CN102438637A - 具有高抗炎活性的细菌菌株 - Google Patents
具有高抗炎活性的细菌菌株 Download PDFInfo
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- CN102438637A CN102438637A CN2009801589932A CN200980158993A CN102438637A CN 102438637 A CN102438637 A CN 102438637A CN 2009801589932 A CN2009801589932 A CN 2009801589932A CN 200980158993 A CN200980158993 A CN 200980158993A CN 102438637 A CN102438637 A CN 102438637A
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Abstract
本发明涉及具有高抗炎活性的益生菌菌株。本发明涉及作为产生白细胞介素10(IL-10)的强力诱导物的细菌菌株。特别地,本发明涉及由所述细菌菌株因其增强IL-10在外周血单个核细胞中的产生而表现出的抗炎活性,另一方面该细菌菌株具有较低的刺激促炎性IL-12产生的能力,因此导致了高IL-10/IL-12比。本发明还涉及至少一种细菌菌株在制备用于预防或治疗炎性肠病(IBD)和肠易激综合征(IBS)的组合物中的应用。本发明最后涉及包含至少一种益生菌菌株作为活性成分的食物产品,例如益生菌食物补充剂。
Description
本发明涉及具有高抗炎活性的益生菌菌株。本发明涉及作为白细胞介素-10(IL-10)的产生的强诱导物的细菌菌株。特别的是,本发明涉及由所述细菌菌株因其增强在外周血单个核细胞中的IL-10产生而显示出的抗炎活性,另一方面该细菌菌株具有较低的刺激促炎性IL-12产生的能力,因此导致了高IL-10/IL-12比。本发明还涉及至少一种细菌菌株在制备用于预防或治疗炎性肠病(IBD)和肠易激综合征(IBS)的组合物中的应用。最后,本发明涉及包含作为活性成分的至少一种益生菌菌株的食物产品,例如益生菌食物补充剂。
已知益生菌是在以充足的量施用时会为宿主带来健康益处的活微生物。正逐渐认识到益生性乳酸杆菌和双歧杆菌是用来预防和/或治疗肠道病况的方法。
与抗原或感染原的多数遭遇都出现在粘膜表面,粘膜表面包括在胃肠道、呼吸道和生殖泌尿道形成内衬的表面。由于通常以口服方式来摄取益生菌,因此理想的是,益生菌适合用来影响在胃肠道的超过300m2的“粘膜边界”发生的免疫应答。
肠免疫系统构成免疫系统的最大部分。其与形式为食物抗原的复杂抗原性负载物、共栖细菌和偶然出现的病原体相互作用。树突状细胞(DC)在最早期的细菌识别中和在T细胞应答定形中起关键作用。树突状细胞感知组织中的抗原,随后迁移至引流淋巴结,在引流淋巴结中树突状细胞具有激活并影响初始T细胞功能分化的独特能力。来自DC的信号能够确定是否会出现针对特定抗原的耐受性或活性免疫应答,并且进一步影响Th1或Th2免疫应答是否会占据优势:DC使共刺激分子CD80和CD86上调,并产生促成Th1应答的IL-12。DC还可以产生IL-10和IL-4,IL-10和IL-4促进Th2应答的产生或促进调节T细胞的生成。
对作为病原体的有害微生物、过敏原和毒素的识别会激活胃肠免疫系统。抗原特异性Treg细胞介导对共栖微生物的口服耐受,并将无害的肠居生物和病原体区分开。口服耐受的发展和保持发生中断时会导致一系列异常的破坏性炎性病况,包括炎性肠病(IBD)和结肠炎。
