CN104894002B - 新颖乳酸菌及其于免疫调节及抗发炎的应用 - Google Patents
新颖乳酸菌及其于免疫调节及抗发炎的应用 Download PDFInfo
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- CN104894002B CN104894002B CN201510098957.9A CN201510098957A CN104894002B CN 104894002 B CN104894002 B CN 104894002B CN 201510098957 A CN201510098957 A CN 201510098957A CN 104894002 B CN104894002 B CN 104894002B
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- lactic acid
- lactobacillus plantarum
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- lactobacillus
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- 240000006024 Lactobacillus plantarum Species 0.000 claims description 41
- 235000013965 Lactobacillus plantarum Nutrition 0.000 claims description 41
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Abstract
本发明涉及新颖乳酸菌及其于免疫调节及抗发炎的应用。本发明提供一种具免疫调节及抗发炎活性的新颖乳酸菌株(LAB)及包含其及使用其的组合物。投予本发明的LAB可调节免疫反应以恢复或预防由慢性发炎引起的代谢疾病。
Description
技术领域
本发明系关于一种益生菌新颖的乳酸菌及包含彼的组合物。特定言之，本发明关于一种新的乳酸菌及其于增强免疫调节及抗发炎活性的用途。
背景技术
发酵食品产品含有各种有用的细菌，包括乳酸菌(lactic acid bacteria；LAB)。LAB的各种菌株可用于制造发酵食品，包括牛奶，面包，蔬菜和其他可食用的植物材料。LAB是一群革兰氏阳性菌，一般用于生产发酵食品。LAB的膳食和临床应用的优点已被广泛研究。LAB已被用作保存食物的发酵剂，采用其下列优点：低pH值及发酵活性期间产生能抑制腐败菌的生长的发酵产物的作用。为此，LAB已被用于制备各种不同的食品，如奶酪，酸奶和其他发酵乳制品。LAB已被发现摄入后呈现出对人类及动物有价值的特性，吸引了大量的关注。特别是，乳杆菌属(Lactobacillus)或双歧杆菌属(Bifidobacterium)的特定菌株已被发现能够定殖于肠道粘膜，并协助维持人类和动物的健康。抗发炎活性和免疫调节活性是众所周知的LAB的特性。
WO97/00078揭露一特定菌株，命名为乳酸杆菌GG (ATCC53103)，其为一种益生菌。WO97/00078中的微生物特别用于预防或治疗食物诱发过敏反应的一种方法。US 8,361,481提供一种具有抗过敏活性的乳酸菌，其为乳酸菌副干酪乳杆菌K71菌株(Lactobacillusparacasei K71strain)，该菌株已寄存于National Institute of Advanced IndustrialScience and Technology,International Patent Organism Depositary，寄存编号为FERM BP-11098。L.Zhang等人报导鼠李糖乳杆菌GG在减少发炎的效果(Journal ofPediatric Gastroenterology and Nutrition,vol.42,no.5,pp.45–52,2006)。此外，数篇先前技艺文献已报导乳酸菌抑制前发炎细胞激素(proinflammatory cytokine)的表达(例如， World Journal of Gastroenterology,vol.16,no.33,pp.4145–4151,2010； andInternational Immunopharmacology,vol.8,no.4,pp.574–580,2008)。
在LPS处理的RAW 264.7细胞中，胚芽乳酸杆菌 KFCC11389P(Lactobacillusplantarum KFCC11389P)的生长代谢产物抑制TNF-α和IL-6的产生。在RAW264.7细胞中，胚芽乳酸杆菌 10hk2(Lactobacillus plantarum 10hk2)已经显示出通过提高前发炎介质，如介白素-1β(IL-1β)，IL-6和TNF-α，及抗发炎介白素-10(IL-10)，呈现抗发炎效果。
然而，由于不同菌株的特性与能力，LAB的效果是可变的。因此，仍有必要发展具优异免疫调节和抗发炎活性的LAB。
