CN105002109B - 乳酸菌、包含该乳酸菌的组合物以及其用途 - Google Patents
乳酸菌、包含该乳酸菌的组合物以及其用途 Download PDFInfo
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Abstract
本发明公开一种乳酸菌、包含该乳酸菌的组合物以及其用途。具体地，本发明提供一种单离的乳酸菌—植物乳杆菌植物亚种(Lactobacillus plantarum subsp.plantarum)菌株PS128，是于2014年3月31日以登录号DSM 28632寄存於德国微生物及细胞培养收集中心(DSMZ)。本发明进一步提供一种组合物，其包含植物乳杆菌植物亚种PS128以及载体。此外，本发明提供一种用于预防或治疗受试者压力引发的失调的方法，其包括将有效量的植物乳杆菌植物亚种PS128给予受试者的步骤。本发明亦提供一种用于预防或治疗受试者功能性胃肠失调的方法，其包括将有效量的植物乳杆菌植物亚种PS128给予受试者的步骤。
Description
技术领域
本发明关于一种乳酸菌，尤其关于一种在受试者中用于预防或治疗压力引发的失调或功能性胃肠失调的新颖乳酸菌菌株。
背景技术
功能性胃肠失调(FGID)为胃肠病医疗中最常见的问题。此等是由于胃肠道不正常作用的结果而发生，而且被界定为慢性腹部复合综合症，诸如，腹痛、腹泻、便秘以及腹胀。根据罗马准则III，已有超过20种功能性胃肠失调被认定。常见的FGID包含，但不限于，功能性腹痛、肠躁症(IBS)、便秘、功能性腹泻以及功能性消化不良。
肠躁症为慢性功能性胃肠失调。全世界约4％至30％的人饱受IBS所苦。IBS的特点包含两种主要症状，即腹痛(慢性痛)和排便习惯改变。根据这些主要的病征，IBS可分类成四个子群：腹泻型IBS(IBS-D)、便秘型IBS(IBS-C)、混合型IBS(IBS-M)以及未分型IBS(IBS-U)。在IBS患者中，约30％的患者在胃肠发炎后饱受IBS所苦，而且彼等患者是属于感染/发炎后IBS。再者，激励患者寻求健康照护和造成生活品质显著下降的主要因素是与内脏过度敏感(VH)相关的腹痛。内脏过度敏感被认为是造成功能性胃肠失调的主要机转之一。此外，最近研究显示内脏过度敏感对IBS高度特异。
内脏过度敏感定义为患者对内脏疼痛的感觉强度增加和阈值降低。持续性VH是与神经元敏化相关，该神经元敏化表现为神经元激化的增加。神经传递物质(诸如，血清素(5-羟基色胺，5-HT))在神经元敏化中扮演重要角色。血清素为单胺神经元传递物质。先前研究已显示对清醒大鼠皮下注射5-羟基色氨酸(5-HTP)(其为一种血清素的前驱体)会引发VH。血清素合成和储存主要的位置是肠粘膜的肠嗜铬细胞。从肠嗜铬细胞释放的血清素活化与肠道分泌、流动性以及感觉相关的神经反射。根据临床研究，IBS的患者通常伴随不正常的血清素代谢。另外，血清素受体拮抗剂已广泛用作治疗药物，表示IBS的病理是与血清素相关。
直肠扩张试验中降低的疼痛阈值表示内脏过度敏感，是IBS患者的主要特征。在动物研究中，大肠直肠疼痛阈值可由响应恒压器扩张的肌电图(EMG)信号监控，而更高的EMG信号反应表示对痛有更高的敏感度。除了VH之外，亦已证实在IBS大鼠模式中，脊髓中物质P(substance P)表达增加为代表大肠直肠扩张期间内脏痛觉的生物标记。
有多种改善IBS病征的治疗方法，包含用血清素受体拮抗剂、抗抑郁药物、促肠动力药物、抗痉挛药物以及益生菌。益生菌是活的微生物，当给予适当量的益生菌时，赋予宿主健康的益处。由于缺乏药理副作用，益生菌似乎为一种治疗IBS的潜在方法。此外，特定益生菌已被描述对便秘病征具有有益效果。
便秘为一种世界性的功能性胃肠失调，被定义为粪便不频繁或难以通过。便秘有许多原因，包含化学化合物、饮食习惯、肠内菌群组成、怀孕以及心理压力。虽然许多类型的泻药已被鉴定，大部分的此等药物具有潜在的不利副作用，诸如，引发耐受性、结肠黑变病或泻剂性结肠。便秘患者的肠内菌群生态失调(dysbiosis)可藉由吃益生菌而改善。另外，益生菌，尤其是乳酸杆菌和双歧杆菌，可降低结肠的pH，进而产生乳酸、醋酸及其他者。较低的pH倾向增加结肠蠕动，结果降低结肠传输时间且对便秘病征的治疗有有益效果。
