CN112869167A - 副干酪乳杆菌k56提升肠道细菌感染抗性和肠道免疫力的应用 - Google Patents
副干酪乳杆菌k56提升肠道细菌感染抗性和肠道免疫力的应用 Download PDFInfo
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Abstract
本发明提供了副干酪乳杆菌K56提升肠道细菌感染抗性和肠道免疫力的应用。具体地，本发明提供了一种副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)在制备用于提升肠道免疫力的组合物中的应用，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。本发明发现该菌株单菌即能够显著提升肠道细菌感染抗性，在肠道系统中抵御致病菌侵入，维持肠道屏蔽功能，和/或预防致病菌引起的腹泻。
Description
技术领域
本发明涉及微生物技术领域，尤其是涉及一种副干酪乳杆菌(Lactobacillusparacasei subsp.paracasei)K56(保藏编号CGMCC No.15139或DSM27447)在提升肠道细菌感染抗性和肠道免疫能力的新应用。
背景技术
肠道上皮细胞是机体抵抗病原菌的第一道屏障。病原菌在上皮细胞上的黏附或侵入，将会刺激肠道上皮细胞产生炎症因子或趋化因子。一些可溶性的介质可以调节肠道免疫系统或者诱发细胞的先天免疫反应。适当的免疫反应及良好的上皮细胞屏障功能将有助于保护宿主免受病原菌的感染。
益生菌是指在摄入足量的数量时，可以对人体健康产生益处的一类活的微生物。益生菌作为肠道微生物组重要的组成成分，对人体健康发挥着不可忽视的重要作用，如营养供给，合成维生素，有助于消化、促进血管新生和肠神经功能。
发明内容
本发明的一个目的在于提供一种副干酪乳杆菌K56的新用途。
本发明提供了一株副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)的新应用，该菌株本发明中命名为K56。该菌株已于2013年6月27日保存于德国微生物及细胞培养物收集中心(German Collection of Microorganisms and Cell Cultures)，保藏编号DSM27447；另外，副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56菌株也已于2017年12月29日保存于中国微生物菌种保藏管理委员会普通微生物中心(ChinaGeneral Microbiological Culture Collection Center,CGMCC)，保藏编号CGMCCNo.15139。
在本发明中，以肠毒性大肠杆菌(Enterotoxigenic Escherichia coli)ETECH10407和致肠病性大肠杆菌(Enteropathogenic Escherichia coli)EPEC O119作为诱发体外肠道感染的病原菌菌株进行了副干酪乳杆菌K56提升肠道免疫力的功能研究。两种类型的E.coli都是常见的致病菌，包含婴儿腹泻、旅行者腹泻、以及在发展中国家或者卫生较差的地区。ETEC H10407是较为成熟、实验常用的模式菌株，也经常用于评价益生菌对于致病菌的黏附能力和炎症信号通路。
本发明的研究发现，副干酪乳杆菌K56(即保藏编号为CGMCC No.15139或DSM27447的副干酪乳杆菌)菌株具有抑制肠道病原菌的黏附的作用，能够显著ETEC H1407和EPECO119对Caco-2细胞的黏附作用，提高肠道屏障完整性，并且具有抑制肠道炎症因子产生的作用，能够缓解由于ETEC H10407引起的炎症反应。
从而，本发明提供了副干酪乳杆菌(Lactobacillus paracaseisubsp.paracasei)在制备用于提升肠道免疫力的组合物中的应用，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。
根据本发明的具体实施方案，本发明的应用中，所述副干酪乳杆菌以活菌和/或死菌的固态或液态菌制剂的形式用于制备所述组合物。
根据本发明的具体实施方案，本发明的应用中，所述提升肠道免疫力包括：提升肠道细菌感染抗性，在肠道系统中抵御致病菌侵入，维持肠道屏蔽功能，和/或预防致病菌引起的腹泻。
根据本发明的具体实施方案，本发明的应用中，所述提升肠道免疫力包括：降低致病菌对肠道上皮细胞的黏附能力，和/或降低致病菌引起的肠道细胞释放炎症因子IP-10。
根据本发明的具体实施方案，本发明的应用中，所述副干酪乳杆菌的应用量为1.0×103CFU～1.0×1012CFU/天，或者以菌体的重量计为0.001μg～1000mg/天。优选地，所述副干酪乳杆菌的应用量为106CFU～1011CFU/天，或者以菌体的重量计为1μg～10mg/天。
