CN102066550A - 具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种新菌株 - Google Patents
具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种新菌株 Download PDFInfo
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- CN102066550A CN102066550A CN2009801187614A CN200980118761A CN102066550A CN 102066550 A CN102066550 A CN 102066550A CN 2009801187614 A CN2009801187614 A CN 2009801187614A CN 200980118761 A CN200980118761 A CN 200980118761A CN 102066550 A CN102066550 A CN 102066550A
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- bacterial strain
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- antimicrobial
- lactobacillus
- immunomodulatory properties
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Abstract
本发明涉及具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种新菌株,还涉及含有所述菌株的组合物。
Description
本发明涉及具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种(Lactobacillus paracasei subsp.paracasei)的新菌株。
大量科学研究已报道了发酵食品(特别是乳制品)中存在的特定微生物对健康的有益影响。这些微生物被通称为“益生菌”。根据目前普遍接受的定义,益生菌是“活的微生物,其在以适当量摄入时,对宿主健康具有有益影响”(FAO/WHO关于益生菌在包括含有活乳酸菌之奶粉在内的食品中的健康和营养特性的评价报告,科尔多瓦,阿根廷,2001年10月1-4日)。
已经发现,摄入含有益生菌的食品能对健康产生有益影响(尤其是通过肠道菌群的再平衡)、提高对感染的抵抗力,并调节免疫应答。
用于人类食品中的益生性微生物通常为乳酸菌,主要属于乳杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium),尤其是属于副干酪乳杆菌副干酪亚种(专利申请号EP0794707中描述的菌株)的物种。
但是,对健康的有益影响并不是同一属甚至同一种的所有细菌所共有的。它们通常只存在于某些菌株中;此外,观察到的效果可能在益生性菌株(包括同一种中的菌株)之间存在定性和/或定量的差异。
微生物要被考虑为有可能用作益生菌,则必须满足以下标准中的至少一项,理想地为几项:
-对可能存在于肠道菌群中的病原微生物表现出抑制活性,该活性可以是由于能粘附于肠道细胞从而阻止或减少病原体的粘附,或是由于能产生可抑制该病原体的物质,或是由于这两种特性的组合。
-表现出免疫调节特性,尤其是免疫刺激和/或抗炎特性。
此外,如果该微生物旨在掺入乳制品中,则其应该优选地在乳中表现出令人满意的生长。
最后,它应该在所掺入食品的生产和贮存过程中以及该食品被消费者摄入后保持良好的生存力,以使其能够到达肠并在肠环境中存活。
不过,需要注意的是,虽然生存力是满足目前“益生菌”的定义所必需的,但已发现,一些与益生菌菌株相关的有益效果即便在不存在活菌时也能够获得,其归功于某些细菌级分或其培养上清液中的活性级分。例如,PCT申请WO2004093898中描述了通过对CNCM I-2219菌株的培养上清液中进行分级分离而得到的免疫调节制备物。
本发明人现已成功分离了满足上述标准的副干酪乳杆菌副干酪亚种的新菌株。
本发明一个主题为此菌株,其根据布达佩斯条约于2006年11月9日以保藏号I-3689保藏于CNCM(法国微生物培养物保藏中心)。
CNCM I-3689菌株具有以下特征:
-形态学:革兰氏阳性微生物,细小杆状,独立或短链。
