CN116782947A - 包含普氏栖粪杆菌菌株的用于预防或治疗特应性疾病的药物组合物 - Google Patents
包含普氏栖粪杆菌菌株的用于预防或治疗特应性疾病的药物组合物 Download PDFInfo
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Abstract
本发明涉及包含普氏栖粪杆菌EB‑FPDK11菌株或其培养物或干燥物的在特应性疾病的预防或治疗中有效的药物组合物。与传统的益生菌通常对特应性疾病的治疗效果微乎其微的情况相比,本发明的药物组合物以与类固醇类药物同等的水平显出对特应性疾病的预防或治疗效果,因此,不仅有望用作药用益生菌(pharmabiotics)治疗剂,还在食品及化妆品的开发中有效。
Description
技术领域
本发明涉及用于预防或治疗特应性疾病的药物组合物,更详细地,涉及包含普氏栖粪杆菌(Faecalibacterium prausnitzii)EB-FPDK11菌株作为有效成分的用于预防或治疗特应性疾病的药物组合物。
背景技术
从严格意义来说,术语“特应性”是指对于从外部进入体内的异物非正常地产生IgE的倾向。因此,虽然与术语“过敏”的含义不同,但实际上以相同的含义混用。这样的过敏反应在临床上表现出症状的情况称为“特应性疾病”或“过敏性疾病”,通常将哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、荨麻疹、过敏性反应(anaphylaxis)、食物过敏(foodallergy)等归类为特应性疾病。
虽然特应性疾病的发病原因尚未明确,但通常专家推断与遗传性、免疫学因素有关,而其他环境、精神因素等则起到恶化因素的作用。已知特应性疾病并非以单一疾病发生,而以特应性皮炎、哮喘及过敏性鼻炎等特应性进程(atopic march)的方式发生或同时发生的多重疾病。
在特应性疾病中,特应性皮炎(Atopic Dermatitis)是广为人知的在新生儿或幼儿中发生并能够持续至长至成人的慢性复发性皮肤疾病。特应性皮炎的主要症状为在病变初期的急性期主要发生瘙痒症并伴有严重的红斑性丘疹和水疱,若抓挠则变为渗出疮水的渗出性病变,这时常发生二次感染。病变发展到亚急性期,发生擦伤、丘疹,临近慢性期时发生皮肤变厚的苔藓样变(lichenification)现象。特应性患者因频繁的复发和症状的恶化而反复进行急救治疗及住院治疗,难以进行正常的学校生活、社会生活或职场生活,经受精神上的痛苦,从而可能给正常的生活带来困难。
由于特应性疾病难以根治并具有症状加剧的倾向,因此特应性疾病不以治疗为目的,而是通过适当的治疗来控制症状。现在,特应性皮炎主要以类固醇、抗组胺剂及抗生素等药物疗法来治疗。现在最常使用的治疗剂为已知为类固醇剂的地塞米松(dexamethasone)。虽然类固醇类药物的抗炎症及免疫抑制效果卓越,但长期使用时具有发生皮肤弱化、全身激素症状及中毒性效果等副作用的问题。虽然抗组胺剂通过抑制从肥大细胞中释放组氨来减少瘙痒症状,但是以临时措施来使用,可会引起常时间的失眠、心悸及食欲不振等副作用。
这样长期使用合成药品时,副作用严重,因此需要既对特应性疾病有效又无副作用的新型特应性治疗方法。作为无副作用的特应性治疗方法,微生物新药这种新型治疗方法而备受关注。虽然益生菌的功效与功能备受关注,但微生物在体内如何工作等相当一部分内容仍是有待查明的难题,而且,在功效方面也仅止步于保持肠内环境的健康,很难期待确实的药学功效。因此,对于作为疑难病的特应性疾病,迫切需要开发具有经过验证的药学功效的新一代药用益生菌(pharmabiotics)治疗剂。
现有技术文献
专利文献
专利文献1:KR20160069733 A
专利文献2:KR20130034764 A
专利文献3:KR101925135 B
发明内容
技术问题
为了克服上述现有的技术限制,本发明的一目的在于,提供包含普氏栖粪杆菌EB-FPDK11菌株(KCCM12621P)作为有效成分的用于预防或治疗特应性疾病的药物组合物。
本发明所要实现的具体技术问题为提供包含抑制作为免疫过敏反应媒介物的IgE的过度分泌、在Th1型细胞因子与Th2型细胞因子的均衡免疫调节方面效果卓越的普氏栖粪杆菌EB-FPDK11菌株的用于预防或治疗特应性疾病的药物组合物。
本发明的再一目的在于,提供包含普氏栖粪杆菌EB-FPDK11菌株(KCCM12621P)作为有效成分的用于预防或改善特应性疾病的保健功能食品。
本发明的还有一目的在于,提供包含普氏栖粪杆菌EB-FPDK11菌株(KCCM12621P)作为有效成分的用于缓解或改善特应性疾病的化妆品组合物。
技术方案
用于实现上述目的的本发明的一实施方式涉及包含保藏编号KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株、上述菌株的培养物或干燥物的用于预防或治疗特应性疾病的药物组合物。
用于实现上述目的的本发明的再一实施方式涉及包含本发明的普氏栖粪杆菌EB-FPDK11菌株(KCCM12621P)、上述菌株的培养物或干燥物的用于预防或改善特应性疾病的食品。
用于实现上述目的的本发明的另一实施方式涉及包含本发明的普氏栖粪杆菌EB-FPDK11菌株(KCCM12621P)、上述菌株的培养物或干燥物的用于缓解或改善特应性疾病的化妆品组合物。
发明的效果
包含本发明的普氏栖粪杆菌EB-FPDK11菌株作为有效成分的用于预防或治疗特应性疾病的药物组合物对特应性疾病的治疗效果突出,表现出与类固醇类药物同等水平的特应性皮炎的预防或治疗效果。
并且,包含本发明的普氏栖粪杆菌EB-FPDK11菌株作为有效成分的用于预防或治疗特应性疾病的药物组合物在Th1细胞与Th2细胞的均衡免疫调节中效果卓越,其特征在于,尤其根据特应性皮炎的疾病严重程度,通过互不相同的免疫调节机制实现Th1型细胞因子与Th2型细胞因子的均衡免疫调节。
并且,本发明的药物组合物具有直接减少作为特应性皮炎的发病主要因子的血清免疫球蛋白IgE的量的效果。因此,可以在能够在特应性疾病的预防及治疗中使用的药物组合物、保健功能食品、化妆品组合物等中应用。
附图说明
本发明的上述目的、特征及优点以及其他目的特征及优点将结合下述附图在以下说明中更为明确。
图1为本发明的普氏栖粪杆菌(F.prausnitzii)EB-FPDK11菌株(KCCM12621P)和作为标准菌株(type strain)的普氏栖粪杆菌A2-165菌株的显微镜观察结果。