益生菌可经由维持肠道菌群平衡、强化粘膜屏障功能以及调节免疫系统，而使宿主获得健康益处。许多证据表示益生菌可作为疾病的治疗方式，这些疾病包含感染性疾病、过敏、癌症以及坏死性小肠结肠炎。因此，值得进一步研究益生菌用于治疗功能性胃肠失调的用途。
其中，乳酸菌(本文中有时称为LAB)为用作益生菌的最重要菌种，由于其能够调节宿主肠道菌群，已被认为能做为预防或治疗肠胃道健康(Vyas and Ranganathan,2012)的另外选择。此外，近年来越来越多的证据也显示乳酸菌能改变宿主对于心理压力的心理和生理反应(Zareie等,2006)。
在人类和动物中，压力是引起情绪失调和神经化学改变的其中一个因素。啮齿类遭受强迫游泳作为急性压力之后，隔天再试验时常表现出较多的不动程度。研究显示，将啮齿类暴露在母子分离的早期生活压力下，会导致它们相较于一般饲养的控制组在成年期有多重异常，包括肠胃道发炎、类焦虑(anxiety-like)和类忧郁(depression-like)行为、缺损的下视丘-脑垂腺-肾上腺轴线功能，以及相較於正常光週期控制(normal-rearedcontrols)受影响的神经传导物(Millstein and Holmes,2007；O'Mahony等,2011)。压力引发的失调包括，但不限于焦虑、忧郁和肠躁症。
除了传统精神病用药，乳酸菌可作为治疗压力引发失调的替代物，因为乳酸菌已显示具有影响宿主肠脑轴线(gut-brain axis，GBA)，且已显示无菌鼠缺乏增加的活动力和减少的焦虑强调了正常菌群在脑部发育的重要角色(Diaz Heijtz等,2011)。先前研究显示鼠李糖乳酸杆菌(Lactobacillus rhamnosus)经由迷走神经改变了健康老鼠中的枢神经系统功能(Bravo等,2011)，且婴儿双岐杆菌(Bifidobacterium infantis)逆转了强迫游泳试验(forced swimming test，缩写为FST)中的行为缺陷，并还原了脑干中的肾上腺素浓度(Desbonnet等,2010)。上述的研究支持益生菌可开发用于治疗精神失调和神经传导物。
许多研究已显示生产和制造方法及食物载体可影响益生菌菌株的性质，而且对临床介入研究的结果有影响。于此，我们辨识出显示预防或治疗精神失调和功能性胃肠失调的潜能的乳酸菌菌株。
发明内容
本发明是有关于一种单离的乳酸菌，其是植物乳杆菌植物亚种PS128(Lactobacillus plantarum subsp.plantarum PS128(后文中有时称为PS128))，并且已于2014年3月31日寄存于德国微生物及细胞培养收集中心(DSMZ-DEUTSCHE SAMMLUNG VONMIKROORGANISMEN UND ZELLKULTUREN)，并取得DSMZ的登录号DSM 28632。
于本发明的一方面，提供了一种包含植物乳杆菌植物亚种PS128及载体的组合物。
于一具体实施例中，载体为生理上可接受的赋形剂或稀释剂。生理上可接受的赋形剂或稀释剂的实例包含，但不限于，乳糖、淀粉、糊精、环糊精、羧甲基淀粉钠、丙酸羧基化淀粉、微晶纤维素、羧甲基纤维素、麦芽糖糊精以及硬脂酸镁。
于本发明的一方面，提供了一种用于预防或治疗受试者压力引发的失调或精神异常，该方法包括给予受试者有效量的植物乳杆菌植物亚种PS128。较佳者，该压力引发的失调或该精神异常是选自焦虑、忧郁和肠躁症所组成的组。
在进一步具体实施例中，于给予植物乳杆菌植物亚种PS128后，血清皮质酮浓度在受试者中有统计上显著下降。此外，于给予植物乳杆菌植物亚种PS128后，神经传导物质浓度在受试者中有统计上显著上升。较佳者，该神经传导物质是多巴胺。
于本发明的另一方面，提供了一种用于预防或治疗功能性胃肠失调的方法，该方法包含给予受试者有效量的植物乳杆菌植物亚种PS128。
在本发明的另一方面，提供一种用于预防或治疗受试者的内脏过度敏感的方法，包括给予该受试者有效量的植物乳杆菌植物亚种PS128的步骤。较佳者，内脏过度敏感是与功能性胃肠失调相关。