根据本发明的具体实施方案，所述组合物可以包括食品组合物、饲料组合物或药品组合物。
根据本发明的具体实施方案，所述组合物可使用于动物或是人类。所述组合物还可包括所属领域中的常规用料组分。例如，对于药物组合物，可包括适量的辅料，所述辅料可以为赋型剂、稀释剂、填充剂、吸收促进剂等。对于食品组合物，本发明的副干酪乳杆菌可以按照现有技术中含副干酪乳杆菌的食品进行生产，所述组合物可根据受施予者的需要，而采用不同形态。例如粉剂、锭剂、造粒、微胶囊、液体制剂等。
在本发明的一具体实施方案中，所述组合物为食品组合物，所述食品可以为液体饮料、固体饮料、口服液、奶制品、片剂或胶囊，例如可以为发酵乳制品(例如发酵乳、风味发酵乳、发酵乳饮料等)、乳酪、含乳饮料、益生菌固体饮料或乳粉等。
在本发明的另一具体实施方案中，所述组合物为饲料组合物。所述饲料组合物中的其他组分可以参照益生菌饲料领域的常规技术进行选择。
在本发明的另一具体实施方案中，所述组合物为药物组合物。所述药物组合物中的其他组分可以参照益生菌药物领域的常规技术进行选择。
综上所述，本发明提供了副干酪乳杆菌K56的新用途，该菌具有显著降低致病菌对肠道上皮细胞的黏附能力、提高肠道屏障功能、激活肠道免疫能力的作用，可以用于制备具有抗感染、调节肠道健康和免疫能力的食品、药物及饲料等，具有广泛的应用前景。
附图说明
图1显示了副干酪乳杆菌K56的活菌数测定曲线。
图2显示了副干酪乳杆菌K56抑制致病性大肠杆菌EPEC O119对Caco-2的黏附效果(p<0.001)。
图3显示了副干酪乳杆菌K56与ETEC H10407共培养1h、2h、3h、4h后TEER(Ω.cm2)变化。
图4A和图4B显示了副干酪乳杆菌K56对Caco-2细胞促炎症因子(IL-8、IP10)表达的影响(无ETEC H10407)。
图5A和图5B显示了副干酪乳杆菌K56对Caco-2细胞炎症因子(IL-8、IP10)的影响。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解，现结合具体实施例及对本发明的技术方案进行以下详细说明，应理解这些实例仅用于说明本发明而不用于限制本发明的范围。实施例中，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。
实施例中所用副干酪乳杆菌K56的活菌数测定：
副干酪乳杆菌K56(保藏编号CGMCC No.15139或DSM27447)，平板涂布法挑出单菌落，16S鉴定后于甘油管-80℃冷冻保藏。实验前菌株于MRS培养基，37℃培养。生长至对数期离心培养基富集菌体。使用荧光细胞分选法(Flourescence activated cell sorting，FACS)测定活菌数和菌活性，测定结果见图1。菌株在8h进入生长平台期，活菌数变化趋于稳定，在8h活菌数稳定在108cfu/mL范围。本发明各实施例用菌株活菌数分为1×108CFU/mL和1×106CFU/mL。
实施例中数据分析：
实验中的所有数据至少重复3次，实验结果表示为平均值±标准差；采用SPSS17.0软件进行数据分析(SPSS，Chicago，IL，USA)，显著性分析采用LSD的方法进行单因素方差分析，P-value<0.05被认为有统计学上的显著差异，显著性差异按照：*p<0.05、**p<0.01、***p<0.001、****p<0.0001区分。图的绘制采用GraphPad Prism 5.0。
实施例1.抗黏附能力测定
采用共培养的方法探究副干酪乳杆菌K56对EPEC O119是否具有Caco-2黏附抗性。Caco-2细胞接种于24孔板中培养。Caco-2细胞使用PBS缓冲液清洗，菌株和Caco-2细胞共同培养1h。EPEC O119以感染复数(multiplicity of infection,MOI)50：1添加至Caco-2细胞中共同培养1h(37℃)，最终活菌数为1×107CFU/mL。以无副干酪乳杆菌K56添加的Caco-2组作为阴性对照。使用1mM氧化锌(Zinc Oxide，ZnO)替代副干酪乳杆菌K56作为阳性对照组。孵育后，清洗并裂解Caco-2细胞，然后致病菌被接种在琼脂上。在37℃琼脂平板上培养过夜后，数细菌的CFU菌落数以衡量致病菌吸附。数生长中的大肠杆菌菌落数并记录为CFU/mL。与抗粘附测试平行的，将大肠杆菌(终浓度为)107CFU/mL添加到1mL受试物(K56菌液)中，并在37℃共培养1小时以测量活性。培养后，从每个样品离心收集大肠杆菌，再悬浮于PBS中，并在琼脂平板上接种。在37℃琼脂平板上培养过夜后，数细菌的CFU菌落数以衡量致病菌吸附。数生长中的大肠杆菌菌落数并记录为CFU/mL。