图2为本发明的普氏栖粪杆菌EB-FPDK11菌株和普氏栖粪杆菌A2-165标准菌株的聚合酶链式反应(PCR)分析结果。
图3为本发明的普氏栖粪杆菌EB-FPDK11菌株和普氏栖粪杆菌A2-165标准菌株的基因组脱氧核糖核酸(DNA)的随机扩增多态性脱氧核糖核酸(RAPD,Random AmplifiedPolymorphic DNA)分析结果。
图4比较示出本发明的普氏栖粪杆菌EB-FPDK11菌株与其他普氏栖粪杆菌菌株的系统发生关系。
图5为分析本发明的普氏栖粪杆菌EB-FPDK11菌株与普氏栖粪杆菌A2-165标准菌株的单链脂肪酸的柱状图。
图6为本发明的普氏栖粪杆菌EB-FPDK11菌株与普氏栖粪杆菌A2-165标准菌株的溶血活性实验结果。
图7为示出诱发特应性皮炎的实验动物在处理本发明的普氏栖粪杆菌EB-FPDK11菌株时的皮肤状态的照片。
图8为示出皮炎指数(dermatitis score)通过本发明的普氏栖粪杆菌EB-FPDK11菌株发生变化的曲线图。
图9为比较示出本发明的普氏栖粪杆菌EB-FPDK11菌株给药组(EB-FPDK11)、地塞米松给药阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的耳部浮肿程度的照片。
图10为分析本发明的普氏栖粪杆菌EB-FPDK11菌株给药组、阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的耳部厚度(ear thickness)的变化的结果。
图11为示出本发明的普氏栖粪杆菌EB-FPDK11菌株给药组、阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的实验动物的抓挠频率(scratch frequency)的柱状图。
图12为本发明的普氏栖粪杆菌EB-FPDK11菌株给药组、阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的脾脏照片。
图13为比较示出本发明的普氏栖粪杆菌EB-FPDK11菌株给药组、阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的脾脏重量的柱状图。
图14为示出本发明的普氏栖粪杆菌EB-FPDK11菌株给药组、阳性对照组(DEX)及普氏栖粪杆菌A2-165标准菌株给药组的作为在介导过敏性疾病中最为重要的免疫指标的IgE的变化的柱状图。
图15为处理磷酸盐缓冲溶液(PBS)或本发明的普氏栖粪杆菌EB-FPDK11菌株的小鼠的苏木精伊红(H&E)染色结果。
图16为确认给药本发明的普氏栖粪杆菌EB-FPDK11菌株给IL-4、IL-6带来的影响的结果。
图17为确认给药本发明的普氏栖粪杆菌EB-FPDK11菌株给血中Th1细胞因子、IFN-γ及IL-12带来的影响的结果。
图18及图19为确认给药本发明的普氏栖粪杆菌EB-FPDK11菌株给血中Th1细胞因子和Th2细胞因子的生成能力带来的影响的结果。
具体实施方式
以下,参照附图更为详细地说明本发明。
若无其他定义,则本申请中使用的所有技术及科学术语与本发明所属技术领域的普通技术人员通常理解的含义相同。
本申请中使用的术语“约”在与引用的特定数值相关来使用时,表示该数值可以与引用的数值具有1%以下的不同。例如,本申请中使用的“约100”的表达包括99和101以及它们之间的所有数值(例如99.1、99.2、99.3、99.4等)。
在本所明书中,当提及某部分“包含”某要素时,若上下文没有特别反对的记载,则表示还可以包含其他结构要素,而不是排除其他结构要素。
本说明书中使用的术语“特应性疾病(atopic disease)”是指发生过敏反应的具有遗传倾向的疾病的一组。特应性疾病的例可以为哮喘、特应性皮炎、过敏性鼻炎(花粉过敏)、荨麻疹、过敏性结膜炎、过敏性反应、血管浮肿、食物过敏等。
本说明书中使用的术语“预防”是指通过给给药本发明的药物组合物来抑制特应性疾病或延迟特应性疾病的发病的所有行为。
本说明书中使用的术语“治疗”、“治疗……”等是指临时或永久缓解症状,或者是指去除症状的原因,或者是指防止或延缓上述疾病或病态症状的表达。
本说明书中使用的术语“改善”是指减少与不正常的状态相关的参数的所有行为,例如降低症状的程度的行为。
本说明书中使用的术语“药学上可接受的”是指在没有过度的毒性、刺激、过敏反应、其他问题或并发症,收益/风险比合理的情况下,适合与对象(例如人类)的组织接触来使用并在健全的医学判断的范围内。
药用益生菌(pharmabiotics)定义为对健康或疾病具有经过检验的药理作用(pharmacological role)的源自人类的细菌或其产物(“Probiotics andpharmabiotics,”Bioeng Bugs.2010Mar-Apr;1(2):79-84.)。本发明的一实施方式涉及包含保藏编号KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株(Faecalibacterium prausnitziiEB-FPDK11)(KCCM12621P)作为有效成分的能够用作药用益生菌制剂的用于预防或治疗特应性疾病的药物组合物。
本发明的保藏编号KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株具有序列1的16s核糖体核糖核酸(rRNA)基因。
本发明中使用的普氏栖粪杆菌EB-FPDK11菌株从健康的韩国人的粪便中分离,为杆状厌氧性细菌,无运动性,为革兰氏阴性、不形成内生孢子的黏蛋白降解性细菌(mucin-degrading bacteria)。可以通过生成几种黏蛋白分解酶将黏蛋白用作碳及氮供应源,可以通过包含葡萄糖、半乳糖、N-乙酰葡糖胺及乳糖来代谢多种碳源,生成丙酸和乙酸等单链脂肪酸作为主要代谢物质。
与过敏性抗原攻击对应生成的IgE触发与特应性疾病相关的强力的激动剂机制。在与肥大细胞及嗜酸性粒细胞上的高亲和性受体结合的情况下,IgE可以与过敏性抗原交叉结合来诱导组氨、白三烯及其他炎症介质的脱颗粒化及释放。这些制剂直接介导与初期及后期过敏反应相关的喘鸣、支气管收缩及鼻炎的症候,通过肥大细胞及嗜碱性粒细胞释放的细胞因子及趋化因子在局部炎症反应中起作用。因此,IgE的中和有望成为在特应性疾病的治疗中奏效的治疗战略。
