形成及降解胞外基质。炎症应答在上述机制中可具有明显作用,因此促进宿主的衰退和肿瘤的进展。由于唾液乳杆菌的抗炎性质,这些细菌菌株可降低恶性细胞转化的速度。另外,肠道细菌从饮食化合物中产生具有基因毒性,致癌性及肿瘤促进活性的物质,而且消化道细菌可将前致癌剂激活为DNA活性剂(28)。通常地,乳杆菌菌种与消化道内其它菌群如类菌体,真细菌和梭菌相比具有低生物异源代谢酶活性。因此,增加消化道内乳杆菌数量可有益于改变这些酶的活性。
疫苗/药物输送
大多数病原微生物通过粘膜表面得以进入体内。在这些部位有效接种可对抗特殊的感染因素入侵。目前口服疫苗策略集中使用减毒的活病原生物体或者纯化的荚膜抗原(29)。工程化为在体内产生来自感染因子抗原的益生菌,可提供有吸引力的另一种选择,因为这些细菌对人体服用是安全的(GRAS状态)。
对鼠进行的研究表明服用表达外源抗原的益生菌可激发保护性免疫应答。将编码破伤风毒素片段C(TTFC)的基因在Lactococcuslactis中表达,并将小鼠通过口服途径免疫。这个系统能诱导抗体滴度足够高以保护小鼠免于致命毒素攻击。除了抗原呈递之外,活细菌载体在体内可产生生物活性化合物,如免疫刺激性细胞因子。分泌生物活性人IL-2或IL-6和TTFC的L.lactis在经鼻内免疫的小鼠中诱导提高10-15倍的血清IgG滴度(30)。然而,就这个特殊的细菌菌株而言,通过与这些细胞因子共表达,总IgA水平未提高。对其它细菌菌株如Streptococcus gordonii也进行测试其作为粘膜疫苗的有效性。在小鼠口腔和阴道内建群的重组S.gordonii诱导对这个细菌表达的抗原的粘膜和全身性抗体应答(31)。因此使用益生菌作为载体口服免疫不仅保护宿主免于感染,而且可代替病原体正常激发的免疫学刺激,因此有助于宿主的免疫学训练。
益生素(prebiotics)
导入益生生物体通过摄取在合适载体内的微生物而实现。在大肠中提供促进这些益生菌生长的介质是有益的。加入一或多种寡糖,多糖或其它益生素增强胃肠道中乳酸菌的生长。益生菌素指任何非存活的食物成分,其在结肠中通过土著细菌特异性发酵,所述土著细菌认为是有阳性价值的,例如双歧杆菌,乳杆菌。益生素的类型可包括含有果糖,木糖,大豆,半乳糖,葡萄糖和甘露糖的那些益生素。益生菌菌株与一或多种益生化合物组合施用可增强施用的益生菌在体内生长,产生更显著的健康获益,因此称为共生的。
其它活性成分
应意识到益生菌可预防性施用或者其自身或与上述其它益生菌和/或益生素组合用于治疗方法。另外,所述细菌可用作预防或治疗方案的一部分,所述方案还使用如用于治疗炎症或其它病变特别是具有免疫学参与的那些病变的其它活性物质。这种组合可以单一配方形式施用,或者以单独配方同时或不同时间及使用相同或不同途径施用。
本发明非限于前述实施方案,可以加以变化。
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Claims (11)
1.分离的唾液乳杆菌菌株AH102,其中所述菌株的保藏号为NCIMB 41044。
2.权利要求1的菌株,其是活细胞形式。
3.权利要求1的菌株,其是非活细胞形式。
4.一种配制剂,其包含前述权利要求任一项的菌株。
5.权利要求4的配制剂,其包括一种可摄食载体。
6.权利要求5的配制剂,其中可摄食载体是一种药物可接受的载体,所述的药物可接受的载体选自胶囊、片剂或粉末。
7.权利要求5或6的配制剂,其中可摄食载体是一种食品,所述的食品选自酸奶、酸乳酪、冷冻酸乳酪、奶粉、浓缩奶、奶酪、调味品或饮料。
8.权利要求4-6中任一项的配制剂,其中所述唾液乳杆菌菌株在配制剂中的量高于106cfu/g。
9.权利要求7的配制剂,其中所述唾液乳杆菌菌株在配制剂中的量高于106cfu/g。
10.包含权利要求1-3中任一项的唾液乳杆菌菌株或者权利要求4-9中任一项的配制剂的食品。
11.包含权利要求1-3中任一项的唾液乳杆菌菌株或者权利要求4-9中任一项的配制剂以及药物学可接受的载体的药物组合物。
Applications Claiming Priority (11)
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IE20010701 | 2001-07-26 | ||
IE01/0705 | 2001-07-26 | ||
IE01/0707 | 2001-07-26 | ||
IE01/0708 | 2001-07-26 | ||
IE01/0702 | 2001-07-26 | ||
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IE20010707 | 2001-07-26 | ||
IE01/0701 | 2001-07-26 | ||
IE20010708 | 2001-07-26 | ||
IE20010705 | 2001-07-26 | ||