通过上述以人体肠道细胞Caco-2为模型，本发明证实了副干酪乳杆菌K56对肠致病性大肠杆菌EPEC O119具有抑制作用。
在本发明的一些批次的实验中，108CFU/mL浓度的副干酪乳杆菌K56对EPEC O119抑制能力的实验结果如图2所示。在没有副干酪乳杆菌K56的干预条件下，肠致病性大肠杆菌EPEC O119对Caco-2细胞的黏附数高达1.73×106CFU/mL(6.23log CFU/mL)。而当肠致病性大肠杆菌EPEC O119和副干酪乳杆菌K56共同作用时，黏附的肠致病性大肠杆菌EPECO119数目为4.83×105CFU/mL(5.68log CFU/mL)，抑制率为72.08％。实验结果表明，副干酪乳杆菌K56对肠致病性大肠杆菌EPEC O119具有显著抑制作用(p<0.001)。
在本发明的另一些批次的实验中，进行了106CFU/mL和108CFU/mL两种不同浓度的副干酪乳杆菌K56对于抑制大肠杆菌EPEC O119粘附到Caco-2细胞的实验，分两组实验进行。实验结果数据(均值±标准误差，重复三次测量)如表1所示。用Dunnett’s posthoc测试对阴性对照与受试组进行比较后，发现在两组实验中，106浓度下的K56比阴性对照显著降低了致病粘附(P<0.05)，108浓度下的K56也显著降低了致病菌粘附(P<0.05)。
表1
上述实验结果表明，副干酪乳杆菌K56对肠致病性大肠杆菌EPEC O119具有抑制作用。
实施例2.肠道屏障完整性测试
理想的小肠上皮屏障功能是保护宿主免受致病菌侵入和/或致病菌来源毒素的先决条件。在此研究中，体外的屏障完整性通过测定肠道细胞层的跨表皮的电阻(TEER)体现。为了研究益生菌对于感染的作用，测定了TEER在大肠杆菌感染前和感染后随时间变化的情况。
Caco-2细胞以2×104cell/cm2的浓度被接种到Transwell聚碳酸酯细胞培养插入物中，平均孔径为0.4μm，面积为0.33cm2直至完全分化(±1000Ω)。用世界精准仪器购入的EVOM2表皮伏特测量器测量跨上皮细胞电阻(TEER)以衡量屏障完整性。
在测试当天，细胞被冲洗，并在37℃下用不含抗生素和血清、但含有受试物质的培养基中培养1小时。紧接着加入大肠杆菌到受试物质之上(感染倍数MOI为200:1)，并培养6小时。在实验开始前(t＝-1)，受试物质暴露1小时后及添加致病菌前(t＝0)，并在致病菌接触后1小时、2小时、3小时、4小时和6小时分别测定TEER。在与致病菌接触后单独条件下的TEER值与其各自在t＝0时的TEER值相关，且被表述成ΔTEER(Ω.Cm2)。阴性对照(只加入大肠杆菌)与未接触致病菌或受试物质的阳性对照也在实验组别中。所有条件重复测定三次，一些对照组被重复测定6次。
ETEC H10407(MOI＝50)攻毒时间达到6h时，空白对照组表现为不理想的TEER数值，表明当攻毒时间达到6小时后，细胞的细胞存活率显著下降，因此，初步确定ETECH10407攻毒时间应控制在4h内。
图3显示了108CFU/mL浓度的副干酪乳杆菌K56与ETEC H10407共培养1h、2h、3h、4h后TEER(Ω.cm2)变化。由图3可知，在添加K56后，跨膜电阻显著增加(p<0.001)。处理4h后，K56组别跨膜电阻以时间依赖方式降低，在t＝4h时，与ETEC H10407组别相比，仍具有显著差异(p<0.01)。表明副干酪乳杆菌K56的干预显著缓解了由于ETEC H10407引起的肠道细胞屏障的完整性破坏。
在本发明的另一些批次的实验中，进行了106CFU/mL和108CFU/mL两种不同浓度的副干酪乳杆菌K56暴露于大肠杆菌ETEC H10407的情况下，对于跨膜电阻TEER的影响。结果参见表2和表3。实验数据重复三次测量。
表2
表3
106CFU/mL浓度和108CFU/mL浓度的副干酪乳杆菌K56，相较于阴性对照，在多个时间点均有提升TEER值的趋势。
实施例3.免疫调节能力测定
副干酪乳杆菌K56的免疫调节能力是基于是否能降低ETCT H10407 Caco-2细胞诱发的IL-8、IP-10的产生。将Caco-2细胞在96孔板养到适合的丰度。在实验最初，用不含抗生素的培养基冲洗细胞一次。将单层细胞与受试物质在37℃下用不含抗生素的培养基中共培养1小时，重复三次。加入大肠杆菌刺激细胞(MOI 200:1)。在1小时培养后，单层细胞与致病菌共培养，并用含有受试物质和50μg/mL庆大霉素的培养液冲洗和培养过夜。作为空白对照(Blank)，只用了培养液而没用大肠杆菌刺激。用大肠杆菌刺激但没用受试物质的培养液被用作大肠杆菌应答的对照。此外，作为Caco-2细胞应答的对照，用含有Rec TNFα(10ng/mL)以及Rec IFNγ(5ng/mL)(均从英国阿宾顿的R&D systems购入)的混合物培养液刺激细胞。刺激24小时候收集上清液并储存于-20℃。按照生产商的使用指导，用Bio-Plex试剂盒(美国加州BioRad公司)测试IL-8、IP-10。