本发明的普氏栖粪杆菌EB-FPDK11菌株通过碳水化合物的厌氧发酵生成丁酸、乙酸及丙酸等单链脂肪酸(SCFA)。单链脂肪酸受体在巨噬细胞、树枝状细胞及中性粒细胞中表达,可以调节T细胞及B细胞介导反应。单链脂肪酸还在调节T(Treg)细胞的生成及变化中起到重要作用。丁酸诱导调节T细胞的胸腺外分化,丙酸在外周强化调节T细胞的生成。单链脂肪酸还通过抑制组蛋白脱乙酰酶抑制剂活性调节T细胞分化为Th17、Th1及IL-10以及生成T细胞。
特应性皮炎患者的B细胞与单核细胞的低亲和性IgE受体的表达增加,外周血单核细胞中IL-4的分泌增加,干扰素γ的分泌减少,结果为IgE的生成增加。特应性患者在辅助型T细胞的亚群中,增加主要分泌IL-4、IL-5的Th2细胞,而分泌IL-2和INF-γ的Th1细胞相对降低。IL-4在生成免疫球蛋白时诱导向IgE的分化,通过激活粘附分子帮助单核细胞或嗜酸性粒细胞等炎症细胞向发生炎症的组织细胞移动。IL-5延长嗜酸性粒细胞的生存时间,在嗜碱性粒细胞中促进组胺的分泌。在过敏性疾病中存在选择性靶向记忆Th2细胞(selective target memory Th2 cells),选择性地在靶向器官中引起病变。
本发明的用于预防或治疗特应性疾病的药物组合物在Th2占优势的状况下起到保持Th1/Th2的均衡的作用。因此,在因Th2反应过剩引起的Th1/Th2不均衡诱发的特应性皮炎、哮喘及鼻炎等的预防或治疗中有效。通常,在特应性皮炎中,细胞因子浓度的变化已知为通过基于非常促进未分化的辅助型T细胞1(Th1)向辅助型T细胞2分化的Th2的激活的免疫体系来诱发的。在这样的Th2细胞的激活过程中,Th2细胞生成IL-4、IL-5、IL-6、IL-13、IL-9及IL-10。
本发明的用于预防或治疗特应性疾病的药物组合物可以包含普氏栖粪杆菌EB-FPDK11菌株的活菌剂或巴氏杀菌的菌株。本发明的普氏栖粪杆菌EB-FPDK11菌株可以在培养后,通过离心分离等过程回收,然后通过干燥,例如通过冷冻干燥制备为活菌剂形态来使用。普氏栖粪杆菌菌株的巴氏杀菌是指在大于等于50℃且小于100℃的温度下加热10分钟以上。例如,可以在70℃的温度下巴氏杀菌30分钟。
相对于组合物总重量,本发明的药物组合物可以包含108CFU至1012CFU普氏栖粪杆菌EB-FPDK11菌株或者具有同等数量的活菌的培养物作为有效成分。
在本发明的一实例中,包含上述普氏栖粪杆菌EB-FPDK11菌株的药物组合物可以根据通常的方法配制为散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳剂、糖浆、喷剂等口服剂型,外用剂、栓剂或灭菌注射溶液的形态来使用,但不限定于此。
本发明的药物组合物可以配制为肠内或口服给药用制品。并且,本发明的药物组合物可以使用公知的方法配制为肠溶包装,以在通过胃肠到达小肠以后在肠内迅速释放作为活性物质的微生物。
在本发明的一实例中,用于口服给药的液体制剂有悬混剂、内溶液剂、乳剂、糖浆剂等,除常用的作为单纯稀释剂的水、液体石蜡以外,还可以包含赋形剂,例如包含湿润剂、甜味剂、芳香剂、保存剂等,但不限定于此。
在其他实施例中,本发明的用于预防或治疗特应性疾病的药物组合物还可以包含至少一种维生素。上述维生素可以为脂溶性或水溶性维生素。适当的维生素包括维生素D、维生素C、维生素A、维生素E、维生素B12、维生素K、维生素B2、烟酸、维生素B6、叶酸、吡哆醇、泛酸及生物素,但不限定于此。上述任意适当的形态为维生素的盐、维生素的衍生物、具有相同或相似活性的维生素的化合物及维生素的代谢产物。
本发明的用于预防或治疗特应性疾病的药物组合物还可以包含具有预防及治疗特应性疾病的效果的公知的追加治疗剂。本发明中可接受的追加治疗剂为免疫抑制剂、镇痛剂、类固醇、非-类固醇类抗炎剂(NSAID)或细胞因子拮抗剂及它们的组合。上述免疫抑制剂可以例示糖皮质激素(Glucocorticoid)、环孢菌素(Cyclosporine)、他克莫司(Tacrolimus)、吡美莫司(Pimecrolimus)、包含ISA(TX)247的钙调神经磷酸酶(calcineurin)抑制剂、雷帕霉素(Rapamycin)、磷酸二酯酶4抑制剂(磷酸二酯酶4inhibitors)、吗替麦考酚酯(Mycophenolate Mofetil)、地塞米松等,但不限定于此,可以一同使用公知的所有免疫抑制剂。并且,可以单独使用一种免疫抑制剂,也可以组合两种以上的免疫抑制剂来使用,优选地,上述免疫抑制剂可以使用选自由环孢菌素、他克莫司、地塞米松、吡美莫司组成的组中的一种以上。在本发明的药物组合物与其他治疗剂联合来给药时,可以依次或同时给药,可以单次或多次给药。
除上述有效成分以外,本发明的药物组合物还可以包含制药学上可接受的载体和/或赋形剂,此外,还可以与粘合剂、分解剂、涂层剂、润滑剂等制药学上通常使用的多种添加剂一同配制来制备。
本发明中可接受的赋形剂包括蔗糖、乳糖、甘露醇、葡萄糖等糖以及玉米淀粉、马铃薯淀粉、大米淀粉、部分预明胶化的淀粉等淀粉。粘合剂包括葡聚糖、海藻酸钠、卡拉胶、瓜尔豆胶、阿拉伯胶、琼脂等多糖、黄芪胶、明胶、谷蛋白等天然大分子物质、羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、羟丙基乙基纤维素、羧甲基纤维素钠等纤维素衍生物以及聚乙烯吡咯烷酮、聚乙烯醇、聚醋酸乙烯酯、聚乙二醇、聚丙烯酸、聚甲基丙烯酸以及醋酸乙烯酯树脂等高分子。
本发明中可接受的分解剂可以使用羧甲基纤维素、羧甲基纤维素钙、低取代羟丙基纤维素等纤维素衍生物以及羧甲基淀粉钠、羟丙基淀粉、玉米淀粉、马铃薯淀粉、大米淀粉以及部分预明胶化的淀粉等淀粉。
本发明中可接受的润滑剂的例包括滑石粉、硬脂酸、硬脂酸钙、硬脂酸镁、胶体二氧化硅、水合二氧化硅、多种蜡以及氢化油。
涂层剂包括甲基丙烯酸二甲基氨基乙酯-甲基丙烯酸共聚物、聚乙烯乙醛二乙胺乙酸酯、丙烯酸乙酯-甲基丙烯酸共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸乙酯三甲基氯化铵共聚物、乙基纤维素等非水溶性聚合物、甲基丙烯酸-丙烯酸乙酯共聚物、邻苯二甲酸羟丙基纤维素、醋酸羟丙甲纤维素琥珀酸酯等的肠性聚合物以及甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇等水溶性聚合物,但不限定于此。
在本发明的用于预防或治疗特应性疾病的药物组合物中,作为有效成分的上述菌株的给药量可以根据包括多种疾病的类型、患者的年龄、体重、性别、患者的医学状态、状态的严重程度、对于药物的敏感度、给药时间、给药途径及代谢比例、治疗期间、同时使用的药物在内的因素以及其他医学领域中众所周知的因素来决定。因此,虽然剂量及治疗方法可以在大范围内变化,但重要的是在考虑上述所有因素后能够以无副作用的最小的量获得最大效果的量来给药,这可以通过相关从业者使用标准方法来轻松确定。