-发酵以下糖类(用api 50 CH strip-API MRS培养基在37℃下48小时所得结果):核糖、半乳糖、D-葡萄糖、D-果糖、D-甘露糖、甘露醇、N-乙酰葡糖胺、熊果苷、纤维二糖、麦芽糖、乳糖、海藻糖、松三糖、D-松二糖、D-塔格糖、葡萄糖酸。
-存在SEQ ID NO:1序列的单个CRISPR基因座,其包含以核苷酸序列SEQ ID NO:2代表的重复序列。
此外,它还具有抗微生物特性,这导致对培养基中病原微生物生长的强抑制能力,所述病原微生物尤其是大肠杆菌(Escherichia coli)、肠炎沙门氏菌(Salmonella enteritidis)和单核细胞增多性李斯特菌(Listeria monocytogenes)。
CNCM I-3689菌株还具有免疫调节(尤其是抗炎)特性。
本发明的主题还包括可通过CNCM I-3689菌株的诱变或遗传转化而获得的副干酪乳杆菌副干酪亚种菌株。优选地,这些菌株保留CNCM I-3689菌株的抗微生物及免疫调节特性。它们可以是这样的菌株,其中CNCM I-3689菌株的一个或多个内源基因发生突变,例如为了修饰其某些代谢特性(如该菌株代谢糖类的能力、其对肠道运输的耐性、其对酸的抗性、其后酸化(post acidification)或其代谢物产生)。它们也可以是用一个或多个目的基因对CNCM I-3689菌株进行遗传转化而产生的菌株,使得可以例如赋予所述菌株以额外的生理特征,或是表达有治疗或疫苗意义的蛋白质,其期望通过所述菌株进行施用。
这些菌株也可以通过以下方式由CNCM I-3689菌株获得:通过用于随机或定点诱变以及乳杆菌遗传转化的常规技术,如Gury等(Arch Microbiol.,182,337-45,2004)或Velez等(Appl Environ Microbiol.,73,3595-3604,2007)所述,或是通过称为“基因组改组(genome shuffling)”的技术(Patnaik等Nat Biotechnol,20,707-12,2002;Wang Y.等,J Biotechnol.,129,510-15,2007)。特别地,这些菌株具有序列SEQ ID NO:1的CRISPR基因座。
本发明的主题还包括获得具有抗微生物和/或免疫调节特性的副干酪乳杆菌副干酪亚种菌株的方法,其包括对CNCM I-3689菌株进行诱变或遗传转化的步骤。
本发明的主题还包括从本发明副干酪乳杆菌副干酪亚种菌株中获得具有抗微生物和/或免疫调节特性的细胞级分的方法。所述细胞级分特别是得自所述菌株培养物的DNA制备物或细菌细胞壁制备物。它们也可以是培养物上清液或上清液的级分。
本发明的主题还包括组合物,其含有本发明副干酪乳杆菌副干酪亚种菌株或从所述菌株中获得的细胞级分。
这些组合物可以特别地为乳发酵物,将本发明副干酪乳杆菌副干酪亚种菌株与一种或多种其它(任选地为益生性)乳酸菌菌株组合在一起。作为乳酸菌菌株的实例,值得一提的是保加利亚乳杆菌(Lactobacillus bulgaricus)和嗜热链球菌(Streptococcus thermophilus)菌株。
它们也可以是食物产品,特别是乳制品,或是药用或化妆用产品,所述产品含有本发明所述副干酪乳杆菌副干酪亚种菌株或从所述菌株中获得的细胞级分。
当所述菌株以活菌形式存在时,它们将优选以至少105cfu/克的比例存在、有利地为至少106cfu/克产品,更有利地为至少107cfu/克,甚至更有利地为至少108cfu/克。
可从下文的进一步描述中更清楚地理解本发明,所述描述是指展示CNCM I-3689菌株抗微生物、免疫调节和抗感染特性以及该菌株的分子分型的实施例。
实施例1:将CNCM I-3689菌株的特性与已知益生菌株进行比较
将CNCM I-3689菌株的特性与多种以益生特性知名的现有技术菌株进行比较。
这些菌株的清单在下文表I中给出。
表I
1-抗微生物活性
抗微生物活性的研究针对三种靶标病原性细菌进行:大肠杆菌E1392-75-2A、肠炎沙门氏菌NIZO B1241和单核细胞增多性李斯特菌4B。将乳酸菌在培养皿中以两种不同培养基进行培养:Elliker培养基(Elliker等,J.Dairy Sci.,39,1611-1612,1956)和TGE培养基(胰蛋白胨-葡萄糖-肉提取物)。
将培养皿在37℃下孵育,直至出现菌落。双歧杆菌的培养在厌氧条件下进行。然后向培养皿表面倒入一层含有BHI(脑-心浸液)培养基和病原体的琼脂。将培养皿再在37℃下孵育24小时。随后测量每个乳酸菌菌落周围病原体抑制区域的直径。1分相当于1-3mm的直径,2分相当于4-6mm直径,3分相当于超过6mm的直径。对每种菌株将每个实验独立进行三次。
将每个试验中靶标病原体所得分数相加,从而获得每种乳酸菌抗微生物活性的总分。