发明内容
本发明提供一种具免疫调节即抗发炎活性的新颖LAB，及一种包含其的组合物与使用其的方法。本发明LAB可被投予以调节免疫反应，恢复或预防由慢行发炎引起的代谢疾病。
本发明提供一种分离的LAB，其为胚芽乳酸杆菌胚芽亚种 (Lactobacillusplantarum subsp.plantarum)，具有含有分别为下列SEQ ID NO:1及SEQ IDNO:2所示核酸序列的16S rRNA基因及pheS基因。在一具体实施例，本发明的LAB是胚芽乳酸杆菌胚芽亚种K21，寄存于 DSMZ-DEUTSCHE SAMMLUNG VON MIKROORGANISMEN UND ZELLKULTUREN(DSMZ)，寄存编号为保藏号DSM 27444。
胚芽乳酸杆菌胚芽亚种K21(K21)为分离自福菜(台湾传统发酵食物)的益生菌株。K21的16S rRNA基因与pheS基因序列显示与胚芽乳酸杆菌胚芽亚种具高度相似性，但与其不同。结果，K21代表一种新的胚芽乳酸杆菌胚芽亚种菌株。K21对TNF-α及前列腺素E2(PGE2)的产生呈现显著抑制，因此K21呈现抗发炎活性。K21在活体内减少前发炎细胞激素如TNF-α、IL-1β及IL-6的产生。另外，K21在活体内降低TNF-α、环加氧酶-2(COX-2)、类Toll受体4(TLR4)及细胞激素信号3抑制子 (SOCS3)的mRNA表达量。
本发明也提供一种组合物，包含本发明的LAB及视需要的可食用载剂。在另一方面，本发明提供一种增强免疫调节及/或抗发炎活性的方法，包括将该LAB或本发明的组合物投予受试者。
附图说明
图1为一套电泳照片，显示三个胚芽乳酸杆菌(Lactobacillus plantarum)菌株的RAPD概况。泳道M，1kb的DNA梯；1，胚芽乳酸杆菌胚芽亚种K21(Lactobacillus plantarumsubsp.plantarum K21)；2，胚芽乳酸杆菌亚种胚芽杆菌ATCC14917T(Lactobacillusplantarum subsp. plantarum ATCC 14917)；3，胚芽乳酸安式亚种ATCC17638T(Lactobacillus plantarum subsp.argentoratensis ATCC 17638T)。
图2显示正常的RAW 264.7细胞、LPS处理(20小时，600 ng/mL)的RAW 264.7细胞及LPS处理(20小时，600ng/mL)与热灭活 K21(1×106CFU)共处理的RAW264.7细胞中，TNF-α及PGE2的产生。
图3显示评出健康对照组(健康)、UC对照组(UC)及K21 组的结肠蛋白质的MPO活性。数据表示为平均值±标准偏差，其中每组n ＝6只小鼠。当p<0.05(*)，K21和UC组间的差异视为统计上显著。
图4(A)～(C)表示在UC小鼠模型中，相较于健康对照组与UC对照组，活的K21(1×109CFU)口服给药对在结肠的总蛋白中的TNF-α(A)、IL-1β(B)及IL-6(C)的影响。
图5表示在UC小鼠模型中，相较于UC对照组对对结肠中的 TNF-α、COX-2、TLR4与SOCS3的mRNA表达量的影响。使用实时PCR 检测mRNA的表达量。
具体实施方式
本发明令人惊讶地发现一种具有免疫调节及抗发炎活性的新颖LAB菌株。本发明的LAB可给药用于调节免疫反应以恢复或预防由慢性发炎引起的代谢疾病。
用语“益生微生物”(probiotic)在本领域中为微生物，当适量给予，提供健康益处予宿主。益生微生物(益生菌)必须符合无毒性，活性，附着力及有益效果的数个要求。此等益生菌特征为应变依赖性，即使为相同菌种中的细菌。
如本文所使用，用语“医药上可接受的”是指化合物、材料、组合物及/或剂型，其在合理的医学判断范围内，适用于与受试者(人类或非人类动物)的组织接触而没有过度的毒性、刺激性、过敏反应或其它问题或并发症，与合理的益处/风险比相称。每种载剂、赋形剂等也必须是在与制剂中的其它成分兼容的意义上为“可接受的”。合适的载剂、赋形剂等可在标准药学课本中找到。
用语“可食用的载剂”是指化合物、材料、组合物及/或剂型适用于与受试者的组织接触。“可接受的”意义为每一载剂必须与制剂中的其它成分兼容。
如本文所使用，用语“有效量”是每一菌株在组合物中菌落形成单位(CFU)的量，在合理的医学判断的范围之内，该量足够高以显著修饰拟治疗病况朝正向发展，但足够低到避免严重副作用(在合理的益处/风险比)。
在一方面，本发明提供一种分离的LAB，其为胚芽乳酸杆菌胚芽亚种(Lactobacillus plantarum subsp.plantarum)，具有含有分别为下列SEQ ID NO:1及SEQIDNO:2所示核酸序列的16S rRNA基因及pheS基因：
SEQ ID NO:1