IBD和结肠炎是其中患者的免疫系统对原生肠内细菌产生过度反应的病症。在这些病况中出现的Treg细胞耗尽会有效地破坏耐受性,并使得在肠中出现大规模的炎症。Treg细胞的体内转移通过IL-10、TGF-β和CTLA-4依赖性机制而抑制上述疾病的发展。
益生菌菌株能够诱导诸如白细胞介素-1(IL-1)、IL-6、IL-12、肿瘤坏死因子α(TNF-α)和γ干扰素(IFN-γ)等促炎细胞因子以及诸如IL-10和转化生长因子β等抗炎细胞因子。IFN-γ和IL-12强力地放大巨噬细胞和NK细胞的功能,这或许是其抗致癌活性和抗感染活性的可能机制。另一方面,据假设,对IL-10和转化生长因子β的诱导会参与炎症的下调,因为这些细胞因子能够抑制巨噬细胞和T细胞的功能并且促进调节性T细胞的发展。IL-10由多种细胞产生,包括Th2细胞、DC、单核细胞(monocyte)、B细胞、角化细胞和调节性T细胞;其具有抗炎效果,并主要起抑制Th1应答的作用。IL-10驱动抑制抗原特异性免疫应答的CD4+T细胞子集(称为调节性T细胞1(Tr1))的生成,并且活跃地下调体内的病理性免疫应答。
“炎性肠病(IBD)”涵盖了若干种肠部病症,包括克罗恩氏病、溃疡性结肠炎和囊炎(pouchitis)。
在炎性肠病中,IL-10是引起特殊治疗兴趣的细胞因子,因为已在动物模型中显示,白细胞介素(IL)-10(-/-)小鼠自发地发展肠部炎症。
已在动物模型中显示,在体外显示出诱导更高水平的抗炎细胞因子IL-10和更低水平的炎性细胞因子IL-12的潜力的益生菌菌株在该模型中提供抵御体内结肠炎的最佳保护。
在对IBD的治疗中,益生菌介导的免疫调节是令人感兴趣的选择,据显示,口服递送的细菌可以调节全身免疫系统和粘膜免疫系统。然而,由于菌株在胃肠道中的存活情况和持续性的不同,且/或由于益生菌与宿主免疫系统之间的菌株特异性相互作用,并非所有候选益生菌都被证明同样高效。因此,对成功的保护性菌株的选择将取决于对大量候选菌株进行的针对其技术性能和免疫调节性能的适当筛选。
所以,仍需要分离并选择具有突出抗炎活性的细菌菌株。特别而言,仍需要分离并选择作为IL-10的产生的强诱导物的特定细菌菌株。此外,仍需要分离并选择具有较低的刺激促炎性IL-12的产生的能力从而使IL-10/IL-12比至少大于1的细菌菌株。最后,仍需要找到并选择在胃肠道中因其对胃液、胆汁盐、胰分泌物和对肠壁的粘附有抗性而显示出高持续性的细菌菌株。最后但并非最次要的是,选择不具有获得性抗生素抗性的细菌菌株是很重要的。
本申请人已选出了一组能够解决现有技术中存在的突出问题的细菌菌株。
根据本发明的第一方面,提供了通过刺激白细胞介素-10而具有免疫调节功能的一组细菌菌株或其细胞组分。
根据本发明的第二方面,提供了含有至少一种细菌菌株或其细胞组分作为活性成分的食物产品。
根据本发明的第三方面,提供了含有用作药物的至少一种细菌菌株或其细胞组分的组合物。
根据本发明的第四方面,提供了至少一种细菌菌株或其细胞组分在制备用于预防或治疗大肠和小肠炎性病症的药物中的应用。
根据本发明的第五方面,提供了至少一种细菌菌株或其细胞组分在制备用于预防或治疗机能性肠障碍的药物中的应用。
本申请人已测试了属于以下物种的细菌菌株:嗜酸乳杆菌、卷曲乳杆菌、加氏乳杆菌、德氏乳杆菌、唾液乳杆菌、干酪乳杆菌、副干酪乳杆菌、植物乳杆菌、鼠李糖乳杆菌、罗伊氏乳杆菌、短乳杆菌、布氏乳杆菌、发酵乳杆菌、青春双歧杆菌、角双歧杆菌、两歧双歧杆菌、短双歧杆菌、链状双歧杆菌、婴儿双歧杆菌、乳双歧杆菌、长双歧杆菌、假链状双歧杆菌和嗜热链球菌。