108CFU/mL浓度的副干酪乳杆菌K56的实验结果参见图4A、图4B、图5A和图5B。由图4A、图4B可知，在未添加ETEC H10407孵育的条件下，副干酪乳杆菌K56对Caco-2的促炎症因子IL-8、IP10的表达无显著影响(p>0.05)。由图5A、图5B可知，ETEC H10407可以诱导肠上皮细胞Caco-2发生促炎反应，Caco-2细胞模型中加入ETEC引起了IL-8、IP10显著上调。ETECH10407干预后，细胞培养液中的IL-8含量从2.62±0.44pg/mL提升至473.84±21.9pg/mL,加入K56处理后，IL-8表达回复至1.33±0.19pg/mL，表明副干酪乳杆菌K56对ETEC H10407诱导的IL-8含量增加具有显著抑制作用(p<0.001)。细胞培养液中的IP10含量从5±0.00pg/mL提升至1454.08±193.31pg/mL,加入K56处理后，IP10表达回复至5.54±0.76pg/mL，表明副干酪乳杆菌K56对ETEC H10407诱导的IP10含量增加具有显著抑制作用(p<0.001)。试验结果表明副干酪乳杆菌K56具有抑制炎症因IL-8、IP10产生，显著抑制ETEC10407引起的炎症反应(p<0.001),进一步说明K56具有一定程度降低ETEC 10407引起炎症反应的潜力。
以上研究结果证实：副干酪乳杆菌K56能够显著ETEC H1407和EPEC O119对Caco-2细胞的黏附作用，缓解由于ETEC H10407引起的炎症反应。表明副干酪乳杆菌K56对于预防婴儿腹泻、旅行者腹泻、肠道炎症等具有良好的潜力。
Claims (10)
1.一种副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)在制备用于提升肠道免疫力的组合物中的应用，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。
2.根据权利要求1所述的应用，其中，所述副干酪乳杆菌以活菌和/或死菌的固态或液态菌制剂的形式用于制备所述组合物。
3.根据权利要求1所述的应用，其中，所述提升肠道免疫力包括：提升肠道细菌感染抗性，在肠道系统中抵御致病菌侵入，维持肠道屏蔽功能，和/或预防致病菌引起的腹泻。
4.根据权利要求1所述的应用，其中，所述提升肠道免疫力包括：降低致病菌对肠道上皮细胞的黏附能力，和/或降低致病菌引起的肠道细胞释放炎症因子IL-8和/或IP-10。
5.根据权利要求3或4所述的应用，其中，所述致病菌为大肠杆菌。
6.根据权利要求5所述的应用，其中，所述大肠杆菌包括肠毒性大肠杆菌ETEC H10407和/或致病性大肠杆菌EPEC O119。
7.根据权利要求3或4所述的应用，其中，所述副干酪乳杆菌的应用量为1.0×103CFU～1.0×1012CFU/天，或者以菌体的重量计为0.001μg～1000mg/天。
8.根据权利要求7所述的应用，其中，所述副干酪乳杆菌的应用量为106CFU～1011CFU/天，或者以菌体的重量计为1μg～100mg/天。
9.根据权利要求1所述的应用，其中，所述组合物包括食品组合物、饲料组合物或药品组合物。
10.根据权利要求9所述的应用，其中，所述食品为液体饮料、固体饮料、口服液、奶制品、片剂或胶囊。
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| EP21896236.3A EP4252553A1 (en) | 2019-11-29 | 2021-05-28 | Application of lactobacillus paracasei subsp. paracasei k56 in improving intestinal bacterial infection resistance and intestinal immunity |
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| AU2021385689A AU2021385689A1 (en) | 2019-11-29 | 2021-05-28 | Use of Lacticaseibacillus Paracasei subsp. paracasei K56 for enhancing resistance of intestinal tract to bacterial infection and improving intestinal immunity |