结果在下文表II中给出。
这些结果表明,在受试的菌株中,CNCM I-3689菌株和ATCC 55544菌株具有最高的抗微生物活性。
2-免疫调节
通过IL-10/IL-12比值来评估多种乳酸菌的免疫调节特性。
将从健康个体获得的人血液样品用PBS-CA(Gibco)以1∶2比例稀释,并用Ficoll(Gibco)梯度纯化。在20℃下以400×g离心30分钟后,取PBMC(外周血单个核细胞)。随后进行三个清洗步骤,并将PBMC重悬于添加有1%胎牛血清、1% L-谷氨酰胺(Gibco)和150μg/ml庆大霉素(Gibco)的RPMI培养基(Gibco)中。将PBMC在显微镜下进行计数,并调节至浓度为2×106细胞/ml,然后以1ml的等分分配到24孔细胞培养板(Corning,Inc.)中。
将乳酸菌菌株培养在MRS培养基(de Man等,J.Appl.Bacteriol.23,130-135,1960)中,将双歧杆菌菌株在厌氧条件下培养在添加有0.03% L-半胱氨酸(Sigma)的MRS培养基中。所有菌株均在37℃的温度下孵育。在稳定期停止细菌的生长,清洗细菌并以3 MacFarlan单位的浓度重悬于含20%甘油的PBS中。
向平板的每个含有PBMC的孔中加入10μl体积的细菌制备物(细菌∶细胞比为10∶1),将平板在含有5% CO2的气氛下以37℃孵育24小时。随后吸取上清液,以2000rpm离心并保存于-20℃。
试验中包括已知具有免疫调节特性的对照细菌菌株。还使用无菌的PBS-20%甘油作为阴性对照。对每个菌株以来自三个不同供体的PBMC进行实验。
使用商品试剂盒(Pharmingen,BD Biosciences)通过ELISA测定来测量细胞因子的表达。研究了两种细胞因子:IL-10和IL-12。
对每种受试菌株计算IL-10/IL-12比值的平均值。这些结果在下文表III中给出。
表III
这些结果显示,CNCM I-3689菌株对此模型表现出可观的抗炎特性。所测试的参照菌株均未表现出如此良好的特性。
图1显示每个细菌菌株的IL-10/IL-12比值,其作为上文测定抗病原体分数(主观单位)的函数显示。该图显示CNCM I-3689菌株与其他测试菌株的差异程度。
3-与肠应激相关的存活
使用了反映肠应激条件的体外模型。
在补充有酵母提取物的乳中制备乳酸菌培养物。根据物种将培养物孵育24至48小时(直至达到培养的稳定期)。
制备包含猪胆汁盐(3.3g/l)和NaHCO3碳酸盐缓冲液(16.5g/l)的人工肠液。将pH值调至6.3。向100μl细菌培养物中加入1ml这种肠液,然后将培养物孵育5个小时。随后,估算应激前和应激后培养皿上的菌群。
该值如下表述:
肠应激=log(cfu5小时/cfu0小时)
cfuX分钟是孵育X分钟后以菌落形成单位(CFU)表示的细菌浓度。
就肠应激而言,当该值大于-0.5时存活情况非常好,当该值在-0.5到-1.5之间时存活适中,而当该值小于-1.5时则存活不佳。
结果在下文表IV中给出。
表IV
4-结论
上文表II、III和IV所示结果表明,在所测试的多种菌株中,仅有CNCM I-3689同时具有可观的抗微生物特性和可观的抗炎特性,另外,还有极佳的肠应激抗性特性。
实施例2:CNCM I-3689菌株在乳中的生长
使用以下方案来测试CNCM I-3689菌株在乳中的生长特性:
-将由脱脂乳粉构成的培养基用CNCM I-3689菌株进行接种(5.6×106cfu/g或1.1×107cfu/g),所述培养基由加入了脱脂乳粉的水重建而成。
通过连续监测生长培养基的pH值来测定该菌株的发酵活性(这与其生长相关联)。
结果图示于图2中。
这些结果表明,CNCM I-3689菌株能够在乳中高效生长,因此它可用于发酵乳制品的生产中。
实施例3:CNCM I-3689菌株的分子分型
许多原核生物具有一个或多个CRISPR基因座——这是“间隔规律的成簇短回文重复(Clustered Regularly Interspaced Short Palindromic Repeats)”的首字母缩写(Jansen等,2002,OMICS,Vol.6,No.1,23-33)。CRISPR基因座的特征在于非连续的重复序列(或DR),通常为21至37个碱基对(bp),由通常为20至40个碱基对的称为可变序列(“间隔区”)的独特序列分隔开。在不同的细菌菌株中间可观察到以下方面的差异:
-CRISPR基因座的数目
-CRISPR基因座在基因组中的位置
-重复序列数,和/或
-可变序列的性质和/或大小
1-鉴定CNCM I-3689菌株中的CRISPR基因座
