CN103961377A - 在胃肠系统中具有镇痛特性的嗜酸乳杆菌菌株 - Google Patents
在胃肠系统中具有镇痛特性的嗜酸乳杆菌菌株 Download PDFInfo
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Abstract
本发明涉及嗜酸乳杆菌的至少一株菌株在制备制剂中的用途,该制剂以在胃肠系统的镇痛目的给药予人类或动物。
Description
本申请是申请日为2005年9月21日、申请号为200580031540.5、发明名称为“在胃肠系统中具有镇痛特性的嗜酸乳杆菌菌株”的发明专利申请的分案申请。
技术领域
本发明的主题是嗜酸乳杆菌的至少一株菌株在制备制剂中的用途,该制剂以在胃肠系统的镇痛目的给药予人类或动物。
背景技术
在微生物特别是细菌当中,有一些对免疫系统具有积极影响,特别是乳杆菌和双歧杆菌,它们被称为“益生”细菌或菌株。
通常,益生菌或菌株是指一种非病原微生物,其被活的摄取,对宿主的健康或生理具有有利作用。这些益生菌株通常能够活着通过消化道上部。它们是非致病非毒性的,一方面通过与消化道中的常居菌群的生态相互作用,另一方面通过它们以积极途径由“GALT”(消化道相关的淋巴组织)影响免疫系统的能力,而发挥它们对健康的有利作用。取决于益生菌的定义,当数量足够时,这些细菌能够活着通过肠,然而它们不能穿越肠屏障,因此它们主要影响于胃肠道腔和/或壁中。然后在给药期间,它们成为常居菌群的一部分。这种集群现象(或暂时集群现象)允许益生菌发挥有利作用,例如对存在于菌群中的潜在的病原性微生物的抑制,以及与肠免疫系统的相互影响。
大多数所使用的益生菌,特别是乳制品中所使用的益生菌,主要是以下属的细菌和酵母:乳酸菌spp.,链球菌属spp.,肠球菌spp.,双歧杆菌属.,和酿酒酵母spp.。上述这些细菌的益生作用中,可提到的例如改善乳糖耐受性、预防或治疗胃肠和泌尿生殖器感染、减少肿瘤、降低血胆固醇水平。然而,必须强调,如果就单独的一株菌株来说,并不是如上所述的所有属的菌株都具有这些作用,仅仅只是它们中的一些具有这些作用,这些菌株必须慎重选择。
为满足工业化的需要,必需发现有效的菌株或菌株混合物,并可以提供一种减少在胃肠水平中体验的疼痛的方案,这种胃肠疼痛通常表现为肠不适,特别是过敏性肠综合征(IBS),或胃肠水平的由炎症所引起的疼痛,特别是在结肠炎或腹泻过程中。
发明内容
因此,本发明要解决的问题是提供一种具有镇痛特性的益生菌。
为此目的,本发明提供嗜酸乳杆菌的至少一株菌株在制备制剂中的用途,该制剂以在胃肠系统的镇痛目的给药予人类或动物。
本发明还提供一种选择一种微生物来制备制剂的方法,该制剂以在胃肠系统的镇痛目的给药予人类或动物,该方法包含以下步骤:
i)使要试验的微生物与至少一个上皮细胞接触;
ii)检测至少一个上皮细胞中阿片样物质受体和/或大麻素受体的表达;
本发明的优势在于提供确实的、将扩大有用菌株范围的优点。
本发明的另一个优势在于本发明的益生菌能用于胃肠系统的治疗或预防目的。
当本发明的益生菌以胃肠系统的治疗或预防目的给药予人类或动物,特别是减少在过敏性肠综合征中体验的疼痛或减少在由炎症反应所引起的疼痛,或调节肠炎时,本发明是特别有利的。
由于本发明的益生菌可以通过调整分泌和消化motricity而调节肠运输,因此当它以治疗或预防目的给药予人类或动物时,本发明也是有利的。
本发明的优势还在于,当该益生菌引入药学可接受制剂或引入食品时,它可保留所有其特性。
通过阅读以下说明和实施例,将更清楚地了解本发明的其他优势和特征,实施例仅仅是说明性而非限制性的。
本发明的主题是嗜酸乳杆菌的至少一株菌株在制备制剂中的用途,该制剂以在胃肠系统的镇痛目的给药予人类或动物。
根据本发明,所使用的嗜酸乳杆菌是一种革兰氏阳性菌株。有利地,它是过氧化氢酶阴性的菌株,以同型发酵的代谢作用引起乳酸的产生。
根据本发明,所使用的嗜酸乳杆菌还可以产生细菌素,例如lactacin,活性对抗其他微生物。
优选地,它是一种能够在酸性pH环境下很好地耐胃蛋白酶、耐胰酶和耐胆汁盐的嗜酸乳杆菌。