在一具体实施例中，该功能性胃肠失调是选自功能性腹痛、肠躁症、便秘、功能性腹泻以及功能性消化不良所组成的组。在一较佳具体实施例中，功能性胃肠失调是功能性腹痛、肠躁症或便秘。
在本发明的另一方面，提供一种用于预防或治疗受试者的功能性腹痛、肠躁症或便秘的方法，包括给予该受试者有效量的植物乳杆菌植物亚种PS128的步骤。
在本发明的进一步具体实施例中，于给予植物乳杆菌植物亚种PS128后，痛觉的生物标记浓度在受试者中有统计上显著下降。较佳者，该生物标记是物质P。此外，于给予植物乳杆菌植物亚种PS128后，受试者中的肌电图信号有统计上显著下降。
在一较佳的具体实施例中，经单离的乳酸菌是口服给予受试者。
附图说明
图1显示植物乳杆菌的ERIC-PCR图，其中M代表DNA梯状条带；DSM 27445代表植物乳杆菌植物亚种；ATCC 14917T代表植物乳杆菌植物亚种；以及ATCC 17638T代表植物乳杆菌argentoratensis亚种。
图2A及图2B显示PS128增加小鼠在旷野试验(open field test)中的总移动距离并且改善小鼠在强迫游泳试验中的类忧郁行为。(*表示与控制组相比p<0.05；$表示与压力组相比p<0.05)。
图3显示血清皮质酮浓度。(*表示与控制组相比p<0.05；$表示与压力组相比p<0.05)。
图4A至图4C显示PS128对小鼠前额叶皮质多巴胺路径的影响。(*表示与控制组相比p<0.05；$表示与压力组相比p<0.05)。
图5A显示评估PS128对5-HTP引发的内脏过度敏感的效果的实验时间轴，而且图5B显示内脏过度敏感试验的实验程序。
图6A至图6C显示响应CRD刺激的肌电图(EMG)信号(n＝8，*p<0.05，**p<0.01，***p<0.0001，基线相对于5-HTP)。
图7显示L6-S1脊髓中的物质P浓度的蛋白质印迹分析，该物质P是从有或没有给予PS128的大鼠单离(n＝3,***p<0.0001)。
图8A和图8B显示口服给予的PS128对于正常(A)和便秘实验组(B)小鼠的粪便重量的影响(数据是以均值±S.D.显示，n＝6，**p<0.01，*p<0.05)。
具体实施方式
以下是藉由特定的具体实施例说明本发明的实施方式，本领域技术人员可由本说明书所揭示的内容轻易地了解本发明的优点及功效。本发明亦可藉由其它不同的实施方式加以施行或应用，本说明书中的各项细节亦可基于不同观点与应用，在不悖离本发明所揭示的精神下赋予不同的修饰与变更。
本发明将以下述实施例来作进一步说明，但应了解到，实施例仅为例示说明之用，而不应被解释为限制本发明的实施。
实施例1：植物乳杆菌植物亚种PS128的单离和利用ERIC-PCR图谱的新颖菌种鉴别
植物乳杆菌植物亚种PS128是从台湾传统发酵芥菜—福菜中单离。
进行ERIC-PCR以进一步区分具有高序列相似度的细菌亚种(Chao等,2008；Chao等,2009；Rademaker等,2007)。以表1及表2所示的条件进行植物乳杆菌菌株的ERIC-PCR图谱。从PS128和三株植物乳杆菌菌株抽取的基因组DNA作为模板进行16S rDNA扩增。所得的扩增产物进行电泳，其图谱比较图如图1所示，其中使用SEQ ID NO：1及SEQ ID NO：2所示的引物：
ERIC1R：(5’-ATGTAAGCTCCTGGGGATTCAC-3’)SEQ ID NO：1
ERIC2：(5’-AAGTAAGTGACTGGGGTGAGCG-3’)SEQ ID NO：2
表1.PCR反应溶液的组成(每PCR试管25微升(μl))
| 组成 | 体积 |
| ddH2O | 16.3微升 |
| 10倍PCR缓冲液 | 2.5微升 |
| dNTP | 2.0微升 |
| MgCl2(25毫摩尔(mM)) | 1.0微升 |
| 引子(GTG)5(10微摩尔(μM)) | 2.0微升 |
| rTaq聚合酶 | 0.2微升 |
| DNA模板(10微摩尔(μM)) | 1.0微升 |
表2.PCR条件