通常,在成人患者的情况下,可以根据需要将1×108以上的活菌或巴氏杀菌的细菌一次或分为多次来给药。在本发明的一实例中,上述用于预防或治疗特应性疾病的药物组合物只要是包含上述普氏栖粪杆菌EB-FPDK11菌株,其含量就不受特别限制,例如,能够以1×108细胞/ml至1×1012细胞/ml的浓度包含上述普氏栖粪杆菌EB-FPDK11菌株,但不限定于此。例如,上述普氏栖粪杆菌EB-FPDK11菌株的浓度可以为1×108细胞/ml至1×1010细胞/ml、2×108细胞/ml至1×1010细胞/ml、3×108细胞/ml至1×1010细胞/ml、5×108细胞/ml至1×1010细胞/ml、1×108细胞/ml至5×109细胞/ml、2×108细胞/ml至5×109细胞/ml、3×108细胞/ml至5×109细胞/ml、5×108细胞/ml至5×109细胞/ml,但不限定于此。
本发明的另一实施方式涉及包含普氏栖粪杆菌EB-FPDK11菌株、其培养物或干燥物的食品或保健功能食品。
含有本发明的菌株的食品可以作为牛奶或乳制品等食品或者营养制品或者食品辅助剂或者保健功能食品来摄取。根据本发明的一实例,上述制品可以为例如乳制品、饮料水、果汁、汤或者儿童食品等食品,但不限定于此。
本发明的又一实施方式涉及包含普氏栖粪杆菌EB-FPDK11菌株、其培养物或干燥物的缓解或改善特应性皮炎的化妆品组合物。
除上述有效成分以外,本发明的化妆品组合物可以包含化妆品组合物中通常使用的成分,例如,可以包含抗氧化剂、稳定剂、溶解剂、维生素、颜料以及香料等通常的辅助剂,而且还可以包含载体。
上述化妆品组合物的特征可以在于,具有改善选自由皮肤过敏、皮疹、特应性皮炎、银屑病、真菌引起的感染以及湿疹组成的组中的一种以上皮肤状态的功能性,但其功能不限定于此。
本发明的化妆品组合物可以制备为相关行业通常制备的任意剂型,例如,可以配制溶液、悬混液、乳浊液、膏、凝胶、霜剂、乳液、粉、香皂、含表面活性剂的洗剂、油、粉底霜、粉状粉底霜、乳浊液粉底霜、蜡状粉底霜、面膜、按摩霜、及喷雾剂等,但不限定于此。更详细地,可以制备为柔肤化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、洁面霜、洁面泡沫、洁面水、面膜、喷雾剂或粉等剂型。
以下,通过实施例详细说明本发明。但下述实施例仅用于例示本发明,本发明的不限定于下述实施例。
实施例
实施例1:分离及鉴定普氏栖粪杆菌EB-FPDK11菌株
1.1.分离及鉴定菌株
为了从健康的韩国人(女性,9岁,BMI 15.5)的粪便中分离普氏栖粪杆菌,根据Martin的方法利用厌氧性腔室在严格的无氧条件(5%的H2、15%的CO2以及80%的N2)下,利用添加了0.5%的酵母提取物、0.1%的D-纤维二糖、0.1%的D-麦芽糖的YBHI培养基(添加0.5%的酵母提取物的脑心浸液培养基(brain heart infusion medium supplementedwith 0.5%yeast extract))(Difco公司生产、美国底特律)培养后,筛选极高氧敏感性(EOS,Extremely Oxygen Sensitivity)菌种后进行分离。
1.2.显微镜观察
为了确认分离的菌株是否为普氏栖粪杆菌菌株,使用显微镜观察分离的菌株。如图1所示,以1000倍的倍率放大来观察作为标准菌株的普氏栖粪杆菌A2-165标准菌株(A)与普氏栖粪杆菌EB-FPDK11菌株(B)的结果,确认到菌株的形状都是类似于直或弯曲的杆形的形状。
1.3.聚合酶链式反应(PCR)分析
为了确认是否为普氏栖粪杆菌菌株,使用下述表1所示的FP特异性引物(序列2及序列3)对分离的菌株实施聚合酶链式反应分析。结果如图2所示,可以确认显出与作为阳性对照组菌株的普氏栖粪杆菌A2-165菌株的条带相似的结果值。
表1
1.4.随机扩增多态性脱氧核糖核酸(Random Amplified Polymorphic DNA,RAPD) 分析
为了验证上述分离的普氏栖粪杆菌EB-FPDK11菌株是否为与已报告的同种普氏栖粪杆菌A2-165标准菌株相同的菌株,实施了作为分子分型的一种的随机扩增多态性脱氧核糖核酸(RAPD)。为此,以从菌体中提取的基因组脱氧核糖核酸为对象,利用下述表2所示的常用引物扩增脱氧核糖核酸后,在1%的琼脂糖凝胶中电泳1小时30分钟,在紫外线(UV)打孔机上比较脱氧核糖核酸分节图案,结果如图3所示。
表2
名称 | 方向 | 序列(5′→3′) | 序列编号 |
ERIC-1 | 正向 | ATG TAA GCT CCT GGG GAT TCA C | 序列4 |
ERIC-2 | 反向 | AAG TAA GTG ACT GGG GTG AGC G | 序列5 |
(GTG)5 | 正向/反向 | GTG GTG GTG GTG GTG | 序列6 |
如图3所示,确认到比较本发明的普氏栖粪杆菌EB-FPDK11菌株与普氏栖粪杆菌A2-165标准菌株时,显出不同的RAPD条带。因此,确认到本发明的普氏栖粪杆菌EB-FPDK11菌株虽然与普氏栖粪杆菌A2-165标准菌株是同种,但却是不同的菌株。
1.5.16s核糖体核糖核酸局部序列排比搜索基本工具(BLAST)
为了确认分离的菌株是否为普氏栖粪杆菌菌株,分析16s核糖体核糖核酸碱基序列后,使用局部序列排比搜索基本工具(BLAST,Basic local alignment search tool)进行确认的结果,确认到与普氏栖粪杆菌种99%以上的一致性。
1.6.利用全长16s核糖体核糖核酸基因碱基序列的系统发生树(phylogenetic tree)分析
为了分析上述分离的普氏栖粪杆菌EB-FPDK11菌株的全长(full-length)16s核糖体核糖核酸基因碱基序列,利用下述表3所示的27F及1492R引物扩增16s核糖体核糖核酸基因后,利用3730xl DNA分析仪确定碱基序列。利用如上所述获得的本发明的EB-FPDK11菌株及已公布的同种的其他菌株的16s核糖体核糖核酸基因碱基序列绘制系统发生树(phylogenetic tree)的结果如图4所示。
表3
名称 | 方向 | 序列(5′→3′) | 扩增子大小 | 序列编号 |
27F | 正向 | AGA GTT TGA TCM TGG CTC AG | 1465bp | 序列7 |