优选地,使用被称为“疏水”的嗜酸乳杆菌,即,一种对极性的或非极性的疏水有机溶剂具有强烈的亲合性的嗜酸乳杆菌。疏水的有机溶剂例如为n-癸烷、氯仿、十六烷或二甲苯。
根据本发明,嗜酸乳杆菌菌株优选嗜酸乳杆菌PTA-4797和嗜酸乳杆菌NCFM。根据布达佩斯条约,嗜酸乳杆菌的嗜酸乳杆菌PTA-4797菌株已由法国Rhodia Chimie,26,quai Alphonse Le GaIIo192512BOULOGNE-BILLANCOURT Cedex在美国典型菌种保藏中心(ATCC)注册,其中它的注册号为PTA-4797。该菌株在WO2004052462中公开。
在根据本发明的用途的范围内,胃肠系统中的镇痛有利地通过阿片样物质受体和/或大麻素受体来调节。
所述的阿片样物质受体总共有三种:δ、κ和μ。它们属于G蛋白偶联受体总科,其由七个跨膜螺旋组成。该受体的胞内部分与G蛋白接触,该G蛋白与受体相关,并可随着所使用的拮抗剂的种类而改变,蛋白质的主要顺序为Gαi3>Gαi2>Gαi1。
该阿片样物质受体,特别是μ受体,具有若干功能。主要的一个功能是镇痛作用,该作用通过利用β-内啡呔-或吗啡-型拮抗剂与该受体特定结合,通过血脑屏障而得到证实。该受体在消化道中的第二个功能是通过抑制分泌和消化motricity减少肠运输。最后,该阿片样物质受体还涉及调节肠炎。
该阿片样物质μ受体存在于中枢和外周神经系统中。已在大部分人体的重要器官中检测到它的存在:脾脏、肝脏、肾脏、小肠和结肠,特别是在粘膜下和肠系膜丛神经元中的肠神经系统中,以及,在体外的淋巴细胞、单核细胞/巨噬细胞和上皮细胞中。
大麻素受体,称为CB1和CB2,属于G蛋白偶联受体总科,其由七个跨膜螺旋组成。CB1主要通过中枢和外周神经系统表达,CB2主要通过免疫反应细胞表达。在人类,这些大麻素受体具有两种内原性配位体,其通常由肠上皮细胞生成。
由肠神经系统表达的大麻素受体CB1减缓胃和小肠的蠕动并抑制胃液分泌。推测大麻素受体具有其他的抗-diarrhoetic和抗癌功能。
在根据本发明的用途的范围内,胃肠系统中的镇痛优选通过阿片样物质μ受体和/或CB1受体和/或CB2受体调节。
本发明中所使用的制剂优选药学可接受的制剂或食品。
药学可接受的制剂尤其是指一种压制片、片剂、胶囊剂、软膏、栓剂或可饮用溶液形式的制剂。
优选地,本发明所用的制剂是食品,例如食品增补剂、酒或基于奶的粉末。它优选是动物或植物来源的乳制品。
乳制品是指含有动物和/或植物来源的奶的介质。可提及的动物来源的奶为牛奶、绵羊奶、山羊奶或水牛奶。可提及的植物来源的奶为任何可根据本发明使用的植物来源的发酵性物质,特别是源自大豆、大米或谷类。
根据本发明,所使用的更优选的制剂是发酵奶或母乳化牛奶。
用于制备本发明制剂的嗜酸乳杆菌菌株可以为细菌悬液、冷冻前后形式,浓缩形式,或者为干燥的、冻干的或冻结形式。无论使用哪种形式,菌株可以冷冻。
用于制备本发明制剂的嗜酸乳杆菌菌株可以包含不同的添加剂,所述添加剂在菌株的干燥或冻干过程中添加。
本发明所使用的嗜酸乳杆菌菌株可包含从106到1012CFU的细菌/克载体,更优选从108到1012CFU的细菌/克载体。CFU代表“菌落形成单位”。克载体优选指食品或药学可接受的载体,对于冻干形式,优选109到1012CFU/g。
用于制备本发明制剂的嗜酸乳杆菌菌株可以是与乳杆菌的混合物形式。根据本发明,所述乳杆菌是适宜的,包括通常用于农食品或制药工业的所有乳杆菌。
用于引导,最常使用于和存在于发酵剂中的所述乳杆菌是那些属于乳球菌属、链球菌属、乳杆菌属、白联珠菌属、小球菌属、双歧杆菌属、短颈细菌属、肉食杆菌属、肠球菌属、微球菌属、漫游球菌属、葡萄球菌属、杆菌属、克氏库克菌属、节核细菌属、Proprionibacterium和棒杆菌属。这些乳杆菌单独使用或混合使用。该列表是非穷举的。
本发明的主题还涉及一种选择一种微生物来制备制剂的方法,该制剂以在胃肠系统的镇痛目的给药予人类或动物,该方法包含以下步骤:
i)使要试验的微生物与至少一个上皮细胞接触;
ii)检测至少一个上皮细胞中阿片样物质受体和/或大麻素受体的表达;