GGAGACTATACATGCAAGTCGAACGAACTCTGGTATTGATTGGTGCTTGCATCAT GATTTACATTTGAGTGAGTGGCGAACTGGTGAGTAACACGTGGGAAACCTGCCCA GAAGCGGGGGATAACACCTGGAAACAGATGCTAATACCGCATAACAACTTGGAC CGCATGGTCCGAGTTTGAAAGATGGCTTCGGCTATCACTTTTGGATGGTCCCGCG GCGTATTAGCTAGATGGTGGGGTAACGGCTCACCATGGCAATGATACGTAGCCGA CCTGAGAGGGTAATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGG GAGGCAGCAGTAGGGAATCTTCCACAATGGACGAAAGTCTGATGGAGCAACGCC GCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAACTCTGTTGTTAAAGAAGAACATA TCTGAGAGTAACTGTTCAGGTATTGACGGTATTTAACCAGAAAGCCACGGCTAAC TACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTATTG GGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGAAAGCCTTCGGCTCA ACCGAAGAAGTGCATCGGAAACTGGGAAACTTGAGTGCAGAAGAGGACAGTGGA ACTCCGTGTGTAGCGGTGAAATGCGTAGATATATGGAAGAACACCAGTGGCGAA GGCGGCTGTCTGGTCTGTAACTGACGCTGATGCTCGAAAGTATGGGTAGCAAACA GGATTAGATACCCTGGTAGTCCATACCGTAACGATGAATGCTAAGTGTTGGAGGG TTTCCGCCCTTCAGTGCTGCAGCTAACGCATTAAGCATTCCGCCTGGGGAGTACG GCGCAGGCTGAAACTCAGAGGAATTGACGGGGGTCCCGCACAAGCGGTGCAGCA TGTGTTTATTCGAAGCTACGCGAAGATCTACAGGTCTGACATACTATGCAAATCT AGAAATAACGTTCTTTCGTGACATGCATACAGTGTGCATGGTGTCGTCAGTCAGTTCCTGATGTCGATTAGTTCAAGACGAGGCACCTACTATCAGTGCCAGCATAGTGGCATCTGTGAGACTGCCGTGACAAAC
SEQ ID NO:2
TGCGAATATTACCAAGACGTGCTACTACGCACGCAGACGTCTGCTGATCAGCCGC GGTCACTTGAAAATCACGATTTTTCTAAAGGACCGCTGAAGGTCTTGTCACCTGG CCGCGTTTATCGGCGTGATACGGATGATGCAACCCATTCCCATCAATTTCATCAA ATTGAAGGGTTAGTCGTGGACAAGCATATTACGATGGCTGATTTGAAGGGCACCT TAATTCTGGTTGCCAAGACTTTGTTTGGCGATCAATTCGATGTTCGGCTACGGCCA AGCTTCTTTCCATTCACGGAACCATCCGTAGAAGCTGATGTAACTTGCTTTAATTG CAATGGCAAGGGCTGTGCAATCTGTAAGCAAACGGGTTGGATCGAAGTACTGGG TGCCGGCATGGTTCACCCCCACGTGTTAGAAATGTCTGGCATTGATCCAGAAGAATATGGTGGCTTTGCTTTCGGGGTCTTGGAACA
在一具体实施例，本发明的LAB是胚芽乳酸杆菌胚芽亚种 K21，寄存于DSMZ-DEUTSCHE SAMMLUNG VON MIKROORGANISMEN UND ZELLKULTUREN(DSMZ)，寄存编号为保藏号DSM 27444。本发明的新颖LAB称为胚芽乳酸杆菌胚芽亚种K21，其基于布达佩斯条约，已于2013年6月27日寄存于DSMZ-DEUTSCHE SAMMLUNG VON MIKROORGANISMEN UNDZELLKULTUREN GmbH(Inhoffenstr.7B,D-38124Braunschweig,Germany)，并被赋予寄存编号为DSM 27444。
胚芽乳酸杆菌胚芽亚种K21(K21)为分离自福菜(台湾传统发酵食物)的益生菌株。K21的16S rRNA基因与pheS基因序列显示与胚芽乳酸杆菌胚芽亚种具高度相似性，但与其不同。结果，K21代表一种新的胚芽乳酸杆菌胚芽亚种菌株。