表1示出了在本发明范围内具有有效应用的一组细菌菌株。
表1
本发明的细菌菌株或其细胞组分有助于预防或治疗包括自身免疫疾病在内的免疫疾病(例如炎性肠病),并且有助于哺乳动物(例如人类、家畜和宠物动物)保持免疫学稳态(保健)。
换言之,本发明的细菌菌株或其细胞组分安全性高,并且可以口服施用。因此,由于将上述微生物及其细胞组分作为药物产品、食物产品和动物饲料中的活性成分来使用能够使免疫调节细胞在体内得到高效的诱导,上述微生物及其细胞组分是有用的。
本发明的其他方面和特征将在以下公开内容和所附权利要求中变得更加清楚。
图1是显示细胞因子IL-10的产生量(pg/ml)的图表。针对不同微生物菌株的IL-10和IL-12释放的菌株特异性图样。
图2是显示IL-10/IL-12比的图表。针对不同微生物菌株的菌株特异性IL-10/IL-12比。
现将通过以下非限制性描述来充分描述本发明。
在优选实施方式中,细菌菌株选自由副干酪乳杆菌LMG P-21380、植物乳杆菌LMG P-21021、乳双歧杆菌LMG P-21384、短双歧杆菌DSM 16604或其细胞组分组成的组,所述细菌菌株诱导白细胞介素-10的产生。另外,所述细菌菌株显示出大于1且小于150、优选为10~100、更优选为30~60的IL-10/IL-12比。
有利的是,细菌菌株是短双歧杆菌DSM 16604,其诱导白细胞介素-10的产生,且显示出50~100、优选为70~80的IL-10/IL-12比。
细菌菌株可以是活细菌或死细菌形式或者其细胞组分形式。
在另一优选实施方式中,食物产品包含作为活性成分的选自由副干酪乳杆菌LMG P-21380、植物乳杆菌LMG P-21021、乳双歧杆菌LMG P-21384和短双歧杆菌DSM 16604组成的组的至少一种细菌菌株。
所述细菌菌株诱导白细胞介素-10的产生。另外,所述细菌菌株显示出大于1且小于150、优选为10~100、更优选为30~60的IL-10/IL-12比。有利的是,细菌菌株是短双歧杆菌DSM 16604,其诱导白细胞介素-10的产生,且显示出50~100、优选为70~80的IL-10/IL-12比。
细菌菌株可以是活细菌或死细菌形式或者其细胞组分形式。
在又一优选实施方式中,组合物包含作为白细胞介素-10产生物的选自由副干酪乳杆菌LMG P-21380、植物乳杆菌LMG P-21021、乳双歧杆菌LMG P-21384和短双歧杆菌DSM 16604或其细胞组分组成的组的至少一种细菌菌株,所述组合物用作用于预防或治疗大肠和小肠炎性病症的药物或者用作用于预防或治疗机能性肠障碍的药物。所述炎症病症选自包含克罗恩氏病和溃疡性结肠炎的组,而所述机能性肠障碍则选自包含痢疾和便秘的组。
所述细菌菌株诱导白细胞介素-10的产生。另外,所述细菌菌株显示出大于1且小于150、优选为10~100、更优选为30~60的IL-10/IL-12比。有利的是,细菌菌株是短双歧杆菌DSM 16604,其诱导白细胞介素-10的产生,且显示出50~100、优选为70~80的IL-10/IL-12比。
细菌菌株可以是活细菌或死细菌形式或者其细胞组分形式。
在优选实施方式中,组合物包含作为活性成分的细菌菌株和/或其细胞组分,其量相对于该组合物的重量为1×106CFU/g~1×1011CFU/g、优选为1×108CFU/g~1×1011CFU/g。
在优选实施方式中,组合物包含作为活性成分的细菌菌株和/或其细胞组分,其量为1×106CFU/剂量~1×1011CFU/剂量、优选为1×108CFU/剂量~1×1010CFU/剂量。
所述剂量可以是1g、3g、5g和10g。