步骤i)或ii)中使用的上皮细胞优选选自细胞株ATCC HTB-38,其通常称为HT-29株,或选自细胞株Caco-2。这些是结肠癌细胞系。上皮细胞还可以是从人类活组织切片中分离和纯化出来的细胞。
步骤i)优选在使用从108到1012CFU的要试验的微生物和至少一个上皮细胞下进行。
步骤i)过程中的接触时间可以从0小时到24小时,优选3小时。
通常,根据步骤i),在本领域技术人员所熟知的标准温度、气调和无菌环境之下进行与细胞的接触,特别是在体外上皮细胞培养环境下。
根据本发明选择的方法,步骤ii)优选在检测阿片样物质μ受体(MOR)和/或CB1受体和/或CB2受体的表达下进行。通常,仅可检测一种受体的表达:仅MOR、仅CB1受体仅或CB2受体。或者,可检测两种受体的表达:MOR和CB1受体;MOR和CB2受体;CB1受体和CB2受体。或者,可检测三种受体的表达:MOR、CB1受体和CB2受体。
根据本发明选择的方法,步骤ii)优选检测阿片样物质受体和/或大麻素受体的信使RNA的表达以及任选其水平,例如由PCR,尤其由定量PCR或由免疫组织化学进行检测。也可使用本领域技术人员熟知的其他信使RNA的检测和它的测量技术。
附图说明
图1表示阿片样物质μ受体的信使RNA作为时间函数的表达动力学,在由4种不同微生物刺激过程中,在ATCC HTB-38上皮细胞中进行表达。
图2表示CB1受体的信使RNA作为时间函数的表达动力学,在由3种不同微生物刺激过程中,在ATCC HTB-38上皮细胞中进行表达。
图3表示CB2受体的信使RNA作为时间函数的表达动力学,在由3种不同微生物刺激过程中,在ATCC HTB-38上皮细胞中进行表达。
图4表示在不同环境下MOR的信使RNA的表达。
图5表示结肠TNF的alpha信使RNA在未经处理的老鼠和经L.acidophilus处理过的老鼠中的表达。
图6表示结肠KC的信使RNA在未经处理的老鼠和经L.acidophilus处理过的老鼠中的表达。
图7表示结肠IL-1β的信使RNA在未经处理的老鼠和经L.acidophilus处理过的老鼠中的表达。
图8、10、12表示免疫染色的上皮细胞。图9、11、13表示免疫染色的上皮细胞的百分比。
具体实施方式
以下实施例是为解释本发明,而非限制本发明的范围。
实施例1
1.上皮细胞的制备
在含有5%CO2的气氛、37℃下,分别用20和10%胎儿小牛血清,在DMEM介质中培养结肠癌细胞株HT-29(ATCC HTB-38)。ATCC HTB-38细胞株与要试验的不同菌株接触1;3;4;8;18或24小时。回收ATCC HTB-38上皮细胞并浸于液氮中,以量化阿片样物质μ受体和/或大麻素受体的信使RNA和蛋白质。
2.阿片样物质μ受体和/或大麻素受体的信息RNA的检测和量化:
实时PCR
培养基中的上皮细胞株的全部RNA通过使用柱萃取元件(Macherey-Nagel)分离出来。简言之,将细胞碾碎在含1%β-硫氢基-乙醇的溶解缓冲液中,然后通过第一柱,以取出所有残渣。用去氧核糖核酸酶(DNAse)处理后,由PCR实时(ABPrism7000,Perkin)在60℃的杂交温度下,使用阿片样物质μ受体或大麻素受体特定的引物将RNA转录成互补DNA:
-对于阿片样物质μ受体(MOR)(正义:ATgCCAgTgCTCATCATTAC,反义:gATCCTTCgAAgATTCCTgTCCT),对于参照基因:β-肌动蛋白(正义:TCACCCACACTgTgCCCATCTACgA,反义:CAgCggAACCgCTCATTgCCAATg);
-对于CB1大麻素受体,正义CCT AGA TGG CCT TGC AGA TAC C;CB1反义TGT CAT TTG AGC CCA CGT ACA G;CB2正义GCT AAG TGCCCT GGA GAA CGT;反义TCA GCC CCA GCC AAG CT。
3.结果
结果列于图到3中。该结果由靶基因(β-肌动蛋白)/阿片样物质μ受体(MOR)和/或大麻素受体(CB1,CB2)之间的比例所表达。
