CN112063541A - 一种加氏乳杆菌tci515或其代谢产物用于制备免疫调节组合物的用途 - Google Patents
一种加氏乳杆菌tci515或其代谢产物用于制备免疫调节组合物的用途 Download PDFInfo
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Abstract
本发明是涉及微生物领域，特别是关于一种加氏乳杆菌TCI515或其代谢产物用于制备免疫调节组合物的用途。本发明提供免疫调节益生菌株，是寄存编号为DSM33105的加氏乳杆菌及加氏乳杆菌或其代谢产物用于制备免疫调节组合物的用途。该益生菌株及其代谢产物能增强先天免疫力调节基因的表现，并且在发炎反应被诱发的情况下抑制促发炎细胞激素的基因表现，因此既可提升个体的先天免疫力，又可避免组织因过度发炎反应而受损。本发明亦提供一种包含该益生菌株的免疫调节组合物。
Description
技术领域
本发明是涉及微生物领域，特别是关于一种加氏乳杆菌TCI515或其代谢产物用于制备免疫调节组合物的用途。
背景技术
人体的免疫系统大致可分为「先天免疫」与「后天免疫」两部分。「先天免疫」系统是由非专一性免疫细胞与保护性蛋白质共同构成，其在病原体(例如细菌、病毒、霉菌、寄生虫等可引起疾病的微生物)通过皮肤或黏膜而进入人体时启动。此时，具有吞噬微生物能力的白血球，例如嗜中性白血球、分化自单核细胞的巨噬细胞等会聚集于病原体入侵处以消灭该病原体。包含白血球在内的某些细胞还会分泌促发炎细胞激素，召集更多的白血球至病原体所在处。同时，自然杀手细胞也会参与围剿，负责毒杀被病原体感染的细胞。此外，体液中也会进行补体蛋白活化以攻击病原体。
当个体免疫力变弱时，疾病便容易发生，例如频繁地出现感冒症状，甚至有较高风险罹患癌症。然而，免疫系统保护身体免于病原入侵是有代价的，当身体因为免疫系统调节失灵而处于慢性发炎状态，体内的正常细胞或组织便会受损害，严重者可能缩短平均寿命。因此，使身体免疫系统处于平衡状态是维持健康的重要原则之一。
已知维系免疫系统正常功能方法包括日常饮食注意营养均衡、避免肥胖、维持规律作息、适度运动、保持心情愉悦等。然而，对于学业繁重或工作忙碌的现代人而言，恪守健康生活习惯有实行上的困难。因此，开发一种方便使用且有助于维持免疫平衡的新颖组合物，以达到减少疾病发生及长寿的目标，实有其必要。
发明内容
缘此，本发明的一目的在提供一种免疫调节益生菌株，其是可供食用的加氏乳杆菌(Lactobacillus gasseri)的新颖菌株。该菌株是寄存于DSMZ-德国微生物保藏中心，其寄存标号为DSM33105。所述加氏乳杆菌经过pH 3的人工胃液内培养3小时的菌数与在pH 7下培养的菌数差异小于101CFU/mL，其中所述加氏乳杆菌经过0.3％胆盐的人工肠液内培养3小时的菌数与在无胆盐环境下培养的菌数菌数差异小于101CFU/mL。
本发明的另一目的在提供一种前述加氏乳杆菌或其代谢产物用于制备免疫调节组合物的用途。所述加氏乳杆菌经过pH 3的人工胃液内培养3小时的菌数与在pH 7下培养的菌数相当，其中所述加氏乳杆菌经过0.3％胆盐的人工肠液内培养3小时的菌数与在无胆盐环境下培养的菌数相当。
在本发明的一实施例中，该加氏乳杆菌或其代谢产物提高先天免疫力。此作用可归因但不限于该加氏乳杆菌或其代谢产物增强介白素-1β(interleukin 1 beta，IL-1β)、肿瘤坏死因子-α(tumor necrosis factor alpha，TNF-α)、介白素-8(interleukin-8，IL-8)、介白素-18(interleukin-18，IL-18)、或其任意组合的基因表现。
在本发明的一实施例中，该加氏乳杆菌或其代谢产物抑制一发炎反应。该发炎反应是可由一病原体或其所产生物质如脂多醣(lipopolysaccharide，LPS)所引发。此作用可归因但不限于该加氏乳杆菌或其代谢产物在该发炎反应时抑制介白素-18、肿瘤坏死因子-α、或其组合的基因表现。