所述组合物还可以包含药物可接受的添加剂和共配物(co-formulate)。
本发明的组合物可以包含维生素(例如叶酸、核黄素、维生素E、抗坏血酸)、抗氧化剂化合物(例如多元酚、类黄酮和前花青素(proanthocyanidine))、氨基酸(例如谷氨酰胺、蛋氨酸)还有矿物质(例如硒和锌)。
在另一特别优选的实施方式中,本发明的组合物还包含至少一种具有益菌素(prebiotic)性质的物质,该物质相对于组合物总重量的量为1重量%~30重量%、优选5重量%~20重量%。
所述益菌素物质优选包括不被生物体消化和吸收的碳水化合物。所述碳水化合物优选选自:低聚果糖(FOS)、短链低聚果糖、菊粉、低聚异麦芽糖、果胶、低聚木糖(XOS)、低聚壳聚糖(COS)、β-葡聚糖、阿拉伯树胶改性淀粉和抗性淀粉、聚右旋葡萄糖、D-塔格糖、阿拉伯树胶纤维、竹、长豆角、燕麦和柑橘纤维。特别优选的益菌素是短链低聚果糖(出于简便,在下文中将其表示为FOSs-c.c);所述FOSs-c.c是不可消化的糖类,通常通过转化甜菜糖而获得,并且含有与三个葡萄糖分子键合的蔗糖分子。
在优选实施方式中,将细菌菌株短双歧杆菌DSM 16604与选自由副干酪乳杆菌LMG P-21380、植物乳杆菌LMG P-21021和乳双歧杆菌LMG P-21384组成的组的至少一种细菌菌株组合。细菌菌株可以是活细菌或死细菌形式或者其细胞组分形式。
已对以下细菌菌株进行了测试。三种乳酸杆菌菌株:鼠李糖乳杆菌(LR04)DSM16605、副干酪乳杆菌(LPC00)LMG P-21380、植物乳杆菌(LP01)LMG P-21021,以及两种双歧杆菌菌株:乳双歧杆菌(BS01)LMG P-21384和短双歧杆菌(BR03)DSM16604属于最具代表性的益生菌物种,并且根据其对酸、消化酶和胆汁的抗性以及诸如抗生素抗性和使用安全性等其他特性选择了这些菌株。
如下,从以下冷冻储存收集物起始制备活(有活力的)细菌和死(已杀灭的)细菌样品。在de Man、Rogosa和Sharpe肉汤培养基(MRS,DeMan等,1960)中培养纯种乳酸杆菌菌株,在补充有0.05%L-半胱氨酸盐酸盐的MRS或胰蛋白胨植物蛋白胨酵母肉汤培养基(TPY,Scardovi 1986)中培养双歧杆菌菌株。在无氧条件下于37℃进行16~22小时的培养。为了收集细胞,在对数生长期和/或稳定生长期通过离心(3000g,15分钟)来收集全部细菌。随后用磷酸盐缓冲盐溶液(PBS)清洗沉淀的细菌,并且通过菌落形成单位(CFU)计数法确定了浓度。
对于制备活(有活力的)细菌样品,将清洗后的沉淀细菌稀释在含20%甘油的PBS中,使其最终工作浓度为1×109CFU/ml,并且存储于-80℃直至用于测定。另一选择是,可以将细菌稀释在RPMI-1640中,而后对悬浮液进行等分分量并将其储存于-20℃。
通过使用菌落形成单位(CFU)计数法和/或借助针对cFA(活)和PI(死)的染色,根据活细菌的量确定了在冷冻和解冻时细菌的生存情况。在所有测试过的细菌中,超过80%在解冻时是活的。活力百分比不依赖于储存时间。在每次新实验中都解冻一个新鲜的等分试样,从而避免不同实验之间的培养物差异。
对于制备死细菌样品,可以使用以下程序之一。通过在100℃对上述重悬于蒸馏水中的经清洗的沉淀细菌进行30分钟的加热,制备了热杀灭的细菌培养物。另一选择是,可以对细菌进行γ-辐射或超声。除了上述用于获得死细菌样品的程序之一以外,可以对液体形式或冷冻-干燥形式的上述样品进行处理。
为了研究诱导免疫强效细胞产生细胞因子的特定能力,将本发明的细菌菌株与PBMC(外周血单个核细胞)进行了共培养。