阿片样物质μ受体和/或大麻素受体在ATCC HTB-38上皮细胞株中表达(图1到3)。
一些微生物例如乳杆菌属菌株能够诱导阿片样物质μ受体和/或大麻素受体的信使RNA的表达。
该结果显示了阿片样物质μ受体和/或大麻素受体的受培养基中上皮细胞的显著诱导。
使用嗜酸乳杆菌菌株时,这种诱导特别强烈。
图1和2显示,用嗜酸乳杆菌培养上皮细胞3小时之后,观察到阿片样物质μ受体(图1)和CB1(图2)的信使RNA的基础表达水平增加了约1000倍。
图3显示,用嗜酸乳杆菌培养上皮细胞3小时之后,观察到CB2(图3)的信使RNA的基础表达水平增加了约100倍。
反之,使用共生大肠杆菌菌株(图1),则没有检测到阿片样物质μ受体的诱导。由嗜酸乳杆菌菌株得到的阿片样物质受体和/或大麻素受体的诱导与由剂量为10ng/ml的TNF-α得到的诱导为同一数量级。
实施例2
1.原料和方法
菌株。
根据本发明,在37℃下,在deMan Rogosa,Sharpe(MRS)肉汤(BectonDickinson)中厌氧产生嗜酸乳杆菌NCFM菌株过夜。对于体外实验,使用达到指数生长期的细菌。在动物接种之前,用革兰氏染色法评估培养基的纯度。
动物和实验性的感染。
根据政府指南,在来自Lille的Institut Pasteur,在公认设施中进行动物试验。12小时的白天周期下,每个笼子中安放五个Balb/c老鼠,老鼠可自由使用标准老鼠食物和自来水。在十四天中,一天一次,通过胃强饲法使动物接受再悬浮在0.5%CMC(羧甲基纤维素,Sigma)中的109CFU的嗜酸乳杆菌菌株。通过颈脱臼法处死动物。切除动物身上的所有结肠并切成两部分。一部分固定在4%酸性多聚甲醛中过夜并埋入石蜡中。另一部分结肠用于mμ-阿片样物质受体(MOR)、大麻素受体(CB1和CB2)和炎性细胞因子TNFα、KC和IL-1β的mRNA的量化。
TNBS结肠炎的诱导和研究设计。因为MOR的表达由炎症调节(PhilippeD等人,JCI2003;Pol O et al,MoI Pharmacol2001;Pol O et al,Curr Top MedChem2004),我们使用TNBS-诱导的结肠炎作为正调控。根据政府指南,在来自Lille的lnstitut Pasteur,在公认设施中进行动物试验。每个笼子中安放五个Balb/c老鼠,老鼠可自由使用标准老鼠食物和自来水。对于结肠炎诱导,使老鼠麻醉90-120分钟,并接受TNBS的直肠内给药(40μl,150mg/kg),所述TNBS溶解在0.9%NaCl∶100%乙醇为1∶1的混合物内。对照组老鼠使用相同的技术接受0.9%NaCl∶100%乙醇为1∶1的混合物或盐溶液。TNBS给药后4天处死动物。
定量实时PCR
根据厂家说明书,用Rneasy元件(Macherey Nagel,Hoerdt,France)将全部RNA从整个结肠组织中分离出来。用分光光度测定法进行RNA的量化。在37C下用20-50单元的无RNase的DNase I(Roche DiagnosticsCorporation,Indianapolis,IN,USA)处理30分钟后,用寡-dT探针(RocheDiagnostics Corporation,Indianapolis,USA)接合单股cDNA。在GeneAmpAbiprism7000(Applera,Courtaboeuf,France)里,用带特定的老鼠寡聚核苷酸(见表1)的SYBR green Master Mix(Applera,Courtaboeuf,France)量化mRNAs。每个试验包括定刻度标准对照和无模板对照。每个样本重复做三次。用Abiprism7000SDS software(Applera,Courtaboeuf,France)分析SYBR绿色染料强度。所有结果标准化到未受影响的看家基因β-肌动蛋白。
表1
MOR-CB1-CB2免疫组织化学