发酵试验指出K21带有类似于胚芽乳酸杆菌胚芽亚种的生物化学特性。K21对下列呈现正反应：L-阿拉伯糖，D-核糖，D-木糖， D-半乳糖，D-葡萄糖，D-果糖，D-甘露糖，L-鼠李糖，D-甘露糖醇，D- 山梨糖醇，甲基-α-D-吡喃甘露糖苷，N-乙酰葡糖胺，苦杏仁苷(amygdalin)，熊果苷(arbutin)，七叶苷(esculin)柠檬酸铁，水杨苷(salicin)， D-纤维二糖，D-麦芽糖，D-乳糖，D-蜜二糖(D-melbiose)，D-蔗糖 (sucrose)，D-海藻糖，菊醣(inulin)，D-melezitose，D-棉子糖(raffinose)，龙胆二糖(gentiobiose)，D-松二糖(turanose)，D-塔格糖(tagatose)和葡萄糖酸钾，但对下列呈现负反应：甘油，赤藓醇(erythritol)，D-阿拉伯糖，L-木糖，D-阿东糖醇(adonitol)，甲基-β-D-吡喃木糖苷，L-山梨糖 (sorbose)，半乳糖醇(dulcitol)，肌醇，甲基-α-D-吡喃葡萄糖苷，阿米登 (amidon)(淀粉)，肝醣(glycogen)，木糖醇，D-来苏糖，D-岩藻糖(fucose)， L-岩藻糖，D-阿拉伯糖醇(arabitol)，L-阿拉伯糖醇，2-酮基-D-葡萄糖酸钾(potassium 2-ketogluconate)及5-酮基-D-葡萄糖酸钾。
K21对TNF-α及前列腺素E2(PGE2)的产生呈现显著抑制，因此K21呈现抗发炎活性。K21在活体内减少前发炎细胞激素如TNF-α、 IL-1β及IL-6的产生。另外，K21在活体内降低TNF-α、环加氧酶-2 (COX-2)、类Toll受体4(TLR4)及细胞激素信号3抑制子(SOCS3) 的mRNA表达量。
在另一方面，本发明提供一种组合物，包含本发明的LAB 及视需要的可食用载剂。在另一方面，本发明提供一种增强免疫调节及/ 或抗发炎活性的方法，包括将该LAB或本发明的组合物投予受试者。
在本发明的组合物中，所述菌株可以活或不活的整个细菌形式使用。较佳地。细菌细胞为活的、能存活的细胞。
本发明组合物可以是适于投予，特别是口服投予，的任何形式。此包括例如固体，半固体，液体和粉末。
例如，组合物可包含至少每克干重105CFU，较佳至少为106 CFU的如上所述的LAB菌株。
当LAB为活体细菌的形式，该组合物典型地每克干重组合物包括105至1013个菌落形成单位(cfu)，较佳为至少106CFU，更佳为至少107CFU，还更佳为至少108CFU，且最佳为至少109CFU。
本发明组合物中的实施例是营养组合物，包括食品，特别是乳制品。
组合物可以是例如胶囊，锭剂，饮料，粉末或乳制品。视需要，可包含其他LAB菌株。较佳地，本发明的营养组合物是婴儿食品，婴儿配方奶粉或较大婴儿配方。较佳地，该组合物是保健品或药品，营养补充品或医药食品。
本发明的营养组合物也包括食品补充品及机能性食品。"食品补充品”指从通常食品中使用的化合物制成的产品，但其为锭剂，粉剂，胶囊，药剂或通常不与滋养品有关且具有对人的健康具有益效果的其他任何形式。"机能性食品”是滋养品，其也对人的健康具有益效果。特别是，食品补充品及机能性食品具有生理作用--保护性或治疗性--对抗疾病，例如针对慢性疾病。
如根据本发明的组合物是膳食补充品，其可如下列方式投予，与合适的可饮用液体混合，例如水，酸奶酪，牛奶或果汁，或可与固体或液体食品进行混合。在本文中，膳食补充品的形式可为锭剂，丸剂，胶囊，药锭糖(lozenge)，颗粒，粉剂，悬浮剂，小药囊，软锭剂，糖果，棒，糖浆及相应的投予形式，通常为单位剂量的形式。较佳地，包含本发明组合物的膳食补充品以锭剂，药锭糖(lozenge)，胶囊或粉末的形式投予，以制备膳食补充品的常规方法制造。
本发明以下面提供的实例更详细说明。然而，此等实施例是为了说明本发明主体而提供，并不构成以任何方式对其限制。足非另有说明，百分比系以重量计。
实例1胚芽乳酸杆菌胚芽亚种K21(Lactobacillus plantarum subsp. PlantarumK21)的单离和基因分类
胚芽乳酸杆菌胚芽亚种K21是从台湾传统发酵食品福菜中单离。K21的16S rRNA基因及pheS基因DNA系以PCR扩增DNA片段的直接定序进行分析。
PCR依照下述表格所述的条件，使用16S rRNA基因引物 (Bact-8F(II):5'-AGAGTTTGATCMTGGCTCAG-3'(SEQIDNO:3))；15R: 5'-AAGGAG GTGATCCAACCGCA-3'(SEQIDNO:4)或phe引物(pheS-正向:5’-CAYCCNGCHCGYGAYATGC-3’(SEQ ID NO:5；pheS-逆向:5’-CCWARVCCRAARGCAAARCC-3’(SEQ ID NO:6)进行PCR。将得到的序列输入美国国家生物技术信息中心(National Center for Biotechnology Information,NCBI)(http://www.ncbi.nlm.nih.gov/)在网络上提供的序列比对软件，进行人工序列比对，并与属于厚壁菌门 (Firmicutes)的生物的代表性pheS基因DNA序列进行比对。为了进行比较，16SrRNA基因与pheS DNA基因序列也可以从NCBI提供的在线数据库获得。
此分析的结果如以下表1，其列出了具有与胚芽乳酸杆菌胚芽亚种K21的pheS的DNA序列相似性最高的pheS DNA序列的微生物。
表1：16S rRNA基因(A)及pheS基因(B)序列的比较