本发明的又一目的在提供一种免疫调节组合物，包含一有效量的加氏乳杆菌或其代谢产物，其中该加氏乳杆菌的寄存编号为DSM33105。
本发明揭示的加氏乳杆菌及其代谢产物能增强先天免疫力调节基因的表现，因此有助于提升个体的先天免疫力以对抗外来病原体入侵。此外，该菌株及其代谢产物在发炎反应被诱发的情况下抑制促发炎细胞激素的基因表现，因此能避免组织或器官因过度发炎反应而受损。是故，加氏乳杆菌DSM33105可用于制备免疫调节组合物。该组合物可具有粉末、颗粒、溶液、或胶体的剂型，且可制成食品、饮品、营养补充剂、或医药品，藉由口服方式给予一个体。
以下将配合图式进一步说明本发明的实施方式，下述所列举的实施例是用以阐明本发明的发明特点及应用，而非以限定本发明的范围，任何熟习此技艺者，在不脱离本发明的精神和范围内，当可做些许更动与润饰，因此本发明的保护范围当视后附的申请专利范围所界定者为准。
附图说明
图1显示人类单核细胞株THP-1以乳杆菌培养基(MRSD)或多种加氏乳杆菌培养物上清液处理后，其IL-1β基因的相对表现量柱形图；
图2显示人类单核细胞株THP-1以MRSD培养基或指定加氏乳杆菌培养物上清液处理后，其TNF-α基因的相对表现量柱形图；
图3显示人类单核细胞株THP-1以MRSD培养基或指定加氏乳杆菌培养物上清液处理后，其IL-8基因的相对表现量柱形图；
图4显示人类单核细胞株THP-1以MRSD培养基或指定加氏乳杆菌培养物上清液处理后，其IL-18基因的相对表现量柱形图；
图5显示人类单核细胞株THP-1以MRSD培养基或指定加氏乳杆菌培养物上清液处理再与脂多醣(LPS)共培养后，其IL-18基因的相对表现量柱形图；
图6显示人类单核细胞株THP-1以MRSD培养基或多种加氏乳杆菌培养物上清液处理再与脂多醣(LPS)共培养后，其TNF-α基因的相对表现量柱形图；
图7显示本发明的加氏乳杆菌在人工胃液模拟试验中的菌数变化柱形图；
图8显示本发明的加氏乳杆菌在人工肠液模拟试验中的菌数变化柱形图。
具体实施方式
本发明提供一种具有免疫调节功效的加氏乳杆菌，其是分离自母乳，经培养及菌种鉴定后确认为一新颖菌株，实验编号TCI515，于2019年5月2日保藏于DSMZ-德国微生物保藏中心(German Collection of Microorganisms and Cell Cultures，DSMZ)，地址为德国布伦瑞克市38124因霍芬大街7B，寄存编号为DSM33105。以下实施例显示该菌株及其代谢产物能增强先天免疫力调节基因的表现，并且在发炎反应被诱发的情况下能抑制促发炎细胞激素的基因表现。
定义
本文中所使用数值为近似值，所有实验数据皆表示在20％的范围内，较佳为在10％的范围内，最佳为在5％的范围内。
本文中所谓「有效量」是指一活性物质在一个体引发特定功效所需要的量。如本技术领域熟习技艺者所认知，有效剂量将依给予途径、赋形剂的使用、以及与其它物质共享的可能而变化。
材料与方法
细菌培养
以下实施例使用分离自人类母乳且经16S rRNA基因序列比对而确定的加氏乳杆菌，包括寄存于DSMZ-德国微生物保藏中心(German Collection of Microorganisms andCell Cultures，DSMZ)的DSM33105菌株，其16S rRNA基因具有SEQ ID NO：1的核苷酸序列；以及LH009菌株及LH028菌株。各该细菌于解冻及活化后，依1％的接种量在37℃静置培养于乳杆菌属MRSD培养基(55g乳杆菌MRS肉汤(BD Difco Lactobacilli MRS Broth；ThermoFischer Scientific)，溶于1L去离子水，pH值约6.8)18小时。所得细菌培养物经过5000rpm离心20分钟后，收集上清液以供进一步分析。该上清液包含细菌代谢产物。