在接受嗜酸乳杆菌菌株的老鼠的埋入石蜡的结肠切片上进行免疫组织化学。未经处理的动物用作对照。4℃下,在含0.1%氚核X-100的PBS中渗透分钟后,用1.5%山羊正常血清培养切片15分钟,并用成块缓冲区(牛奶中1%BSA)培养15分钟,以将抗体的非特异性吸收最小化。随后,在室温下用直接抗CB1(1∶200,Cayman Chemical,Ann Arbor,USA)或CB2(1∶10,Alpha Diagnostic,San Antonio,USA)或MOR(1∶500,Diasorin,Antony,France)的兔子多克隆探针抗体培养该组织2到12小时。然后在室温下用与FITC荧光染料相配的Alexa488山羊的抗-兔子IgG(dilution1∶100,Dako Laboratories,Trappes,France)培养切片1小时。在每个步骤之间,切片在含0.05%氚核X-100中清洗两次,每次5分钟。然后用Hoescht溶液(0.125mg/mL)复染色载波片,并放置载波片用于镜检。由正常家兔血清染色的阴性对照代替特异性抗体。免疫荧光在荧光显微镜(Leica,Bensheim,Germany)下揭示。在五个不同的高倍视野(HPF)里计算MOR、CB1和CB2免疫反应性的上皮细胞的数目,该数目以每100上皮细胞表示。
2.结果
结679显示在图4到13中。
1)在体内,嗜酸乳杆菌诱导MORmRNA在老鼠结肠中表达(图4)。
给药嗜酸乳杆菌(每天109CFU)两周后,与未经处理的动物相比,发现结肠中MOR的mRNA表达增加24倍(p<0.05)。这种由嗜酸乳杆菌菌株引起的MORmRNA的诱导,比在我们在正调控中发现的两倍诱导更重要,正调控相当于由TNBS诱导的结肠炎(图4)。
2)在体内,嗜酸乳杆菌诱导MOR、CB1和CB2在老鼠的结肠上皮细胞中的表达(图8-13)。
为在平移水平评估MOR、CB1和CB2特别在结肠上皮细胞的诱导,我们使用特别是直接抗这些受体的抗体进行免疫组织化学。在所有切片中,与对照组老鼠相比,MOR(60±10vs5±3%)、CB1(60±8vs20±4%)或CB2(40±7vs20±5%)的上皮染色细胞在接受嗜酸乳杆菌菌株的老鼠内明显更众多(图8-13)。
3)给药嗜酸乳杆菌与在老鼠结肠中的降低的炎性细胞因子表达有关(图8-13)。
为评估如果嗜酸乳杆菌诱导的结肠上皮细胞的MOR、CB1和CB2表达在老鼠中有着起作用的意义,我们比较了未经处理的老鼠和在14天内接受嗜酸乳杆菌菌株的动物中不同的炎性细胞因子的mRNA水平。与对照组相比,在嗜酸乳杆菌处理过的动物中观察到炎性细胞因子TNFα、KC和IL-1βmRNA的表达水平降低50%以上,暗示着嗜酸乳杆菌菌株通过至少部分由上皮细胞引起的MOR、CB1和CB2的超表达,降低了老鼠结肠中炎性细胞因子的生理性表达。
实施例3
1.原料和方法
用不同的益生素或细菌(100细菌/细胞)体外培养上皮结肠细胞HT-29或Caco-20到6个小时:嗜酸乳杆菌(NCFM),L salivarius(UCC118),L。paracasei(LPC37)、共生大肠杆菌、吸附入侵大肠杆菌(LF82)。在mμ-阿片样物质受体(MOR)和大麻素受体(CB1和CB2)的由益生素引起的表达诱导中NFkappaB路径的作用通过由特定的抑制剂(乙氧苯基酯咖啡酸(CAPE))预处理HT-29细胞来进行测试。TNFalpha(10ng/ml,2小时),其是G偶联蛋白表达的诱导物,作为阳性对照组。选定最有效的用于在体外诱导受体(MOR、CB1和CB2受体)表达的益生菌后,由Balb/c老鼠(n=10)在15天内口服给药109CFU的益生菌,我们做出了体内研究。MOR、CB1和CB2的表达在上皮细胞中和在经实时PCR和免疫组织化学处理的老鼠结肠中评估。炎性细胞因子(TNF alpha、KC和IL-1β)mRNA由老鼠结肠中的实时PCR进行评估。
2.结果