PCT/IE2002/000111 WO2003010298A1 (en) | 2001-07-26 | 2002-07-26 | 'probiotic lactobacillus salivarius strains |
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CN1639317A CN1639317A (zh) | 2005-07-13 |
CN1639317B true CN1639317B (zh) | 2011-04-27 |
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CN028185803A Expired - Fee Related CN1639317B (zh) | 2001-07-26 | 2002-07-26 | 益生菌唾液乳杆菌菌株 |
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US (2) | US20030091549A1 (zh) |
EP (1) | EP1409645B1 (zh) |
JP (1) | JP4415164B2 (zh) |
CN (1) | CN1639317B (zh) |
AT (1) | ATE439426T1 (zh) |
AU (1) | AU2002329007C1 (zh) |
BR (1) | BR0211441A (zh) |
CA (1) | CA2454804C (zh) |
DE (1) | DE60233326D1 (zh) |
DK (1) | DK1409645T3 (zh) |
IL (2) | IL160049A0 (zh) |
IN (1) | IN2004KO00092A (zh) |
MX (1) | MXPA04000808A (zh) |
NZ (1) | NZ543584A (zh) |
PE (1) | PE20030274A1 (zh) |
WO (1) | WO2003010298A1 (zh) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103154235A (zh) * | 2010-02-02 | 2013-06-12 | 生命大地女神有限公司 | 乳杆菌属菌株的免疫调节性质的改善 |
CN103154235B (zh) * | 2010-02-02 | 2016-04-13 | 生命大地女神有限公司 | 乳杆菌属菌株的免疫调节性质的改善 |
CN103555604A (zh) * | 2013-03-25 | 2014-02-05 | 浙江大学 | 能够抑制白色念珠菌生长的唾液乳酸杆菌及其分离方法 |
CN103555604B (zh) * | 2013-03-25 | 2014-09-17 | 浙江大学 | 能够抑制白色念珠菌生长的唾液乳酸杆菌及其分离方法 |
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BR0211441A (pt) | 2004-11-09 |
JP4415164B2 (ja) | 2010-02-17 |
AU2002329007B2 (en) | 2008-03-06 |
WO2003010298A1 (en) | 2003-02-06 |
PE20030274A1 (es) | 2003-05-08 |
US7390519B2 (en) | 2008-06-24 |
EP1409645A1 (en) | 2004-04-21 |
JP2005506063A (ja) | 2005-03-03 |
US20060078547A1 (en) | 2006-04-13 |
IL160049A0 (en) | 2004-06-20 |
IN2004KO00092A (zh) | 2006-03-03 |
DE60233326D1 (de) | 2009-09-24 |
NZ543584A (en) | 2008-04-30 |
CA2454804A1 (en) | 2003-02-06 |
AU2002329007C1 (en) | 2008-10-30 |
CA2454804C (en) | 2011-02-01 |
ATE439426T1 (de) | 2009-08-15 |
IL160049A (en) | 2009-12-24 |
CN1639317A (zh) | 2005-07-13 |
US20030091549A1 (en) | 2003-05-15 |
EP1409645B1 (en) | 2009-08-12 |
MXPA04000808A (es) | 2004-05-21 |
DK1409645T3 (da) | 2009-12-14 |
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