细胞培养
以下实施例使用购自美国典型培养物保存中心(American Type CultureCollection，ATCC)的人类单核细胞株(human monocytic cell line)THP-1(ATCC TIB-202)及人类大肠癌上皮细胞株(human colon adenocarcinoma cell line)CACO2(ATCCHTB-37)。THP-1细胞是在37℃、5％二氧化碳的条件下培养于添加10％胎牛血清(fetalbovine serum，FBS)及1％青霉素/链霉素的RPMI 1640培养基(Gibco RPMI medium 1640；Thermo Fisher Scientific)，以下称RPMI细胞培养基。CACO2细胞是在37℃、5％二氧化碳的条件下培养于添加10％FBS及1％青霉素/链霉素的DMEM培养基(Dulbecco′s modifiedEagle’s medium；Thermo Fischer Scientific)，以下称DMEM细胞培养基。
基因表现量分析
基于定量聚合酶链锁反应(quantitative polymerase chain reaction，简称qPCR)测定THP-1细胞中有关调节先天免疫力的细胞激素的基因表现量，其步骤简述如下。依据厂商使用说明，利用RNA萃取套组(RNA Extraction Kit；Geneaid)自细胞分离出核醣核酸(RNA)，于37℃下以反转录酶
III Reverse Transcriptase(Invitrogen)将2000ng RNA反转录为cDNA。其后，利用qPCR套组(KAPA CYBR FAST qPCRKit(2X)；KAPA Biosystems)以及目标基因与作为内部对照的甘油醛3-磷酸脱氢酶(Glyceraldehyde 3-phosphate dehydrogenase)基因GAPDH的引物对(表1)在PCR反应仪(Step One Plus Real-Time PCR system；Applied Biosystems)对前述cDNA进行qPCR，并分析PCR产物的解链曲线(melting curve)。
表1
最终，使用2-ΔΔCT方法测定目标基因的相对表现量。该方法以GAPDH基因的循环阈值(CT)作为内部对照的参考基因的循环阈值，按照以下公式计算相对倍数变化：
ΔCT＝实验组或控制组的目标基因的CT-内部对照的CT
ΔΔCT＝实验组的ΔCT-控制组的ΔCT
倍数变化＝2-ΔΔCt平均值
抗发炎功效试验中，基因表现量的测定是依前述方法进行，但使用TATA框结合蛋白(TATA-box binding protein)基因TBP作为内部对照，其正向引物及反向引物的核苷酸序列分别为5’-GCCAGCTTCGGAGAGTTCTGGGATT-3’(SEQ ID NO：12)及5’-CGGGCACGAAGTGCAATGGTCTTTA-3’(SEQ ID NO：13)。
统计分析是使用Excel软件中的STDEV函数计算各基因相对表现量的标准偏差，并以单尾学生t检定(TTEST)判定统计上显著性。
实施例1
加氏乳杆菌对先天免疫力调节基因表现的增强作用
为评估本发明的加氏乳杆菌的免疫力增强作用，利用qPCR测定人类单核细胞株THP-1经指定加氏乳杆菌培养物上清液处理后，其先天免疫力调节基因的表现变化。简言之，将THP-1细胞依1×106个细胞/孔接种于6孔盘，各孔含有2mL RPMI细胞培养基。在37℃培养细胞3至6小时后，移除该培养基，并以下列方式处理各孔细胞：(a)施以2mL RPMI细胞培养基(控制组)；(b)施以2mL含0.5mg/mL MRSD培养基的RPMI细胞培养基(MRSD组)；(c)施以2mL含0.5mg/mL LH009菌株培养物上清液的RPMI细胞培养基(LH009组)；(d)施以2mL含0.5mg/mL LH028菌株培养物上清液的RPMI细胞培养基(LH028组)；或(e)施以2mL含0.5mg/mL DSM33105菌株培养物上清液的RPMI细胞培养基(DSM33105组)。前述各组细胞于37℃培养6小时后用于qPCR分析。