仅嗜酸乳杆菌和L salivahus菌株能早在培养的第一小时起迅速诱导上皮细胞中强烈的MOR表达。这种表达诱导类似于用TNF alpha诱导的细胞中观察到的表达诱导。对于CB1(848+-180vs229+-55,p<0.05)和CB2(1498+-333vs341+-163,p<0.01),仅嗜酸乳杆菌诱导这些受体的表达。由CAPE抑制的NFkappaB路径没有诱导由嗜酸乳杆菌刺激的上皮细胞的MOR的表达改变。在体内,嗜酸乳杆菌的给药在结肠水平强烈地诱导MORmRNA(24+-0.75,p<0.01)的表达。免疫组织化学研究证实了体内由接受嗜酸乳杆菌的动物结肠细胞引起的MOR、CB1和CB2的表达诱导。这些受体的诱导与结肠炎性细胞因子的表达减少至少50%相关。
3.结论
嗜酸乳杆菌是诱导体外上皮细胞株中和体内结肠中的MOR、CB1和CB2表达最有效的菌株。
Claims (9)
1.嗜酸乳杆菌菌株在制备在患有过敏性肠综合征的人类或动物的胃肠系统中获得镇痛的载体中的用途,其中所述镇痛通过大麻醇类受体和/或阿片受体来介导。
2.如权利要求1所述的用途,其中所述载体含有106到1012CFU的细菌/克载体。
3.如权利要求1或2所述的用途,其中所述的嗜酸乳杆菌菌株为以注册号为PTA-4797注册在ATCC的菌株即嗜酸乳杆菌NCFM。
4.如权利要求1或2所述的用途,其中所述载体是药学可接受的载体或食品。
5.如权利要求1或2所述的用途,其中所述载体是动物或植物来源的乳制品。
6.选择益生菌来制备给药予人类或动物用于胃肠系统的镇痛目的的载体的方法,该方法包括以下步骤:
i)将待测试益生菌与至少一个上皮细胞接触;
ii)检测至少一个上皮细胞中阿片受体和/或大麻醇类受体的表达,
其中,如果所述待测试益生菌诱导阿片受体和/或大麻醇类受体的表达,则选择该待测试益生菌。
7.如权利要求6所述的方法,其特征在于,步骤i)或ii)中的至少一个上皮细胞来自细胞株ATCC HTB-38或细胞株Caco-2。
8.如权利要求6或7所述的方法,其特征在于,步骤ii)通过检测μ阿片受体和/或CB1受体和/或CB2受体来进行。
9.如权利要求6或7所述的方法,其特征在于,步骤ii)通过检测阿片受体和/或大麻醇类受体的信使RNA的表达而进行。
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CN108102960A (zh) * | 2017-12-25 | 2018-06-01 | 齐鲁工业大学 | 一种嗜酸乳杆菌ncfm耐酸保护剂 |
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FR2875406B1 (fr) * | 2004-09-21 | 2007-01-05 | Danisco | Souche de lactobacillus acidophilus ayant des proprietes analgesiques au niveau du systeme gastro-intestinal |
WO2007132359A2 (en) * | 2006-05-12 | 2007-11-22 | Danisco A/S | Composition containing lactobacillus sp. and a cannabinoid receptor and/or a opioid receptor agonist |
US9055763B2 (en) * | 2007-10-11 | 2015-06-16 | Dupont Nutrition Biosciences Aps | Probiotics for use in relieving symptoms associated with gastronitestinal disorders |
JP6077303B2 (ja) | 2009-05-07 | 2017-02-08 | タト エ リル アングルディアント フランス ソシエテ パ アクシオンス シンプリフィエ | アルファ−(1,2)−分岐アルファ−(1,6)オリゴデキストランを含有する組成物及びアルファ−(1,2)−分岐アルファ−(1,6)オリゴデキストランの製造方法 |