(A)
(B)
16S rRNA基因的比对指出K21属于一种戊糖乳酸杆菌，胚芽乳酸杆菌胚芽/安氏亚
种的新菌株(Lactobacillus pentosus,Lactobacillus plantarum subsp.Plantarum/
argentoratensis)或乳酸杆菌属(Lactobacillus paraplantarum))的一个新物种，由于其
相似度均大于98％，因而无法区别。此外，K21的16S rRNA基因与pheS基因的序列分析的综
合结果显示对胚芽乳酸杆菌胚芽亚种具最高相似度。因此，K21代表胚芽乳酸杆菌胚芽亚种
的新菌株。
| 成份 | 体积 |
| 分子生物等级水 | 15.3μl |
| 10x PCR缓冲液 | 2.5μl |
| dNTP(2.5mM) | 2μl |
| 正向引物(10μM) | 2μl |
| 逆向引物(10μM) | 2μl |
| TaKaRa Taq | 0.2μl |
| 模板DNA(10ng/μl) | 1μl |
PCR条件：94℃，5分钟；35循环(94℃，30秒；55℃，30 秒；72℃，90秒；72℃，10分钟)；4℃，∞。
胚芽乳酸杆菌胚芽亚种K21的16S rRNA基因序列(SEQ ID NO:1)：
GGAGACTATACATGCAAGTCGAACGAACTCTGGTATTGATTGGTGCTTGCAT CATGATTTACATTTGAGTGAGTGGCGAACTGGTGAGTAACACGTGGGAAACCTGC CCAGAAGCGGGGGATAACACCTGGAAACAGATGCTAATACCGCATAACAACTTG GACCGCATGGTCCGAGTTTGAAAGATGGCTTCGGCTATCACTTTTGGATGGTCCCGCGGCGTATTAGCTAGATGGTGGGGTAACGGCTCACCATGGCAATGATACGTAGC CGACCTGAGAGGGTAATCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTA CGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGAAAGTCTGATGGAGCAAC GCCGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAACTCTGTTGTTAAAGAAGAAC ATATCTGAGAGTAACTGTTCAGGTATTGACGGTATTTAACCAGAAAGCCACGGCT AACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTA TTGGGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGAAAGCCTTCGGC TCAACCGAAGAAGTGCATCGGAAACTGGGAAACTTGAGTGCAGAAGAGGACAGT GGAACTCCGTGTGTAGCGGTGAAATGCGTAGATATATGGAAGAACACCAGTGGC GAAGGCGGCTGTCTGGTCTGTAACTGACGCTGATGCTCGAAAGTATGGGTAGCAA ACAGGATTAGATACCCTGGTAGTCCATACCGTAACGATGAATGCTAAGTGTTGGA GGGTTTCCGCCCTTCAGTGCTGCAGCTAACGCATTAAGCATTCCGCCTGGGGAGT ACGGCGCAGGCTGAAACTCAGAGGAATTGACGGGGGTCCCGCACAAGCGGTGCA GCATGTGTTTATTCGAAGCTACGCGAAGATCTACAGGTCTGACATACTATGCAAA TCTAGAAATAACGTTCTTTCGTGACATGCATACAGTGTGCATGGTGTCGTCAGTC AGTTCCTGATGTCGATTAGTTCAAGACGAGGCACCTACTATCAGTGCCAGCATAGTGGCATCTGTGAGACTGCCGTGACAAAC
胚芽乳酸杆菌胚芽亚种K21的pheS基因序列(SEQ ID NO:2)：
TGCGAATATTACCAAGACGTGCTACTACGCACGCAGACGTCTGCTGATCAGC CGCGGTCACTTGAAAATCACGATTTTTCTAAAGGACCGCTGAAGGTCTTGTCACC TGGCCGCGTTTATCGGCGTGATACGGATGATGCAACCCATTCCCATCAATTTCATC AAATTGAAGGGTTAGTCGTGGACAAGCATATTACGATGGCTGATTTGAAGGGCACCTTAATTCTGGTTGCCAAGACTTTGTTTGGCGATCAATTCGATGTTCGGCTACGGC CAAGCTTCTTTCCATTCACGGAACCATCCGTAGAAGCTGATGTAACTTGCTTTAAT TGCAATGGCAAGGGCTGTGCAATCTGTAAGCAAACGGGTTGGATCGAAGTACTG GGTGCCGGCATGGTTCACCCCCACGTGTTAGAAATGTCTGGCATTGATCCAGAAG AATATGGTGGCTTTGCTTTCGGGGTCTTGGAACA