如图1所示，M排代表DNA梯状条带(250至10000碱基对)；DSM 27445代表植物乳杆菌植物亚种；ATCC 14917T代表植物乳杆菌植物亚种；以及ATCC 17638T代表植物乳杆菌argentoratensis亚种。
如白色箭头所示，PS128的条带位置在DSM 27445、ATCC 14917或ATCC 17638中是独特的。因此，图1的结果显示，即使PS128、DSM 27445,ATCC 14917T或ATCC 17638T全属于植物乳杆菌，这些仍是不同的菌株。因此，此结果显示PS128是一株新的植物乳杆菌植物亚种。
植物乳杆菌植物亚种PS128已于2014年3月31日根据布达佩斯条约寄存于德国微生物及细胞培养收集中心(Inhoffenstr.7B,D-38124Braunschweig，Germany)，并已取得由国际保存机构DSMZ的登录号DSM 28632。此生物性材料已进行并通过存活性试验。
实施例2：分析型材指数(Analytical Profile Index，API)的鉴定
本发明使用API 50CHL试剂盒(bioMerieux，法国)评估PS128的糖利用性，其结果示于表3。其酦酵试验指出PS128具有和植物乳杆菌植物亚种相似的生化特性。
表3：酦酵试验结果
a+，阳性；－，阴性。
实施例3：植物乳杆菌植物亚种PS128对受压力的小鼠行为、压力荷尔蒙和神经传导物质浓度的改变
(1)PS128的制备
将乳酸菌PS128接种于培养基(10％脱脂奶、1％酵母粉、0.1％吐温80(Tween 80)以及2％葡萄糖)中，并且在37℃下培养18小时，以離心收集。将PS128以保护剂(1％脱脂奶、2％糖、2％果寡糖、3％麦芽糖糊精以及2％甘油)和赋形剂包埋，并且冷冻干燥，以调整至最终浓度为每克粉有1×1011菌落形成单位(菌落形成单位，以下简称CFU)。将PS128粉储存在-20℃冰箱备用。
(2)实验动物和饲养
8周龄的雄性C57BL/6JNarl小鼠或定时怀孕C57BL/6JNarl母小鼠均购自中国台湾的实验动物中心并于生产约一周前饲养在阳明大学无特定病原菌的动物中心内，备有标准实验室饮食(LabDiet Autoclavable Rodent Diet 5010,PMI Nutrition International,Brentwood,USA)及有滤盖的育种盒中，水和饲料无限制供应(动物房保持室内温度为22℃和50-60％的湿度，12小时的光照和黑暗循环)。所有动物实验程序皆由阳明大学动物管理委员会进行审查并核准。
(3)早期生命压力
根据之前研究(Desbonnet等,2010)修改后，藉由低温环境下的母亲剥夺方式做为早期生命压力。简言之，新生儿于出生后第2-14天每天在室温下(约22℃)与它们的母亲和兄弟姊妹分离3小时(11：00-14：00)。接下来两周，除了每周换垫料以外不被打扰，之后受压力的幼鼠断奶并被随机分配到每一笼5-6只。只有雄性幼鼠才被用来进行实验(压力组有12只，另有12只压力组喂食109的PS128)。这些无受过早期生命压力的小鼠则当作控制组(控制组有10只)。
(4)实验设计及采样
从断奶(出生后第28天)到八周龄的小鼠，该小鼠连续四周被投予生理食盐水或PS128(109CFU于0.2mL盐水/小鼠/天)。这些在光照期经过一连串的行为试验，包括从最轻微到最大压力的旷野试验(OFT)和强迫游泳试验(FST)。牺牲当天，该小鼠眼窝采血后接着进行颈椎错位，这些都在11：00-14：00之间进行，以减少昼夜节律的影响。该小鼠的脑被迅速地移除，特定区域之前额叶皮质被切取放置冰上，然后冷冻在液态氮或保存在0.6％过氯酸缓冲液中，然后存放在-80℃备用。
(5)旷野试验(open field test，简称OFT)
旷野试验是一种常用来测量大小鼠探索行为和基本活动力的测量方法，且同时能定性和定量。
以旷野活动系统(Tru Scan activity系统,Coulbourn Instruments,宾州,美国)来监控和测量运动能力，包含一个具有两个光束侦测环围绕其压克力墙的竞技场(25.4×25.4×38厘米)。每只小鼠从同一个角落被放入竞技场10分钟，以便测量包括总移动距离在内的数种活动。每次试验结束后，该竞技场以水及70％乙醇清洗，该小鼠则被放回原饲育笼。该活动由Tru Scan 2.2软件(Coulbourn Instruments)自动记录和定量。