据描述,PBMC分离自从健康捐献者的外周血中。简言之,在进行Ficoll梯度离心后,收集单个核细胞并用PBS清洗,在由补充有L-谷氨酰胺(300mg/l)、青霉素(100U/ml)、链霉素(64U/ml)和10%热失活的FCS(胎牛血清)的RPMI 1640组成的完全培养基中将该单个核细胞调节至2×106个细胞/毫升。
另一选择是,还可以通过向RPMI-1640中补充L-谷氨酰胺(300mg/l)、庆大霉素(500μg/ml)、青霉素(100U/ml)、链霉素(64U/ml)和20%热失活的人AB血清或10%FCS来获得RPMI完全培养基。
通过负向磁性细胞分选可以从PBMC中纯化出单核细胞。可以将经正向选择的细胞用作外周血淋巴细胞(PBL)源。可以对单核细胞和外周血淋巴细胞进行计数,并将其以5×106个细胞/毫升的浓度重悬于RPMI完全培养基中。为进行单个核细胞(PBMC、单核细胞和PBL)在液氮中的冷冻保存,将在Ficoll梯度离心后收集的细胞以1×106个细胞/毫升的浓度重悬于由补充有10%DMSO(二甲亚砜)的RPMI 1640组成的完全培养基中。
在96孔平底或圆底的聚苯乙烯微孔板中,以二等分或三等分方式来添加PBMC培养物。所有培养物都含有在完全培养基中的0.1×106~0.5×106个PBMC(或单核细胞或PBL)。仅在培养基中培养PBMC,或用最终浓度为50μg/ml的植物血细胞凝集素(phytoemoglutinine)(PHA)对其进行刺激,或用最终浓度为0.5μg/ml~1μg/ml的脂多糖(LPS)对其进行刺激。将解冻的活细菌样品的等分试样添加到细胞∶细菌比为1∶1、1∶10或1∶200的PBMC培养物中,从而获得了带有活细菌样品的共培养物。
在用不同的相对浓度(例如,从106CFU/ml到109CFU/ml的不同的细菌细胞部分的浓度)进行增殖测试后,可以确定上述的细菌-细胞最佳浓度。
对于用死细胞样品进行的共培养测试,用5~20μg/ml(优选10μg/ml)的冷冻-干燥形式的(经热杀灭、γ-辐射或超声的)死细菌样品或者用细菌∶细胞比为50∶1~250∶1(优选为200∶1)的液体形式的死细菌样品与PBMC一起培养。
对照培养物含有未经刺激的PBMC、经PHA刺激的PBMC、单核细胞、PBL(以上都不含细菌菌株)或仅活细菌样品。
在5%CO2中于37℃温育平板。在24、48、72小时和5天时收集培养物的上清液,离心澄清,并储存于-20℃直至进行细胞因子分析。未观察到培养基酸化或细菌增殖。
按照制造商的操作指导,并如本领域技术人员所公知的,使用商购的试剂盒(如Quantikine试剂盒,R&D Systems Minneapolis,MN)通过标准酶联免疫吸附测定(ELISA)来测量细胞因子IL-10和IL-12的水平。
简言之,将标准物和样品(来自上述共培养物的上清液)添加到平板中并于室温温育2小时。在将孔清洗4次后,将特异性的与辣根过氧化物酶偶联的抗体添加到所有孔中,随后于室温温育平板1小时。随后清洗平板,并用3,3′,5,5′-四甲基联苯胺底物试剂溶液温育平板30分钟。添加1.8M H2SO4来使反应停止。用微孔板读取仪在450nm读取所有ELISA的吸光度。绘制针对细胞因子的标准曲线。
IL-10和IL-12的最小可检测剂量通常分别低于3.9pg/ml和5.0pg/ml。
用Wilcoxon Mann-Whitney测试进行了统计学分析,从而揭露了不同细菌菌株所对应的细胞因子产生之间存在显著差异。在P<0.05时,认为差异是显著的。
对IL-10和IL-12的产生的评估