对CNCM I-3689菌株进行测序。用ERGOTM软件系列对其基因组进行分析,使得可以鉴定出该菌株中的单个CRISPR基因座。此基因座大小为3323bp,位于ORF RDBK00370下游20碱基对处。其基因组DNA序列用序列SEQ ID NO:1表示。它由与ATCC 334菌株(干酪乳杆菌(Lactobacillus casei))中CRISPR基因座相同的重复单元(GTTTTCCCCGCACATGCGGGGGTGATCC;SEQ ID NO:2)和54个可变序列(间隔区)构成。
2-构建对CNCM I-3689菌株具有特异性的PCR扩增引物
以CNCM I-3689菌株CRISPR基因座的可变序列为基础,确定几个寡核苷酸引物对。通过对几种细菌菌株的PCR扩增来测试这些引物,以确定其对CNCM I-3689菌株的特异性。
保留了一对引物:
-引物OFF2486(CTCAACAGGATAAGTGCCAC;SEQ ID NO:3),位于CRISPR基因座的第33个可变序列中,2049-2068位,TM=60℃;
-引物OFF2488(GGTTGGCTGGGTTTAACGC;SEQ ID NO:4),定位于CRISPR基因座的第37个可变序列中,2093-2110位,TM=60℃。
保留的PCR条件如下:
反应混合物:
DNA: 1μl
dNTP: 4μl
10×缓冲液: 5μl
引物OFF2486: 0.3μl
引物OFF2488: 0.3μl
Ex taqTM DNA聚合酶: 0.2μl
水: 39.2μl
循环:
CNCM I-3689菌株的PCR产物的预计大小为263bp。
将引物对OFF2486/OFF2488用CNCM I-3689菌株和18种其他不同的干酪乳杆菌菌株进行测试,包括CNCM I-1518和ATCC 334菌株。CNCM I-1518和ATCC 334菌株代表阴性对照,因为所述引物在上述PCR条件下不能与这些菌株的基因组DNA序列杂交。
结果通过图3所示的PCR扩增产物琼脂糖凝胶电泳显示,其中“121”代表CNCM I-3689菌株,“001”代表CNCM I-1518菌株,“S3”至“S18”分别代表16种不同的干酪乳杆菌菌株,“SL”代表分子量标记(SmartLadder;Eurogentec)。
这些结果表明,引物对OFF2486/OFF2488确实对CNCM I-3689菌株具有特异性,因为只在该菌株中获得了预计大小的PCR扩增产物(即约260bp)。
Claims (6)
1.具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种(Lactobacillus paracasei subsp.paracasei)菌株,其特征在于所述菌株是以保藏号I-3689保藏于CNCM的菌株。
2.具有抗微生物及免疫调节特性的副干酪乳杆菌副干酪亚种菌株,其特征在于所述菌株可通过诱变或遗传转化而得自权利要求1的菌株。
3.用于获得具有抗微生物和/或免疫调节特性的副干酪乳杆菌副干酪亚种菌株的方法,其特征在于所述方法包括对CNCM I-3689菌株进行诱变或遗传转化的步骤。
4.用于获得具有抗微生物和/或免疫调节特性的细胞级分的方法,其特征在于所述细胞级分得自权利要求1和2中任一项的副干酪乳杆菌副干酪亚种菌株。
5.组合物,其包含权利要求1的副干酪乳杆菌副干酪亚种菌株或者根据权利要求4的方法获得的细胞级分。
6.权利要求4的组合物,其特征在于所述组合物为食品。
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PCT/FR2009/000443 WO2009130423A2 (fr) | 2008-04-18 | 2009-04-16 | Nouvelle souche de lactobacillus paracasei subsp. paracasei dotee de proprietes antimicrobiennes et immunomodulatrices |
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KR100419132B1 (ko) | 2000-12-29 | 2004-02-18 | 조성근 | 위·장 점막 부착성과 증식성, 내산성, 내담즙성 및헬리코박터 파일로리, 대장균 0157:h7에 대한 항균성이우수한 락토바실러스 파라카제이 서브스패시즈 파라카제이csk 01 |