US8445226B2 (en) | 2010-02-01 | 2013-05-21 | Microbios, Inc. | Process and composition for the manufacture of a microbial-based product |
US7888062B1 (en) | 2010-02-01 | 2011-02-15 | Microbios, Inc. | Process and composition for the manufacture of a microbial-based product |
WO2011148219A1 (en) | 2010-05-28 | 2011-12-01 | Compagnie Gervais Danone | Probiotic strains for use in improving the enteric nervous system |
RU2642306C2 (ru) | 2012-05-21 | 2018-01-24 | ДюПон НЬЮТРИШН БАЙОСАЙЕНСИЗ АпС | Штамм lactobacillus, обладающий ингибирующей активностью против дрожжей и плесневых грибов (варианты), и его применение |
RU2640255C2 (ru) | 2012-05-21 | 2017-12-27 | ДюПон НЬЮТРИШН БАЙОСАЙЕНСИЗ АпС | Штамм propionibacterium, обладающий ингибирующей активностью против дрожжей и плесневых грибов (варианты) и его применение |
US9730969B2 (en) | 2015-11-06 | 2017-08-15 | Mead Johnson Nutrition Company | Nutritional compositions for promoting gut barrier function and ameliorating visceral pain |
CN108949643A (zh) * | 2018-08-31 | 2018-12-07 | 重庆子和杉农业发展有限公司 | 一种培育兔用乳酸菌的方法和无公害养兔的方法 |
WO2021156777A1 (en) * | 2020-02-06 | 2021-08-12 | Buzzelet Development And Technologies Ltd. | Microbial combinations and uses thereof |
WO2021161205A1 (en) * | 2020-02-13 | 2021-08-19 | Eyal Research Consultants Ltd | Microbial combinations with modulators of the opioid system and uses thereof |
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US5858356A (en) * | 1995-12-21 | 1999-01-12 | Abbott Laboratories | Lactobacillus acidophilus to inhibit cryptosporidiosis in mammals |
US6203797B1 (en) * | 1998-01-06 | 2001-03-20 | Stephen C. Perry | Dietary supplement and method for use as a probiotic, for alleviating the symptons associated with irritable bowel syndrome |