5种活细菌菌株对收集自健康捐献者的PMBC的体外免疫刺激作用揭露了这些菌株诱导IL-10和IL-12的独特能力,由此IL-10和IL-12水平显示出菌株特异性图样,如图1所示。
图1显示出针对不同益生菌菌株的IL-10和IL-12释放的菌株特异性图样。5个实验中的一个代表性实验。
IL-10浓度的变动基本都在200pg/ml~1700pg/ml范围内,视细菌菌株而定。对于IL-12的产生,还观察到了不同菌株间的显著变化,覆盖了10pg/ml~1200pg/ml的细胞因子水平范围。
短双歧杆菌BR 03能够通过诱导体外培养的单个核细胞产生IL-10来调节免疫应答。短双歧杆菌BR 03强力诱导IL-10的产生(1688pg/ml)。与之相反,其刺激促炎性IL-12的产生(22pg/ml)的能力较低。
益生菌菌株短双歧杆菌BR 03的促进IL-10产生的能力明显有别于所研究的其他菌株,在所研究的菌株中可以认为短双歧杆菌BR 03是最强力的诱导物,见图1。
除了较高的IL-10诱导潜力外,当考虑选择用于抗炎应用的菌株时,使益生菌对IL-12的诱导最小化也是重要的。促炎性细胞因子IL-12主要由吞噬细胞和抗原呈递细胞(APC)在对细菌、细胞内寄生物或其他感染原做出快速反应时产生。除了在抵抗感染的第一道防线中起重要作用外,IL-12还会限制或抑制Th2 T细胞的分化,其本身充当Th1应答中的免疫调节分子。IL-12会诱导IFN-γ,并直接或间接地激活天然杀伤细胞,因此增强了促进抗原特异性免疫应答的促炎细胞因子的进一步释放。
这种由IFN-γ介导的增强IL-12的产生的反馈机制,会潜在地使细胞因子的产生失去控制。幸运的是,作为调节性细胞因子的IL-10是这些吞噬细胞产生IL-12的强抑制剂,并且可以抑制失衡的Th1应答的出现,例如在急性炎症期的IBD患者的胃肠道中见到的失衡的Th1应答;因此,其在用有利的IL-10/IL-12比来进行益生菌菌株选择中是重要的。
对IL-10/IL-12比的评估
可行的是,用IL-10/IL-12比来对显示出“促炎”特征的菌株和显示出“抗炎”特征的菌株(分别为低IL-10/IL-12比和高IL-10/IL-12比的菌株)进行区分。已发现该方法可用于鉴定具有明显相反特征的菌株,并且能够作为标准化的体外测试来使用,使得可以根据候选益生菌菌株的免疫调节能力来对候选益生菌菌株进行初步分类,所述候选益生菌菌株的免疫调节能力将会预示其体内效果。
Peran等最近也展示了这两种细胞因子间的比率的重要性。在该研究中,通过施用唾液乳杆菌唾液亚种的特定菌株,促进了大鼠结肠炎TNBS模型中的发炎组织的恢复。该有益效果与该菌株修改巨噬细胞中细胞因子特征的能力部分相关,即降低炎性细胞因子IL-12的量同时升高抗炎细胞因子IL-10的量。
使用来自多个健康人类捐献者的PBMC,通过直接刺激来对候选益生菌菌株的免疫调节活性进行筛选,这看似可以为体内抗炎菌株提供良好的预示性指征。
虽然事实上该测定未阐明所涉及的生理学机制,但其似乎模仿免疫系统可以如何感知细菌菌株并由此使免疫应答发生极化。导致高IL-10/IL-12比的菌株会更容易使早期Th1应答变缓。
在此背景下,通过对5种不同的益生菌进行评估,发现了短双歧杆菌BR 03是最强力的“抗炎”菌株,其引发最佳IL-10/IL-12比,如图2所示。
图2显示出针对不同益生菌菌株的菌株特异性IL-10/IL12比。5个实验中的一个代表性实验。
考虑到上述内容,本发明中鉴定出的所有细菌菌株显示出:
-较强的诱导抗炎性IL-10的产生的能力,
-较低的刺激促炎性IL-12的产生的能力,