1492R | 反向 | GGT TAC CTT GTT ACG ACT T | 1465bp | 序列8 |
如图4所示,通过系统发生树分析通过16s核糖体核糖核酸基因碱基序列分析得出的进化学亲缘关系的结果,确认到普氏栖粪杆菌EB-FPDK11菌株在遗传学上是属于普氏栖粪杆菌种的菌株。通过以普氏栖粪杆菌(A2-165)为对照组的生物化学方法(API)及分子生物学方法(16s核糖体核糖核酸序列分析、16s核糖体核糖核酸局部序列排比搜索基本工具分析、随机扩增多态性脱氧核糖核酸)鉴定从人类粪便中分离的本发明的普氏栖粪杆菌EB-FPDK11菌株,通过后述的抗生素耐药性检查确认到是可以具有益生菌的功能的安全的菌株。基于上述结果将分离的普氏栖粪杆菌菌株命名为“普氏栖粪杆菌EB-FPDK11”菌株,保藏在韩国微生物保藏中心(KCCM),保藏编号为KCTC 12398BP。
实施例2:分析普氏栖粪杆菌EB-FPDK11菌株的特性及安全性
2.1.分析功能性代谢物(单链脂肪酸)
为了确认分离的普氏栖粪杆菌EB-FPDK11菌株的功能性代谢物,通过气相色谱法分析培养液中含有的单链脂肪酸(SCFA,short chain fatty acids)的含量。为此,在YBHI培养基(添加0.5%(w/v)的酵母提取物(Difco公司)、0.1%(w/v)的D-纤维二糖、0.1%(w/v)的D-麦芽糖的脑心浸液培养基(Brain-heart
infusion medium supplemented with 0.5%w/v yeast extract(Difco公司),0.1%w/v Dcellobiose,0.1%w/v D-maltose))中培养菌株24小时后,在12000Хg的条件下离心分离5分钟来获得上清液,使用0.2μm的针筒式过滤器过滤上清液后用于分析。使用了安装有FFAP气相色谱柱(column)(30m×0.320mm,0.25μm phase)的气相色谱仪(Agilent7890N),条件的设定如下述表4所示。
表4
分析功能性单链脂肪酸的结果,如图5的柱状图所示,确认到本发明的普氏栖粪杆菌EB-FPDK11菌株消耗乙酸并生成丁酸。
2.2.确认抗菌剂敏感性
为了掌握如上所述分离的普氏栖粪杆菌EB-FPDK11菌株的抗菌剂敏感性,根据美国临床和实验室标准协会(Clinical&Laboratory Standard Institute,CLSI)指导的液基微量稀释(broth microdilution)方法确定对厌氧性细菌用抗菌剂哌拉西林/他唑巴坦(PTZ)、头孢替唑(CTZ)、氯霉素(CHL)、克林霉素(CLI)、美罗培南(MEM)、莫西沙星(MXF)、甲硝哒唑(MTZ)、环丙沙星(CIP)的最小抑菌浓度(minimum inhibitory concentration,MIC)(CLSI,2017),结果如下述表5所示。
表5
如表5所示,可知本发明的普氏栖粪杆菌EB-FPDK11菌株对哌拉西林/他唑巴坦、头孢替唑、美罗培南以及作为氟喹诺酮系列抗生素的莫西沙星和环丙沙星(CIP)显出耐药性,对氯霉素、克林霉素以及甲硝哒唑显出敏感性。与标准菌株(A2-165)比较,在对氯霉素抗生素的耐药性上有较大差异。
2.3.溶血活性(hemolytic activity)分析
为了验证如上所述分离的普氏栖粪杆菌EB-FPDK11菌株的安全性,评估了是否保有溶血活性。为此,利用向胰蛋白酶大豆琼脂(17.0g/L的酪蛋白的胰腺消化物、3.0g/L的大豆的胰腺消化物、2.5g/L的葡萄糖、5.0g/L氯化钠、2.5g/L的磷酸钾、15g/L的琼脂)加入5%(w/v)的脱纤维绵羊血(defibrinated sheep blood)制备的血液琼脂培养基培养菌株,结果如图6所示。
如图6所示,可知本发明的普氏栖粪杆菌EB-FPDK11菌株在菌落周围不出现完全透明的部分,确认到不引起与病原性相关的β-溶血(β-hemolysis)。
实施例3:确认普氏栖粪杆菌菌株治疗特应性疾病的功效
3.1.菌株试样
本实验中使用的普氏栖粪杆菌A2-165标准菌株与普氏栖粪杆菌EB-FPDK11活菌制备为1×108CFU/150μl磷酸盐缓冲溶液(PBS)(25%的丙三醇,0.05%的半胱氨酸/磷酸盐缓冲溶液)的浓度。
3.2.动物模型及取样
为了观察特应性皮炎病变,从DaehanBiolink公司(忠清道,韩国)获得6周龄的体重为21g-25g左右的雄性NC/Nga小鼠(SLC Inc公司,日本(Japan))。动物实验是在遵守机构动物护理和使用委员会(Institutional Animal Care and Use Committee,IACUC)的试验动物使用和护理协议(Animal use and Care Protocol)来进行。经过一周的适应期间后,进行9周的饲育,饲育环境在保持规定的温度(22℃)和相对湿度(40%~60%)的条件下以12小时的周期调节明暗来饲育。
3.3.诱发特应性皮炎
将6周龄的NC/Nga小鼠的背部干净地去毛后,放置24小时以使皮肤微小的伤口治愈。以一周两次的频率在小鼠的背部涂敷1%的2,4-二硝基氯苯(DNCB)溶液(Sigma-Aldrich韩国(Korea)公司)共三周来诱发免疫反应后,一周涂敷两次0.5%的2,4-二硝基氯苯来诱发接触性皮炎。除正常组的所有组都诱发了严重的伤口和糜烂引起的特应性皮炎。本实施例中使用的DNCB是在以3∶1的比例混合丙酮与橄榄油的溶液中稀释为0.5%和1%来使用的。
利用各相关药物诱发特应性皮炎后,在6周内每天实施口服给药。作为阳性对照组,使用蒸馏水将地塞米松稀释为60μg/ml的浓度,每天口服给药200μl(参照表6)。
表6
组 | 给药组 | 给药药物 |
组I | 正常组(Normal) | 磷酸盐缓冲溶液(PBS) |
组II | 特应性诱导组(DNCB-特应性诱导) | 磷酸盐缓冲溶液 |
组III | A2-165标准菌株给药组 | A2-165活菌,1×108CFU |
组IV | EB-FPDK11菌株给药组 | EB-FPDK11活菌,1×108CFU |
组V | 阳性对照组(地塞米松给药组) | 60μg/ml,200μl |
3.4.评估特应性皮炎
通过DNCB诱发特应性皮炎后,使用含有地塞米松、ATCC BAA-835菌株及EB-AMDK19菌株的药剂治疗6周,为了确认临床症状,确认了将皮肤状态分数化的皮炎指数(dermatitis score)。修正了作为特应性皮炎中通常使用的临床肉眼评估法的特应性皮炎积分(SCORAD,Scoring Atopic Dermatitis)指数,以临床肉眼评估法实施感官评估。检测如下皮肤状态:皮肤干燥状态(dryness)、浮肿(edema)、红疹和出血(erythema/hemorrhage)、糜烂和伤口(erosion/excoriation),已如下方式打分:无症状(0分)、症状轻(1分)、普通(2分)、症状严重(3分)。评估结果如图7及图8所示。