(6)强迫游泳试验(forced swimming test，简称FST)
强迫游泳是一种啮齿动物行为试验，用来评估这些造成或预防类忧郁状态的抗忧郁药物、新化合物的抗忧郁疗效，或实验操作。
强迫游泳试验的评估方式如先前描述(Cryan等,2001)且有修改。简言之，不动程度(immobility)是以摄影机纪录小鼠被放入透明压克力圆柱(30厘米高×10厘米内径,含有15厘米深的水，水温调整到23±1℃)中，并进一步以轨迹追踪软件EthoVision(NoldusInformation Technology,Wageningen,荷兰)分析单一次6分钟强迫游泳内4分钟(1至5分钟)的不动程度。试验结束后，小鼠被以擦手纸擦干并放回原饲育笼。1至5分钟的不动时间皆以相同参数计算，以避免人为误差。
如图2A及图2B所示，在旷野试验中，受压力的小鼠具有与控制组相似的总移动距离(图2A)，同时在强迫游泳试验中，它们有较多的不动时间(图2B)。给予受压力小鼠PS128能够显著增加旷野试验中的总移动距离，并且减少在强迫游泳试验中的不动程度(图2A和图2B)至接近控制组小鼠的程度。*代表和控制组相比p<0.05；$代表和压力组相比p<0.05。
(7)血清皮质酮测定
血浆皮质酮浓度是下视丘-脑垂腺-肾上腺轴线(hypothalamic-pituitary-adrenal axis)活化的指标，压力或恐惧下身体-脑交互作用的基本反应。
牺牲之前，自小鼠收集血液样本，且于4℃下经3000×g离心10分钟获得血清。血清经过适当稀释后加至市售皮质酮酶免疫分析试剂盒(CORT EIA kit，Cayman,美国)，且由该试剂盒提供的标准品内插计算出浓度。
如图3所示，透过测量血清浓度，本案发明人发现皮质酮在受压力的小鼠中显著升高并且在投予PS128(压力组喂食109)后逆转。*代表和控制组相比p<0.05；$代表和压力组相比p<0.05。
(8)以HPLC-ECD定量单胺类物质及其代谢物
高效能液相层析-电化学侦测器对生物或环境样本例如儿茶酚胺(多巴胺、正肾上腺素和肾上腺素)、单胺类(例如，血清素、多巴胺、正肾上腺素和肾上腺素)、乙酰胆碱、谷氨酸、精胺酸、γ-氨基丁酸，和其它物质的例行检测上具有高效能(Cheng等,2000)。
待测量的神经传导物包括多巴胺(dopamine，以下简称DA)及其代谢物，二羟基苯乙酸(dihydroxyphenylacetic acid，以下简称DC)和高香草酸(homo-vanillic acid，以下简称HVA)。该高效能液相层析-电化学侦测器(HPLC-ECD)系统如先前所描述(Cheng等2000)，包含微量泵浦(CMA-100，CMA，斯德哥尔摩，瑞典)、线上注射器(CMA-160)、Microtech的液相层析泵浦(Micro-tech Scientific,Sunnyvale,加州)，以及BAS-4C电化学侦测器(Bioanalytical Systems,Inc.,West Lafeyette,IN)。逆相层析管柱(Kinetex C18，2.6微米(μm)，100×内径2.1公厘(mm)，Phenomenex，美国)用于分析。在室温下(25℃)相对于Ag/AgCl之参考电击，玻璃碳工作电极之电位设定于+650毫伏特(mV)。含有0.1M磷酸二氢钠(NaH2PO4)、8％甲醇,0.74mM辛基硫酸钠(SOS)、0.03mM乙烯二胺四醋酸(EDTA)和2mM氯化钾(KCl)的移动相缓冲溶液以磷酸调整至pH 3.74。整颗脑在小鼠颈椎错位后立刻被收集，冰在干冰上。前额叶皮质被切下来后保存在0.6％过氯酸缓冲液中，并且存放在-80℃直到以超音波均质化且以12000×g离心10分钟。分析前，上清液以0.22μm PVDF膜过滤(4mm针筒过滤器，Millex-GV，Millipore，美国)。适当稀释过后的上清液(20μl)被注射至流速为每分钟0.2毫升(ml)的层析系统。单胺类物质的浓度透过以下标准品内插计算出：多巴胺、二羟基苯乙酸以及高香草酸(Sigma-Aldrich,St.Louis,MO,美国)，范围从每毫升1到100ng。