图1显示前述各组细胞相对于控制组细胞的IL-1β基因的相对表现量；图2显示前述各组细胞相对于控制组细胞的TNF-α基因的相对表现量；图3显示前述各组细胞相对于控制组细胞的IL-8基因的相对表现量；图4显示前述各组细胞相对于控制组细胞的IL-18基因的相对表现量；图中**及***分别表示相比控制组为p＜0.01及p＜0.001。依据图1、2、3及4，对细胞施予LH009、LH028、或DSM33105菌株的培养物上清液明显提升IL-1β、TNF-α、IL-8、及IL-18等基因表现，特别以DSM33105菌株的效果最显著。鉴于IL-1β与TNF-α可整体性加强个体对病原体的先天免疫力，又IL-8可促进嗜中性白血球的聚集与吞噬作用，以及IL-18可增加自然杀手细胞活性，此结果说明加氏乳杆菌DSM33105及其代谢产物有助于提升个体的先天免疫力。
实施例2
加氏乳杆菌在脂多醣刺激下对促发炎基因表现的抑制作用
为评估本发明的加氏乳杆菌的抗发炎作用，利用qPCR测定人类单核细胞株THP-1与指定加氏乳杆菌培养物上清液及诱导发炎的脂多醣(LPS)共培养后，其促发炎细胞激素基因的表现变化。简言之，将THP-1细胞依1×106个细胞/孔接种于6孔盘，各孔含有2mLRPMI细胞培养基。在37℃培养细胞3至6小时后，移除该培养基，并以下列方式处理各孔细胞：(a)施以2mL RPMI细胞培养基(控制组)；(b)施以2mL添加100ng/mL脂多醣的RPMI细胞培养基(LPS组)；(c)施以2mL含0.5mg/mL MRSD培养基的RPMI细胞培养基1小时，再施以100ng/mL脂多醣(MRSD+LPS组)；(d)施以2mL含0.5mg/mL LH009菌株培养物上清液的RPMI细胞培养基1小时，再施以100ng/mL脂多醣(LH009+LPS组)；(e)施以2mL含0.5mg/mL LH028菌株培养物上清液的RPMI细胞培养基1小时，再施以100ng/mL脂多醣(LH028+LPS组)；或(f)施以2mL含0.5mg/mL DSM33105菌株培养物上清液的RPMI细胞培养基1小时，再施以100ng/mL脂多醣(DSM33105+LPS组)。前述各组细胞于37℃培养3小时后用于qPCR分析。
图5显示前述各组细胞相对于控制组细胞的IL-18基因的相对表现量；图6显示前述各组细胞相对于控制组细胞的TNF-α基因的相对表现量；图中***表示相比LPS组为p＜0.001。依据图5及图6，单纯脂多醣的处理导致TNF-α与IL-18等促发炎细胞激素的基因表现增加。然而，同时对细胞施予DSM33105菌株或LH0028菌株的培养物上清液明显抑制TNF-α与IL-18基因表现。相对地，LH009菌株的培养物上清液无此抑制效果。此结果说明加氏乳杆菌DSM33105及其代谢产物在发炎刺激下能抑制发炎讯号生成，因此能减少组织或器官因过度发炎反应而受损。并且，此抗发炎功效非任何品种的加氏乳杆菌皆具备。
实施例3
加氏乳杆菌的耐酸与耐胆盐特性
为测试本发明的加氏乳杆菌能否抵抗胃部的酸性环境与肠道中的胆盐，将该菌株的隔夜培养菌液(菌量约为5x109CFU/mL)用于人工胃液或肠液模拟试验。在人工胃液模拟试验中，该菌液依1％的添加量添加至人工胃液(0.2％氯化钠水溶液，pH 3)，并于37℃、50rpm震荡培养3小时。在人工肠液模拟试验中，该菌液依1％的添加量添加至人工肠液(含0.68％磷酸二氢钾及或0.3％胆盐(oxgall)的水溶液，pH 6.8)，并于37℃、50rpm震荡培养3小时。作为对比，另设置对照组，是将本发明的加氏乳杆菌的菌液培养于pH 7且不含胆盐的0.2％氯化钠或0.68％磷酸二氢钾水溶液。前述试验后所得菌液取100μL涂布于乳杆菌属MRS琼脂培养基，于37℃培养隔夜以计算菌数。