在6周的治疗期间以间隔一周的方式通过肉眼观察各组的皮肤状态来测定皮炎指数(Dermatitis score),可以确认特应性诱导组(DNCB)在6周期间保持特应性皮炎的症状,与之相反,在给药A2-165标准菌株、EB-FPDK11菌株以及地塞米松的实验组中,特应性皮炎的症状显著减少。
在第6周的以皮炎指数为基准的数值评估中,与特应性诱导组(DNCB)相比,可以在A2-165标准菌株给药组(P=0.02)及本发明的EB-FPDK11给药组(P=0.02)分别确认到32.5%、30.9%的减少现象。确认到与普氏栖粪杆菌A2-165标准菌株给药组相比,本发明的EB-FPDK11菌株给药组显出更优秀的特应性皮肤状态改善效果。
3.5.给因特应性皮炎引起的耳部浮肿带来的影响
实验结束后,使用CO2麻醉小鼠来安乐死后,使用厚度测量仪(thickness gauge,Digimatic thickness gauge,547-301,三丰(Mitutoyo)公司,日本(Japan))通过速度变化法来测量小鼠双侧耳部的浮肿程度,结果如图9及图10所示。
NC/Nga小鼠的耳部浮肿在第6周中,正常组为0.55mm,特应性诱导组(DNCB)为1.50mm,A2-165给药组为1.37mm,EB-FPDK11给药组为1.16mm(P=0.02),阳性对照组(DEX)为1.00mm(P<0.001)。通过耳部浮肿状态来观察特应性程度的结果,在阳性对照组(DEX)中显出最优秀的特应性改善效果,并且在普氏栖粪杆菌A2-165标准菌株和EB-FPDK11菌株给药组中也都显出优秀的特应性改善效果。如上所述,可以确认本发明的药物组合物在DNCB-诱发的小鼠的耳部浮肿动物模型中具有显著的浮肿抑制效果。
3.6.测量抓挠分数(Scratching score)
在实验结束前一天测量各组因瘙痒引起的患处抓挠频率。抓挠频率(scratchingfrequency)测量是在给小鼠10分钟的适应期间后使用计数器测量10分钟的抓挠频率。
参照图11,与正常组比较时,处理DNCB的特应性皮炎诱导组抓挠身体的频率显著增加(P<0.001)。确认到普氏栖粪杆菌A2-165标准菌株给药组与本发明的普氏栖粪杆菌EB-FPDK11给药组的抓挠次数分别比特应性诱导组减少69.4%(P=0.01)、76.19%(P=0.01)。阳性对照组的抓挠频率显出比特应性诱导组(DNCB)较少59.4%(P=0.03)左右。因此,可以确认无论是与给药地塞米松的阳性对照组相比,还是与普氏栖粪杆菌A2-165标准菌株给药组相比,本发明的普氏栖粪杆菌EB-FPDK11给药组都显出更为优秀的抗瘙痒效果。
3.7.测量脾脏重量及大小
脾脏是显出一级淋巴器官和二级淋巴器官的所有特性的器官,由过滤红细胞的红髓(red pulp)与显出体液免疫和细胞免疫活性的白髓(white pulp)构成,是免疫反应中的又一重要器官(Mebius,R E and Kraal,G 2005Structure and function of the spleenNat Rev Immunol 5,pp606-616)。并且,脾脏是进行B细胞发生的最终阶段的场所,同时,具有对血液来源的抗原产生反应的特化器官的功能(Boehem,T and Bleul,CC 2007Theevolutionary history of lymphoid organs Nat.Immunol 8,131-135)。特应性皮炎的反应在免疫器官内诱导多种反应,这些反应会一次性地给作为免疫器官的脾脏的重量带来影响。
因此,为了观察本发明的用于预防或治疗特应性疾病的组合物给通过DNCB诱导特应性皮炎的NC/Nga小鼠的免疫器官带来的影响,测量了脾脏(spleen)的重量。更具体地,实验结束后,使用CO2麻醉实验动物后通过脊椎脱臼法安乐死后开腹摘取脾脏组织。使用生理盐水清洗上述摘取的脾脏组织并去除水分后,使用微量天平测量重量并用肉眼观察其大小。结果如图12及图13所示。
确认到特应性诱导组(DNCB)的脾脏重量比正常组增加约2倍(P<0.001),在A2-165标准菌株给药组、EB-FPDK11菌株给药组、地塞米松给药组中,与特应性诱导组(DNCB)相比,分别减少17.37%(P=0.010)、19.98%(P=0.0006)、23.26%(P=0.007)。尤其,在普氏栖粪杆菌A2-165标准菌株和本发明的EB-FPDK11菌株给药组中都表现出与阳性对照组(DEX)相似的效果。因此,可以确认包含本发明的EB-FPDK11菌株的组合物抑制免疫的效果优秀。
3.8.测量血清内IgE浓度
实验结束时使用CO2麻醉后,通过心脏穿刺采取血液,以10000rpm的转速离心分离采取的血液5分钟分离血清(serum)来测量IgE浓度,结果如图14所示。IgE浓度测量使用了酶联免疫吸附测定(ELISA)试剂盒(未包被(uncoated)IgE的小鼠酶联免疫吸附测定试剂盒(IgE mouse uncoated ELISA kit),cat#88-50460,Invitrogen,加利福尼亚州(CA),美国(USA))。
参照图14,在特应性诱导组(DNCB)中,血清内IgE的生成量比正常组增加约13倍(1545.08ng/ml,P<0.001),但在普氏栖粪杆菌A2-165标准菌株给药组与本发明的普氏栖粪杆菌EB-FPDK11菌株给药组中都比处理2,4二硝基氯苯的对照组显著减少。在给药A2-165菌株、EB-FPDK11菌株、地塞米松(DEX)的给药组中,与特应性诱导组(DNCB)相比,分别减少32.23%、40.00%、40.70%,确认到显著减少(P<0.001)。因此,确认含有本发明的EB-FPDK11菌株的组合物的IgE生成抑制功效与地塞米松给药组中的效果匹敌,在缓解特应性症状方面效果显著。
3.9.组织病理学观察
实验结束时安乐死小鼠后,摘取皮肤并在10%的甲醛溶液中固定后制备石蜡块来制备切片后,实施苏木精伊红(hematoxylin&eosin,H&E)染色后使用光学显微镜放大200倍来观察表皮层及真皮层的厚度变化,结果如图15所示。