如图4A至图4C所示，藉由施加早期生命压力方式，改变前额叶皮质内的神经传导物质。在多巴胺路径中，多巴胺本身减少了，且其代谢物二羟基苯乙酸与控制组相似(图4A和图4B)，同时另一个代谢物高香草酸有显著下降(图4C)。给予PS128显著增加受压力小鼠的多巴胺、二羟基苯乙酸和高香草酸浓度(图4A至第4C图)。*代表和控制组相比p<0.05；$代表和压力组相比p<0.05。
实施例4.植物乳杆菌植物亚种PS128对大鼠中内脏过度敏感和物质P浓度的改变
先前研究已显示对苏醒的大鼠皮下注射5-羟基色氨酸(5-HTP)(其是一种血清素的前驱体)会引发VH。在此研究中，5-HTP引发的VH模式是用以评估益生菌菌株—植物乳杆菌植物亚种PS128对大鼠的改善效果。
(1)PS128的制备
将PS128接种于培养基(10％脱脂奶、1％酵母粉、0.1％吐温80以及2％葡萄糖)中，于37℃下培养18小时，以及藉由离心而收集。将PS128与保护剂(脱脂奶1％、糖2％、果寡2％、麦芽糖糊精3％以及甘油2％)与赋形剂包埋且冷冻干燥，以调整至最终浓度每克粉有1×1011菌落形成单位(CFU)。将PS128粉储存于-20℃，并且在动物治疗之前溶解于盐水溶液而得5x109CFU/mL。
(2)动物和饲养
将购自实验动物中心(台北，中国台湾)的六至八周龄雄性斯普拉-道来(Sprague–Dawley,SD)大鼠(220至330g)于恒温和湿度及12小时光照和黑暗循环下饲养，而且无限制供应食物和水。所有动物实验程序皆由阳明大学动物管理委员会进行审查并核准。
(3)实验流程
参阅图5A，首先以异氟烷麻醉大鼠，以进行电极植入。进行埋入电极的手术之后，单独饲养大鼠。手术后约第7至10天，大鼠经历大肠直肠扩张(CRD)试验，以进行由5-HTP注射所引发的基线和内脏过度敏感侦测。此试验的目的是要验证没有喂食细菌情况下，清醒雄性大鼠的5-HTP-内脏过度敏感。在第10天，口服给予大鼠PS128(每天约109CFU，于0.2mL盐水中)或盐水(每天200μl)两周，接着进行另一次CRD试验，以测定PS128对VH的效果。CRD流程与肌电图(EMG)记录同时进行。计算EMG曲线下的面积(AUC)作为参数。为了以蛋白质印迹侦测脊髓中的物质P的蛋白质浓度，以戊巴比妥钠(65mg/kg，腹膜内注射)麻醉大鼠，并且将其经心灌注生理食盐水。将负责大鼠腹部感觉的L6-S1脊髓单离。
(4)电极植入
以异氟烷麻醉大鼠。实验前7天，将经铁氟龙涂布的不绣钢线(A-M Systems inc.)所制造的电极植入大鼠的腹部外斜肌。将电极外置在颈部的后方上。
(5)大肠直肠扩张(CRD)试验
大肠直肠扩张(CRD)为一种用于评估内脏敏感度所广泛使用且可再现的方法。肌电图信号的测量是CRD中的评估项目之一，而且是最准确的定量试验项目。
参阅图5B，CRD试验是在5-HTP皮下注射(5mg/Kg)之前和之后进行，以测定5-HTP引发的内脏过度敏感。
将大鼠放置在塑胶通道(直径为6厘米，长度为25厘米)中以进行CRD试验。试验前3天的期间，将大鼠以每天3小时单独放置通道中，以训练成适应实验条件。大肠直肠扩张(CRD)气球是由附接直肠导管(Medtronic Inc.)的乳胶手套指部(7厘米长)所组成。将气球膨胀，并且留置过夜，以帮助平衡该气球壁中的张力。将可膨胀的装置透过肛管完全导入有意识的大鼠直肠，并且固定到尾基部。接着，将管连接至恒压器(Medtronic Inc.)。藉由将气球膨胀至期望的压力(20、40或60mmHg)10秒钟以扩张结肠，每次扩张之间有30秒间隔。针对各实验方案重复4次扩张，且各系列之间有5分钟间隔。CRD的反应是由EMG装置所记录。EMG信号分析是以Spike 2(Cambridge Electronic Design Limited)处理成内脏运动反射(面积/秒)。