-引发高IL-10/IL-12比的强力“抗炎”活性,
-因其对胃液、胆汁盐、胰分泌物和对肠壁的粘附有抗性而具有在胃肠道中的高持续性,和
-使用安全,不具有获得性抗生素抗性。
Claims (14)
1.一种细菌菌株,所述细菌菌株是白细胞介素-10的诱导物,所述细菌菌株选自由副干酪乳杆菌LMG P-21380、植物乳杆菌LMG P-21021、乳双歧杆菌LMG P-21384和短双歧杆菌DSM 16604或其细胞组分组成的组。
2.如权利要求1所述的细菌菌株,其中,所述细菌显示出大于1且小于150、优选为10~100、更优选为30~60的IL-10/IL-12比。
3.如权利要求1或2所述的细菌菌株短双歧杆菌DSM 16604,所述短双歧杆菌DSM 16604是白细胞介素-10的诱导物,且显示出50~100、优选为70~80的IL-10/IL-12比。
4.如权利要求1~3中任一项所述的细菌菌株,其中所述细菌为活细菌形式或死细菌形式或其细胞组分形式。
5.一种食物产品,所述食物产品包含至少一种作为活性成分的权利要求1~4中任一项所述的细菌菌株。
6.一种组合物,所述组合物包含至少一种用作药物的权利要求1~4中任一项所述的细菌菌株。
7.如权利要求6所述的组合物,所述组合物用作用于预防或治疗大肠和小肠炎性病症的药物。
8.如权利要求7所述的组合物,其中,所述炎性病症选自由克罗恩氏病和溃疡性结肠炎组成的组。
9.如权利要求6所述的组合物,所述组合物用作用于预防或治疗机能性肠障碍的药物。
10.如权利要求9所述的组合物,其中,所述机能性肠障碍选自由痢疾和便秘组成的组。
11.权利要求1~4中任一项所述的细菌菌株中的至少一种在制备用于预防或治疗大肠和小肠炎性病症的药物中的应用。
12.如权利要求11所述的应用,其中,所述炎性病症选自由克罗恩氏病和溃疡性结肠炎组成的组。
13.权利要求1~4中任一项所述的细菌菌株中的至少一种在制备用于预防或治疗机能性肠障碍的药物中的应用。
14.如权利要求13所述的应用,其中,所述机能性肠障碍选自由痢疾和便秘组成的组。
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ES2778836T3 (es) | 2020-08-12 |
RU2011139211A (ru) | 2013-04-10 |
KR20110125667A (ko) | 2011-11-21 |
US20150283185A1 (en) | 2015-10-08 |
EP2403510B1 (en) | 2020-02-26 |
BRPI0924902A2 (pt) | 2015-07-07 |
EP2403510A1 (en) | 2012-01-11 |
AU2009341473A1 (en) | 2011-10-06 |
AU2009341473B2 (en) | 2016-04-21 |
PL2403510T3 (pl) | 2020-06-29 |
CA2754300A1 (en) | 2010-09-10 |
PT2403510T (pt) | 2020-04-02 |
US20120064118A1 (en) | 2012-03-15 |
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WO2010099824A1 (en) | 2010-09-10 |
DK2403510T3 (da) | 2020-03-23 |
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