通过苏木精伊红染色观察NC/Nga小鼠的背部皮肤组织的结果如图15所示,与正常组相比,在特应性诱导组(DNCB)中观察到表皮层向真皮层变后下沉扩张的肥厚化、皮肤屏障的严重损伤以及炎症细胞浸润增加的组织病理学现象。在显微镜观察时,在普氏栖粪杆菌给药组和阳性对照组(DEX组)都观察到炎症细胞的浸润减少的状态,诱发特应性皮炎时观察到的表皮厚度和真皮厚度都扩张的现象得到抑制,显出与正常组相似的组织病理学特征。
图15的(A)部分示出将角化过度症(hyperkeratosis)和上皮肥大增生(hyperplasia)现象分数化为正常组的厚度为0分,正常组厚度的2倍为1分,3倍为2分,4倍为3分,4倍以上为4分,以此来在组织学上等级化。
如图15的(B)部分及(C)部分的柱状图所示,确认到与正常组相比,角化过度症和上皮肥大增生现象在特应性诱导组(DNCB)中显著增加3倍~4倍,而与特应性诱导组(DNCB)相比,包括阳性对照组在内,在普氏栖粪杆菌A2-165标准菌株和本发明的普氏栖粪杆菌EB-FPDK11中都被显著抑制。尤其,在给药本发明的普氏栖粪杆菌EB-FPDK11的组中,与A2-165标准菌株相比,角化过度症和上皮肥大增生现象显著减少,可观察到与阳性对照组(DEX)相似的组织病理学现象。
3.10.测量血清内细胞因子浓度
为了确认诱导特应性皮炎后给药本发明的普氏栖粪杆菌EB-FPDK11菌株的免疫反应,测量了与Th1和Th2相关的细胞因子的浓度。所有实验的统计使用了GraphPad Prism7.04.One-way ANOVA。
实验结束时使用CO2麻醉后,通过心脏穿刺采取血液,以10000rpm的转速离心分离采取的血液10分钟分离血清后在-80℃的温度下保管。使用酶联免疫吸附测定试剂盒(Invitrogen公司,加利福尼亚州,美国)测量IL-4、IL-12、IFN-γ、IL-6等细胞因子的浓度,结果如图16及图17所示。
首先,确认诱导Th2细胞的活性并已知为炎症反应指标的细胞因子IL-4与IL-6的浓度。如图16的(A)部分所示,在作为特应性诱导组的特应性诱导组(DNCB)中,与正常组相比,IL-4的浓度增加20.54%(P=0.02)。并且,与特应性诱导组相比,作为阳性对照组的阳性对照组(DEX)、普氏栖粪杆菌A2-165标准菌株以及本发明的普氏栖粪杆菌EB-FPDK11给药组都显著减少,测量到正常组水平的IL-4浓度。并且,测量小鼠血中IL-6的浓度的结果,可以确认在特应性诱导组(DNCB)中,比正常组增加1.54倍(P=0.009),与特应性诱导组(DNCB)相比,阳性对照组(DEX)减少35.5%(P=0.009),普氏栖粪杆菌A2-165标准菌株减少41.8%(P=0.003),本发明的EB-FPDK11给药组减少40.7%(P=0.01)(参照图16的(B)部分)。
3.11.EB-FPDK11菌株给血中Th1细胞因子、IFN-γ以及IL-12带来的影响
在本实验中,测量作为Th1细胞因子的IFN-γ及作为其诱导剂(inducer)的IL-12的结果,如图17所示,确认到在普氏栖粪杆菌EB-FPDK11给药组中都显著增加。测量IL-12浓度的结果,与正常组相比,特应性诱导组(DNCB)显著减少(P=0.03),与特应性诱导组(DNCB)相比,在阳性对照组(P=0.008)、普氏栖粪杆菌A2-165标准菌株(P=0.03)给药组、EB-FPDK11给药组(P=0.004)中显著增加。尤其,与A2-165标准菌株给药组相比,本发明的EB-FPDK11给药组示出更显著的增加结果。而小鼠的血中IFN-γ的浓度,与特应性诱导组(DNCB)相比,阳性对照组(DEX)给药组(P=0.03)与普氏栖粪杆菌EB-FPDK11(P=0.03)分别显著增加。因此,确认到给药本发明的普氏栖粪杆菌EB-FPDK11菌株在通过促进血清IL-12及IFN-γ的生成来诱导Th1分化方面示出比地塞米松更好的功效。
3.12.在特应性实验动物中给药EB-FPDK11菌株给Th1和Th2细胞因子的生成能力
带来的影响
从免疫学观点来说,过敏性特应性皮炎是因Th1和Th2特定免疫反应过度发声而打破平衡引起的疾病。因此,基于前面测量的细胞因子的浓度而表示为Th2/Th1细胞因子的比例如图18及图19所示。
参照图18的(A)部分,分析IL-4/IFN-γ的结果,确认到与正常组相比,特应性诱导组(DNCB)显著增加,与特应性诱导组(DNCB)相比,普氏栖粪杆菌A2-165标准菌株、EB-FPDK11菌株给药组都显著减少,与阳性对照组(DEX)的水平相似。分析IL-4/IL-12的结果,特应性诱导组(DNCB)比正常组增加35.4%(P=0.02)。这表示在特应性皮炎中有代表性地出现的Th2细胞因子的增加。在包括阳性对照组(DEX)在内的作为普氏栖粪杆菌给药组的A2-165标准菌株和EB-FPDK11给药组中,都确认到数值比特应性诱导组(DNCB)显著减少(分别为DEX:23.7%(P=0.02),A2-165:30.4%(P=0.002),EB-FPDK11:23.0%(P=0.04))(参照图18的(B)部分)。
并且,参照图19,可以确认到IL-6/IFN-γ和IL-6/IL-12的比例都示出与前述结果相似的情况。观察IL-6/IFN-γ的比例,确认到特应性诱导组(DNCB)比正常组显著增加,与DNCB组相比,阳性对照组(DEX)、普氏栖粪杆菌A2-165标准菌株及EB-FPDK11都显著减少(参照图19的(A)部分)。
参照图19的(B)部分,IL-6/IL-12的比例,特应性诱导组(DNCB)比正常组增加58%(P=0.02),相反,与特应性诱导组(DNCB)相比,阳性对照组(DEX)减少35.8%(P=0.002),普氏栖粪杆菌A2-165标准菌株减少46.8%(P=0.01),EB-FPDK11给药组减少44%(P=0.04)。
综合考察来看,确认到与正常组相比,诱导特应性皮炎的小鼠中的IL-4/IFN-γ、IL-4/IL-12、IL-6/IFN-γ及IL-6/IL-12都增加,而观察到本发明的普氏栖粪杆菌EB-FPDK11菌株抑制其增加。也就是说,确认到本发明的普氏栖粪杆菌EB-FPDK11菌株的摄取抑制诱发特应性时诱导的Th2细胞因子IL-4、IL-6的生成,其结果为抑制IgE的过度生成。并且,可以解释为促进Th1细胞因子IFN-γ、IL-12的生成以实现Th1与Th2的免疫平衡,从而起到有效地使特应性皮炎好转的作用。
包含本发明的普氏栖粪杆菌EB-FPDK11菌株(Faecalibacterium prausnitziiEB-FPDK11)作为有效成分的用于预防或治疗特应性疾病的药物组合物治疗特应性疾病的效果突出,尤其,卓越地改善了现有益生菌制剂的局限性,表现出与地塞米松等类固醇类药物同等水平的预防、改善或治疗特应性疾病的效果,因此在产业上的可应用性大。