实例2使用RAPD-PCR鉴定细菌菌株
K21与另外两个胚芽乳酸杆菌菌株(ATCC14917T和 ATCC17638T)的RAPD标记进行比较。在表3所列条件下，使用随机引物1254 (5'-CCGCAGCCAA-3'，SEQ ID NO：7)进行PCR。从这些菌株中分别萃取的DNA被用作模板。所得到的扩增产物进行电泳并比对模式，如图1所示。此结果显示K21带有自其基因组衍生的特定PCR指纹图谱，代表K21是一种新的菌株。
表3：PCR反应溶液(25μl)的组合物
| 成份 | 体积 |
| ddH<sub>2</sub>O | 17.9μl |
| 10X PCR缓冲液 | 2.5μl |
| dNTP Mix(2.5mM) | 2.0μl |
| MgCl<sub>2</sub>(25mM) | 1.0μl |
| 引物 | 0.4μl |
| rTaq | 0.2μl |
| DNA模板(10μM) | 1.0μl |
PCR条件：94℃，2分钟；5循环(94℃，30秒；36℃，1分钟； 72℃，1.5分钟)；30循环(94℃，20秒；36℃，30秒；72℃，1.5分钟)；72℃， 3分钟。
实例3分析轮廓指数(Analytical Profile Index；API)Typing
用于本发明的K21的糖利用率系使用API50CHL试剂盒 (bioMerieux，法国)进行研究，其结果示于表4。发酵试验指出K21带有类似于胚芽乳酸杆菌胚芽亚种的生物化学性质。
表4：发酵试验的结果a
实例4胚芽乳酸杆菌胚芽亚种K21的制备
将胚芽乳酸杆菌胚芽亚种K21接种于de Man，Rogosa，and Sharpe(MRS，pH 5.4；Difco，USA)的液体培养基，并且在30℃培养21小时。 K21活菌的制备先将菌液以1500g速度离心10分钟后，无菌磷酸盐缓冲盐水 (PBS)清洗两次，然后于PBS中再悬浮至最终浓度为1×109CFU/mL。而热灭活的K21制备，则是如活的K21制备程序，将K21配置至特定浓度，再以100 ℃热灭活20分钟，而后储存在-20℃冰箱备用。
实例5胚芽乳酸杆菌胚芽亚种K21对TNF-α及PGE产生的抑制
RAW264.7细胞的制备与刺激
老鼠巨噬细胞株RAW264.7是从ATCC(American Type Culture Collection；Manassas，VA，USA)购买并培养在含有10％小牛血清(Fetal bovine serum，FBS)、100IU/ml盘尼西林、0.1mg/ml链霉素与0.25μg/ml两性霉素(amphotericin)与1％L-麸胺酸的Dulbecco's modified Eagle's medium (DMEM；Gibco BRL，Grand Island，NY)培养液中。细胞培养于细胞培养箱以温度37℃含5％CO2的状态培养。RAW264.7细胞以1×105cells/mL的浓度接种入96孔盘中培养24小时，再以浓度600ng/mL的脂多醣(LPS)刺激，热灭活的K21(1×106CFU)存在下。实验控制组则以单独加入脂多醣刺激的 RAW264.7作为正控制组而单纯培养液的RAW264.7作为负控制组。培养20 小时后收取各组培养上清液分析其中细胞激素TNF-α与PGE2浓度。图2显示正常RAW264.7细胞、LPS处理(20小时，600ng/mL)的RAW 264.7细胞、及LPS处理(20小时，600ng/mL)的RAW 264.7细胞与热灭活K21(1×106 CFU)共同处理的TNF-α与PGE2产生。结果显示K21减毒治疗减低巨噬细胞中回应LPS刺激升高产生的TNF-α和PGE 2，指出K21具有抗发炎活性。
实例6 胚芽乳酸杆菌胚芽亚种K21在活体内的免疫及发炎评估
实验动物和分组
五周龄的雌性BALB/c小鼠均购自台湾地区实验动物中心。将小鼠置于无病原菌室的过滤器顶笼，在标准条件下饲养(22℃，50-60％湿度及12小时的光照/黑暗循环)，进行标准实验室饮食(LabDiet Autoclavable Rodent Diet 5010，PMI NutritionInternational，Brentwood，USA)及水喂养。在实验室条件适应一周后，小鼠分成三组。健康对照组及UC对照组从第1 天到第14天只投予PBS(0.2ml)，UC+K21组则口服投予K21(1×109CFU配置于PBS 0.2mL)。UC及UC+K21组的饮水在第8-天改为含有5％硫酸葡聚糖 (DSS)自由饮取至第14天。
胚芽乳酸杆菌胚芽亚种K21减少体重减轻及在葡聚醣硫酸钠(DSS)诱导的小鼠溃疡性结肠炎(UC)的结肠缩短
口服投予DSS可在BALB/c小鼠引起急性UC症状，包括体重减轻，便血，结肠黏膜炎症和结肠缩短。
健康对照组(健康管理)、UC对照组及K21组在第14天的重量变化及结肠长度：体重