依据图7，本发明的加氏乳杆菌经过人工胃液(pH 3)内培养3小时的菌数与在pH 7下培养的菌数相当，菌数差异小于101CFU/mL，显示其具有耐胃酸性。依据图8，本发明的加氏乳杆菌经过人工肠液(0.3％胆盐)内培养3小时的菌数与在无胆盐环境下培养的菌数相当，菌数差异小于101CFU/mL，显示其对胆盐的耐受性。该些结果说明加氏乳杆菌DSM33105经由口服进入人体后得以在消化道中生存，因此能发挥免疫调节的效用。
实施例4
加氏乳杆菌的肠道定殖试验
为测试本发明的加氏乳杆菌固着于肠道的能力，利用人类大肠癌上皮细胞株Caco-2进行肠道定殖试验。简言之，将Caco-2细胞依1×104个细胞/孔接种于24孔盘，各孔含有1mL DMEM细胞培养基。在37℃培养细胞数天至形成一细胞单层后，以不含抗生素的DMEM培养基替换原培养基，再将自加氏乳杆菌DSM33105的隔液培养菌液收集得的该菌细胞以磷酸缓冲盐溶液(phosphate buffered saline，PBS；Thermo Fischer Scientific)配制成一细菌悬浮液以用于感染Caco-2细胞(0.5mL/孔)约30分钟。其后，利用含0.05％TritonX-100的PBS溶液裂解Caco-2细胞，并将所得细胞裂解物连同附着于细胞表面或进入细胞的加氏乳杆菌涂布于乳杆菌属MRS琼脂培养基，于37℃培养48小时以计算菌数。依据肠道定殖试验的结果，每个肠细胞上附着约33个加氏乳杆菌细胞(定殖率约为33)，显示加氏乳杆菌DSM33105经由口服进入人体后能稳定地附着于肠道。
综上所述，本发明揭示的加氏乳杆菌能提升个体的先天免疫力，并且具有抑制发炎反应的功效，因此可用于制备一免疫调节组合物。该组合物可具有粉末、颗粒、溶液、或胶体的剂型，且可制成食品、饮品、医药品、或营养补充剂，藉由口服方式给予一个体。
Claims (10)
1.一种免疫调节的加氏乳杆菌株，是寄存编号为DSM33105的加氏乳杆菌，所述加氏乳杆菌经过pH3的人工胃液内培养3小时的菌数与在pH7下培养的菌数差异小于101CFU/mL，其中所述加氏乳杆菌经过0.3％胆盐的人工肠液内培养3小时的菌数与在无胆盐环境下培养的菌数菌数差异小于101CFU/mL。
2.一种加氏乳杆菌或其代谢产物用于制备免疫调节组合物的用途，其中所述加氏乳杆菌的寄存标号为DSM33105，所述加氏乳杆菌经过pH3的人工胃液内培养3小时的菌数与在pH7下培养的菌数相当，其中所述加氏乳杆菌经过0.3％胆盐的人工肠液内培养3小时的菌数与在无胆盐环境下培养的菌数相当。
3.根据权利要求2所述的用途，其特征在于，所述加氏乳杆菌或其代谢产物提高先天免疫力。
4.根据权利要求3所述的用途，其特征在于，所述加氏乳杆菌或其代谢产物增强介白素-1β、肿瘤坏死因子-α、介白素-8、介白素-18、或其任意组合的基因表现。
5.根据权利要求2所述的用途，其特征在于，所述加氏乳杆菌或其代谢产物抑制一发炎反应。
6.根据权利要求5所述的用途，其特征在于，所述发炎反应是由一脂多醣引起。
7.根据权利要求5所述的用途，其特征在于，所述加氏乳杆菌或其代谢产物在该发炎反应时抑制介白素-18、肿瘤坏死因子-α、或其组合的基因表现。
8.一种免疫调节组合物，包含一有效量的加氏乳杆菌或其代谢产物，其中所述加氏乳杆菌的寄存编号为DSM33105。
9.根据权利要求8所述的组合物，具有粉末、颗粒、溶液、或胶体的剂型。
10.根据权利要求8所述的组合物，是一食品、一饮品、一营养补充剂、或一医药品。
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