如图6A所示，内脏运动是从原始EMG信号计算，并且在每个群组中以压力依赖性的方式缓慢地增加。相对于大鼠中的基线信号，皮下注射5-HTP显著地增加CRD引发的EMG信号。
如图6B所示，给予盐水两周后，5-HTP注射后的EMG信号仍显著上升，而给予PS128两周的大鼠可抑制5-HTP所引发的EMG信号的上升。
另外，我们计算在第10天和第24天的5-HTP注射后EMG上升的差，以确认给予PS128对EMG信号上升的抑制效果。EMG差的公式显示如下：
EMG差＝(在第24天注射5-HTP后EMG上升的差)-(在第10天注射5-HTP后EMG上升的差)
如图6C所示，给予盐水之后，在所有扩张压力刺激中，在第24天的EMG信号上升相较于在第10天者更多。然而，在PS128组中，在第24天的EMG信号上升相较于在第10天者低。此等数据表示PS128有改善5-HTP注射所引发的VH的潜能。
(6)蛋白质印迹
将L6-S1脊髓组织中的总蛋白质以商业蛋白质提取试剂盒(EC21Inc.)提取，以蛋白质印迹确认PS128对与痛觉相关的脊髓神经元胜肽的效果。将提取物于10％聚丙烯酰胺凝胶上区分，而且接着以电泳法转移到聚偏氟乙烯膜(Roche Ltd.)，接着以阻断缓冲液(含有5％脱脂奶的TBST)阻断1小时，以及与初级抗血清物质P(1：1000；GeneTex Inc.)在阻断缓冲液中于4℃下培养过夜。以TBST清洗两次之后，将膜与山羊抗大鼠IgG-HRP(1：5000；Santa Cruz Biotechnology,Inc.)在阻断缓冲液中反應。将抗体-蛋白质复合体以ImmobilonTM Western Chemiluminescent HRP Substrate(Millipore Inc.)显现，并且由发光影像分析器(FUJIFILM Holdings Corporation)侦测。
物质P为大鼠脊髓中的痛觉的生物标记。这暗示物质P的不正常表达浓度涉及IBS的病理机转。再者，含物质P的神经通路被认为是发挥调节胃肠功能作用的神经通路之一。如图7中所示，发现在5-HTP注射和CRD实验之后，口服给予盐水两周的大鼠在L6-S1脊髓中有高浓度的物质P产生，同时没有注射5-HTP的控制组大鼠具有基础浓度。给予PS128两周，抑制5-HTP注射引发的物质P产生的上升。亦即，给予PS128使物质P的浓度逆转到几乎是没有注射5-HTP大鼠的浓度。
实施例5.PS128的通便效果
洛哌丁胺是一种μ-鸦片类剂受体的激动剂，其是由于经由肠肌丛中的G蛋白抑制腺苷酸环化酶的结果而抑制内源性乙酰胆碱释放。洛哌丁胺经评估是直接作用在肠神经系统以引发便秘，并且频繁使用于便秘小鼠模式中。
进一步检验PS128对于使正常和洛哌丁胺引发的便秘的小鼠两者排泄的通便效果。口服给予小鼠安慰剂(0.2mL盐水/小鼠/天)或PS128(109CFU于0.2mL盐水/小鼠/天)。2周之后，测量各小鼠3小时的粪便湿重量。实验组便秘小鼠，于口服给予盐酸洛哌丁胺(5mg/kg)30分钟之后，开始测量各实验组便秘小鼠3小时的粪便湿重量。如图8中所示，相较于安慰剂组，PS128组的粪便湿重量显著地增加，藉此暗示PS128的通便效果。彼等结果暗示PS128具有缓和便秘的潜能。
实施例6.统计分析
以Prism版本6(Prism,San Diego,CA)分析各实验组间的差异。本文所呈现的所有数据均以平均値±标准差(SD)表示。图2、图3、图4以及图7的统计分析是以单因子变数分析计算，并以邦弗朗尼(Bonferroni)作事后比较检定。两样本t-检定是用以分析EMG信号(图6)和通便效果(图8)之间的差异。若p<0.05，则差异被认为是统计学上显著的。各组间之统计差异若p<0.05以星号(*)或美元符号($)表示，**若p<0.01，若***p<0.001。
本发明找到一株潜力菌株植物乳杆菌植物亚种PS128，在受压力小鼠上展现益处，并且藉由给予乳酸杆菌菌株PS128，该小鼠的行为被改善了。
再者，本发明亦发现PS128对内脏过度敏感和便秘发挥益处，而且PS128亦除去5-HTP注射后大鼠的EMG信号的上升，以及抑制脊髓中的P物质的上升的产生。