变化＝小鼠第14天的体重–第1天的体重；结肠长度从回盲部(ileocecal junction)测到肛
门。数据表示为平均值±标准偏差，每一组n＝8只小鼠。当p<0.05(*)，对照组间的差异视为
统计学上有显著。a，相较于健康对照组，UC对照组及UC+K21组；b，相较于UC对照组，UC+K21
组。此等结果显示相较于健康组，在UC对照组中，显著的体重减轻与结肠长度缩短，这些症
状可藉K21的口服给药减轻。
| 健康对照组 | UC对照组 | K21 | ||
| K21 | 体重变化(g) | 1.9±0.7 | ﹣1.1±0.7<sup>*a</sup> | ﹣0.3±0.9<sup>*a,b</sup> |
| 结肠长度(cm) | 9.0±0.6 | 6.0±0.6<sup>*a</sup> | 6.5±0.5<sup>*a,b</sup> |
MPO是血红素过氧化物酶超家族的成员，并存储于白细胞 (leukocyte)的嗜天青颗粒(azurophilic granules)中。MPO于循环性中性球细胞，单核细胞和一些组织的巨噬细胞内被发现。MPO衍生的氧化剂也导致组织损伤与急性和慢性血管发炎性疾病的引发和扩大。DSS的治疗已经在实验动物中显示出显著增加结肠MPO活性。健康对照组(健康)，UC对照组 (UC)及K21组的结肠蛋白的MPO活性被进行了评估。数据表示为平均值±标准偏差，其中n＝6只小鼠为一组。当p<0.05(*)，K21和UC组间的差异为统计学上显著。图3显示相较于UC对照组，减少的MPO活性表示UC+K21 组的中度嗜中性球浸润，指出K21带有活体内的抗发炎活性。
免疫球蛋白及细胞激素的测定
TNF-α、IL-1β、IL-6、IFN-γ、IL-10及PGE2的浓度使用酵素免疫分析法(Enzyme-linked immunosorbent assay，ELISA)并遵循套组厂商建议操作流程测定(TNF-α、IL-1β与IL-6使用eBioscience，Boston，MA；IFN-γ与 IL-10使用R&D Systems，Minneapolis，MN；PGE2使用Cayman Chemical， Ann Arbor，MI；Insulin使用Uppsala，Sweden)。使用100μg个别老鼠的结肠组织蛋白进行结肠组织细胞激素分析。结肠组织细胞激素浓度以每毫克(mg)结肠组织中含有多少皮克(pg)细胞激素的方式(pg/mg)呈现。图4(A) ～(C)显示相较于UC对照组，活的K21(1×109CFU)口服给药对TNF-α (A)、IL-1β(B)和IL-6(C)在UC小鼠模型的结肠总蛋白中的浓度。结果指出该DSS处理引起发炎细胞激素，TNF-α、IL-1β及IL-6，的升高，其可借口服投予K21而减少。
实例7 使用定量实时PCR分析特定基因表达
透过使用RNeasy mini套组(Qiagen GmbH,Hilden,Germany)从小鼠结肠组织中萃取总RNA，接着使用oligo(dT)15引物与SuperScriptTM II反转录试剂(Life Technologies,Carlsbad,CA)进行cDNA合成。定量实时PCR则是使用LightCycler仪器(RocheDiagnostics,Mannheim,Germany)与 DyNAmo Capillary SYBR Green qPCR套组(Finnzymes,Espoo,Finland)根据制造商的建议来进行。每一个循环都会侦测一次荧光讯号。实验结果使用仪器中内建LDCA软件进行分析运算而熔解曲线则用来确定PCR产物的专一性。每个mRNA表达量均以GAPDH作为内对照进行正常化运算。实验结果以与健康控制组相对表达比率方式呈现。所有使用的引物皆呈现于表5 中。
表5：RT-PCR所使用的侦测引物组
＊F：正向引物；R：反向引物。
本文所呈现的所有数据均表示为平均值±标准偏差(SD)。数值的间的差异系藉由Tukey's事后比较检定(Tukey’s post-hoc)使用单因子变异数分析(One-way ANOVA)统计显著性。当P<0.05(*)或<0.01(**)时，对照组和其他组别间的差异被认为具有统计学意义。图5显示相较于UC对照组，口服投予活的K21(1×109CFU)对TNF-α、COX-2，TLR4及SOCS3在UC小鼠模型的结肠中的mRNA表达量的影响。使用实时PCR测定mRNA的表达量。结果指出该DSS处理引起TNF-α、COX-2，TLR4及SOCS3的表达量升高，指出K21在活体内的免疫调节作用。
【生物材料寄存】
台湾地区寄存信息【请依寄存机构、日期、号码顺序注记】
食品工业发展研究所
2014年4月8日
BCRC 910618
国外寄存信息【请依寄存国家、机构、日期、号码顺序注记】
德国微生物菌种保藏中心(DSMZ-DEUTSCHE SAMMLUNG VON MIKROORGANISMEN UNDZELLKULTUREN GmbH)
2013年6月27日
DSM 27444
Claims (7)