CH693625A5 (it) * | 1999-02-18 | 2003-11-28 | Inpharma Sa | Composizioni farmaceutiche contenenti composti ad attività promotrice di assorbimento di principi attivi. |
KR100357668B1 (ko) * | 2000-02-19 | 2002-10-18 | 주식회사 한국야쿠르트 | 헬리코박터 필로리에 대해 항균활성을 갖는 락토바실러스애시도필러스 에이치 와이 2177, 락토바실러스 카제이에이치 와이2743 및 그를 이용한 유산균 제제, 발효유 |
US7125884B2 (en) * | 2001-03-02 | 2006-10-24 | Euro-Celtique S.A. | N-but-3-enyl norbuprenorphine and its use as analgesic |
AU2002329043A1 (en) * | 2001-07-30 | 2003-02-24 | Claudio De Simone | Treatment of radiation-induced diarrhea with probiotics |
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FR2875406B1 (fr) * | 2004-09-21 | 2007-01-05 | Danisco | Souche de lactobacillus acidophilus ayant des proprietes analgesiques au niveau du systeme gastro-intestinal |
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US20150023936A1 (en) | 2015-01-22 |
ES2376864T3 (es) | 2012-03-20 |
US20070298080A1 (en) | 2007-12-27 |
AU2005287482A1 (en) | 2006-03-30 |
FR2875406A1 (fr) | 2006-03-24 |
PT1796698E (pt) | 2012-02-07 |
EP1796698B1 (en) | 2011-11-02 |
CN107982283A (zh) | 2018-05-04 |
DK1796698T3 (da) | 2012-02-27 |
FR2875406B1 (fr) | 2007-01-05 |
CA2578736A1 (en) | 2006-03-30 |
CA2578736C (en) | 2016-08-23 |
JP2012246300A (ja) | 2012-12-13 |
ATE531379T1 (de) | 2011-11-15 |
JP2008513411A (ja) | 2008-05-01 |
KR20070054670A (ko) | 2007-05-29 |
JP5162243B2 (ja) | 2013-03-13 |
CN107982283B (zh) | 2021-09-28 |
PL1796698T3 (pl) | 2012-05-31 |
EP1796698A1 (en) | 2007-06-20 |
US20200323930A1 (en) | 2020-10-15 |
US20180036355A1 (en) | 2018-02-08 |
NZ553616A (en) | 2010-05-28 |
AU2005287482B2 (en) | 2011-08-25 |
CN101094682A (zh) | 2007-12-26 |
WO2006032542A1 (en) | 2006-03-30 |
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