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| WO2022100127A1 (zh) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | 副干酪乳杆菌k56在抗衰老、提高先天免疫方面的新应用 |
| WO2022100125A1 (zh) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | 副干酪乳杆菌et-22在抗衰老、提高先天免疫方面的新应用 |
| CN115300531A (zh) * | 2022-09-02 | 2022-11-08 | 东北农业大学 | 一种副干酪乳杆菌jy062组合物及其制备方法和应用 |
| CN116121120A (zh) * | 2022-11-30 | 2023-05-16 | 天津小薇生物科技有限公司 | 具有抑菌作用的副干酪乳杆菌gf009、其后生元制备方法及其应用 |
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| CN114145355A (zh) * | 2021-11-30 | 2022-03-08 | 内蒙古伊利实业集团股份有限公司 | 副干酪乳杆菌与母乳低聚糖组合物在婴幼儿配方粉中的应用 |
| CN114452296A (zh) * | 2021-11-30 | 2022-05-10 | 内蒙古伊利实业集团股份有限公司 | 用于改善免疫应答的母乳低聚糖组合物及其应用 |
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- 2020-11-30 CN CN202011369292.8A patent/CN112869168B/zh active Active
- 2020-11-30 CN CN202410177194.6A patent/CN118020940A/zh active Pending
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- 2021-05-28 WO PCT/CN2021/096955 patent/WO2022110726A1/zh unknown
- 2021-05-28 EP EP21896236.3A patent/EP4252553A1/en active Pending
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| WO2022100127A1 (zh) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | 副干酪乳杆菌k56在抗衰老、提高先天免疫方面的新应用 |
| WO2022100125A1 (zh) * | 2020-11-16 | 2022-05-19 | 内蒙古伊利实业集团股份有限公司 | 副干酪乳杆菌et-22在抗衰老、提高先天免疫方面的新应用 |
| CN115300531A (zh) * | 2022-09-02 | 2022-11-08 | 东北农业大学 | 一种副干酪乳杆菌jy062组合物及其制备方法和应用 |
| CN116121120A (zh) * | 2022-11-30 | 2023-05-16 | 天津小薇生物科技有限公司 | 具有抑菌作用的副干酪乳杆菌gf009、其后生元制备方法及其应用 |
| CN116121120B (zh) * | 2022-11-30 | 2024-04-19 | 天津小薇生物科技有限公司 | 具有抑菌作用的副干酪乳杆菌gf009、其后生元制备方法及其应用 |
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| Publication number | Publication date |
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| CN112869168A (zh) | 2021-06-01 |
| WO2022110726A1 (zh) | 2022-06-02 |
| US20240189371A1 (en) | 2024-06-13 |
| CN118020940A (zh) | 2024-05-14 |
| AU2021385689A1 (en) | 2023-07-20 |
| EP4252553A1 (en) | 2023-10-04 |
| CN112869168B (zh) | 2023-06-06 |
| AU2021385689A9 (en) | 2024-07-25 |
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