1.一种分离的乳酸菌(LAB)，其为胚芽乳酸杆菌胚芽亚种K21(Lactobacillusplantarum subsp.plantarum)，具有含有分别为SEQ ID NO:1及SEQ ID NO:2所示核酸序列的16S rRNA基因及pheS基因，寄存于德国微生物菌种保藏中心，寄存编号为DSM 27444，对下列呈现正反应：L-阿拉伯糖，D-核糖，D-木糖，D-半乳糖，D-葡萄糖，D-果糖，D-甘露糖，L-鼠李糖，D-甘露糖醇，D-山梨糖醇，甲基-α-D-吡喃甘露糖苷，N-乙酰葡糖胺，苦杏仁苷，熊果苷，七叶苷柠檬酸铁，水杨苷，D-纤维二糖，D-麦芽糖，D-乳糖，D-蜜二糖，D-蔗糖，D-海藻糖，菊醣，D-松三糖，D-棉子糖，龙胆二糖，D-松二糖，D-塔格糖和葡萄糖酸钾，但对下列呈现负反应：甘油，赤藓醇，D-阿拉伯糖，L-木糖，D-阿东糖醇，甲基-β-D-吡喃木糖苷，L-山梨糖，半乳糖醇，肌醇，甲基-α-D-吡喃葡萄糖苷，淀粉，肝醣，木糖醇，D-来苏糖，D-岩藻糖，L-岩藻糖，D-阿拉伯糖醇，L-阿拉伯糖醇，2-酮基-D-葡萄糖酸钾及5-酮基-D-葡萄糖酸钾。
2.一种组合物，包含如权利要求1的分离的乳酸菌及视需要的可食用载剂。
3.如权利要求2的组合物，其中该乳酸菌以活或不活的整个细菌形式使用。
4.如权利要求2的组合物，其为饮料，锭剂，丸剂，胶囊，药锭糖，颗粒，粉剂，悬浮剂，小药囊，软锭剂，糖果，棒或糖浆的形式。
5.如权利要求2的组合物，其为可用于医药产品、食品或营养补充品的形式。
6.如权利要求2的组合物，其每克干重组合物包括105至1013个菌落形成单位(cfu)的如权利要求1的乳酸菌。
7.一种根据权利要求1的乳酸菌或如权利要求3的组合物用于制备增强免疫调节及/或抗发炎活性的药剂的用途。
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| EP3196318A1 (en) | 2016-01-19 | 2017-07-26 | Symrise AG | Probiotics for altering the composition of oral biofilms |
| US11020441B2 (en) | 2016-01-19 | 2021-06-01 | Symrise Ag | Probiotics for use as anti-inflammatory agents in the oral cavity |
| GB201600975D0 (en) | 2016-01-19 | 2016-03-02 | Probi Ab | Novel strain of probiotic bacteria and compositions and uses thereof |
| EP3351259A1 (en) | 2017-01-18 | 2018-07-25 | Symrise AG | Probiotics for aggregation with disease-associated species in the oral cavity |
| TWI645854B (zh) * | 2017-03-20 | 2019-01-01 | 大江生醫股份有限公司 | 胚芽乳酸桿菌tci378及其於減脂及改善腸胃功能之應用 |
| US11357803B2 (en) | 2017-09-22 | 2022-06-14 | Iowa State University Research Foundation, Inc. | Probiotic compositions for production of dopamine |
| TWI636133B (zh) * | 2017-10-20 | 2018-09-21 | 葡萄王生技股份有限公司 | 一種胚芽乳酸桿菌、組合物、培養方法及排除體脂肪、降低肝腫大及／或抗發炎的用途 |
| KR102335710B1 (ko) | 2017-10-31 | 2021-12-07 | (주)아모레퍼시픽 | 유산균 유래의 세포밖 베지클을 포함하는 면역조절용 조성물 |
| WO2020118576A1 (zh) * | 2018-12-12 | 2020-06-18 | 生合生物科技股份有限公司 | 胚芽乳酸杆菌twk10在制备抗运动后发炎或降体脂组合物的用途 |
| CN110893195B (zh) * | 2019-09-30 | 2023-03-14 | 内蒙古伊利实业集团股份有限公司 | 一种具有缓解肠道炎症功能的副干酪乳杆菌et-22 |
| SE544508C2 (en) * | 2020-08-21 | 2022-06-28 | Haakansson Aasa | Lactobacillus plantarum strains |
| CN112006286A (zh) * | 2020-09-22 | 2020-12-01 | 上海泓商生物科技有限公司 | 增强免疫力益生菌组合物 |
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