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SE529185C2 (sv) * | 2005-10-07 | 2007-05-22 | Arla Foods Amba | Användning av probiotiska bakterier för tillverkning av livsmedel eller läkemedel för förhindrande av övervikt |
WO2008047391A1 (en) * | 2006-10-17 | 2008-04-24 | S.I.F.Fr.A. Farmaceutici Srl | Nutriceutic composition comprising lactoferrin and proteasic probiotics |
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CN104673700A (zh) * | 2013-11-29 | 2015-06-03 | 晨晖生物科技股份有限公司 | 乳酸菌株及引物组 |
CN114836340A (zh) * | 2013-11-29 | 2022-08-02 | 晨晖生物科技股份有限公司 | 乳酸菌株及引物组 |
CN104862240A (zh) * | 2013-12-28 | 2015-08-26 | 萧夏青 | 乳酸菌株及其引物组 |
CN106604736A (zh) * | 2014-04-15 | 2017-04-26 | 达能日尔维公司 | 副干酪乳杆菌促进生态失调后肠道菌群多样性恢复的应用 |
CN106604736B (zh) * | 2014-04-15 | 2021-01-29 | 达能日尔维公司 | 副干酪乳杆菌促进生态失调后肠道菌群多样性恢复的应用 |
CN104523762A (zh) * | 2014-12-10 | 2015-04-22 | 中国农业大学 | 具有抗过敏作用的副干酪乳杆菌的应用和功能食品组合物及其制备方法 |
CN104523762B (zh) * | 2014-12-10 | 2019-01-22 | 中国农业大学 | 具有抗过敏作用的副干酪乳杆菌的应用和功能食品组合物及其制备方法 |
CN110878270A (zh) * | 2019-12-21 | 2020-03-13 | 福建省农业科学院农业工程技术研究所 | 一株副干酪乳杆菌副干酪亚种及其应用 |
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CA2721704C (fr) | 2019-04-02 |
ZA201007510B (en) | 2011-08-31 |
AR071330A1 (es) | 2010-06-09 |
KR20110009152A (ko) | 2011-01-27 |
BRPI0911420A8 (pt) | 2016-06-28 |
JP5649564B2 (ja) | 2015-01-07 |
WO2009130423A2 (fr) | 2009-10-29 |
CA2721704A1 (fr) | 2009-10-29 |
EP2271744A2 (fr) | 2011-01-12 |
FR2930264A1 (fr) | 2009-10-23 |
BRPI0911420A2 (pt) | 2015-08-04 |
US8557561B2 (en) | 2013-10-15 |
CN102066550B (zh) | 2013-10-30 |
MX2010011465A (es) | 2011-01-21 |
RU2010146956A (ru) | 2012-05-27 |
PL2271744T3 (pl) | 2013-08-30 |
FR2930264B1 (fr) | 2013-02-22 |
ES2410263T3 (es) | 2013-07-01 |
CL2009000911A1 (es) | 2010-02-19 |
US20110150852A1 (en) | 2011-06-23 |
KR101609401B1 (ko) | 2016-04-05 |
EP2271744B1 (fr) | 2013-03-20 |
JP2011517570A (ja) | 2011-06-16 |
RU2501850C2 (ru) | 2013-12-20 |
WO2009130423A3 (fr) | 2009-12-17 |
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