因此，本发明提供的方法是用于藉由给予乳酸杆菌菌株PS128，而预防或治疗压力引发失调或功能性胃肠失调。上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。本领域技术人员均可在不违背本发明的精神及范畴下，对上述实施例进行修饰与改变。因此，举凡本领域技术人员，在未脱离本发明所揭示的精神与技术原理下所完成之一切等效修饰或改变，仍应由前述的权利要求书所涵盖。
以下所列的参考文献以及本发明所引用的DSMZ和ATCC编号是各别以引用方式并入本文。
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Claims (15)
1.一种单离的乳酸菌，是植物乳杆菌植物亚种(Lactobacillus plantarumsubsp.plantarum)PS128，且以登录号DSM 28632寄存于德国微生物及细胞培养收集中心(DSMZ)。
2.一种组合物，其包含：
权利要求1所述的单离的乳酸菌；以及
载体。
3.一种如权利要求1所述的单离的乳酸菌用于制备预防或治疗受试者压力引发的失调或精神失调的药物的用途，包括将该乳酸菌给予该受试者，其特征在于，于该给予之后，血清皮质酮浓度在该受试者中有统计上显著下降。
4.根据权利要求3所述的用途，其特征在于，该压力引发的失调或该精神失调选自焦虑、忧郁和肠躁症所组成的组。
5.根据权利要求3或4所述的用途，其特征在于，于该给予之后，神经传导物质浓度在该受试者中有统计上显著上升。
6.根据权利要求5所述的用途，其特征在于，该神经传导物质是多巴胺。
7.一种如权利要求1所述的单离的乳酸菌用于制备预防或治疗受试者的功能性胃肠失调的药物的用途，包括将该乳酸菌给予该受试者，其特征在于，于该给予之后，痛觉的生物标记的浓度有统计上显著下降。
8.一种如权利要求1所述的单离的乳酸菌用于制备预防或治疗受试者的内脏过度敏感的药物的用途，包括将该乳酸菌给予该受试者，其特征在于，于该给予之后，痛觉的生物标记的浓度有统计上显著下降。
9.根据权利要求8所述的用途，其特征在于，该内脏过度敏感与功能性胃肠失调相关。
10.根据权利要求7或9所述的用途，其特征在于，该功能性胃肠失调是选自功能性腹痛、肠躁症、便秘、功能性腹泻以及功能性消化不良所组成的组。
11.根据权利要求10所述的用途，其特征在于，该功能性胃肠失调是功能性腹痛、肠躁症或便秘。
12.一种如权利要求1所述的单离的乳酸菌用于制备预防或治疗受试者的功能性腹痛、肠躁症或便秘的药物的用途，包括将该乳酸菌给予该受试者，其特征在于，于该给予之后，痛觉的生物标记的浓度有统计上显著下降。
13.根据权利要求7至9及12中任一项所述的用途，其特征在于，该生物标记是物质P。
14.根据权利要求7至9及12中任一项所述的用途，其特征在于，于该给予之后，肌电图信号在该受试者中有统计上显著下降。
15.根据权利要求3、4、7至9及12中任一项所述的用途，其特征在于，该单离的乳酸菌是口服给予该受试者。
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| Publication number | Publication date |
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| JP6035578B2 (ja) | 2016-11-30 |
| EP2937424A1 (en) | 2015-10-28 |
| EP2937424B1 (en) | 2017-03-29 |
| CN105002109A (zh) | 2015-10-28 |
| JP2015213501A (ja) | 2015-12-03 |
| ES2624673T3 (es) | 2017-07-17 |
| PL2937424T3 (pl) | 2017-09-29 |
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