本说明书中记载的具体实施例仅用于说明本发明的优选实例,而不应解释为限制本发明。本发明在不脱离其思想及范围的情况下能够以多种变形及变化来实施,这些事实是本发明所属技术领域中的普通技术人员应该自明的。本发明的保护范围应由随附的发明要求保护范围来定义,上述多种变形及变化意图包括在本发明的保护范围中。
保藏编号
保藏机构名称:韩国微生物保藏中心(国外)
保藏编号:KCCM12621P
保藏日期:2019年11月01日
国际承认用于专利程序的微生物保藏布达佩斯条约
对于原保藏的保藏证书
国际格式
保藏人:安泰微生物科技有限公司 国际保藏机构根据规则
地址:韩国京畿道高阳市一山东区 7.1签发的原始保藏文件
东国路32号,东国大学, 在本页底部
产学协同大厦,#347
1:根据规则6.4,该日期为获得国际保藏机构保藏地位的日期
样式BP/4(单页)
序列表
<110> 安泰微生物科技有限公司
<120> 包含普氏栖粪杆菌菌株的用于预防或治疗特应性疾病的药物组合物
<130> ETB-P2105
<150> PCT/KR 2021/002433
<151> 2021-02-26
<150> KR 10-2020-0107619
<151> 2020-08-26
<160> 8
<170> KoPatentIn 3.0
<210> 1
<211> 1433
<212> DNA
<213> 未知
<220>
<223> 普氏栖粪杆菌(Faecalibacterium prausnitzii)
<400> 1
gacgaacgct ggcggcgcgc ctaacacatg caagtcgaac gagcgagaga gagcttgctt 60
tctcgagcga gtggcgaacg ggtgagtaac gcgtgaggaa cctgcctcaa agagggggac 120
aacagttgga aacgactgct aataccgcat aagcccacag gtcggcatcg accagaggga 180
aaaggagcaa tccgctttga gatggcctcg cgtccgatta gctagttggt gaggtaacgg 240
cccaccaagg caacgatcgg tagccggact gagaggttga acggccacat tgggactgag 300
acacggccca gactcctacg ggaggcagca gtggggaata ttgcacaatg ggggaaaccc 360
tgatgcagcg acgccgcgtg gaggaagaag gtcttcggat tgtaaactcc tgttgttgag 420
gaagataatg acggtactca acaaggaagt gacggctaac tacgtgccag cagccgcggt 480
aaaacgtagg tcacaagcgt tgtccggaat tactgggtgt aaagggagcg caggcgggaa 540
gacaagttgg aagtgaaatc tatgggctca acccataaac tgctttcaaa actgtttttc 600
ttgagtagtg cagaggtagg cggaattccc ggtgtagcgg tggaatgcgt agatatcggg 660
aggaacacca gtggcgaagg cggcctactg ggcaccaact gacgctgagg ctcgaaagtg 720
tgggtagcaa acaggattag ataccctggt agtccacacc gtaaacgatg attactaggt 780
gttggaggat tgaccccttc agtgccgcag ttaacacaat aagtaatcca cctggggagt 840
acgaccgcaa ggttgaaact caaaggaatt gacgggggcc cgcacaagca gtggagtatg 900
tggtttaatt cgacgcaacg cgaagaacct taccaagtct tgacatccct tgacgaacat 960
agaaatgtgt tttctcttcg gagcaaggag acaggtggtg catggttgtc gtcagctcgt 1020
gtcgtgagat gttgggttaa gtcccgcaac gagcgcaacc cttactgtca gttactacgc 1080
aagaggactc tggcaggact gccgttgaca aaacggagga aggtggggat gacgtcaaat 1140
catcatgccc tttatgactt gggctacaca cgtactacaa tggcgttaaa caaagagaag 1200
caagaccgcg aggtggagca aaactcagaa acaacgtccc agttcggact gcaggctgca 1260
actcgcctgc acgaagtcgg aattgctagt aatcgtggat cagcatgcca cggtgaatac 1320
gttcccgggc cttgtacaca ccgcccgtca caccatgaga gccgggggga cccgaagtcg 1380
gtagtctaac cgcaaggagg acgccgccga aggtaaaact ggtgattggg gtg 1433
<210> 2
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> FP1正向引物
<400> 2
actcaacaag gaagtga 17
<210> 3
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> FP2反向引物
<400> 3
cagaggtagg cggaatt 17
<210> 4
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> ERIC-1正向引物
<400> 4
atgtaagctc ctggggattc ac 22
<210> 5
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> ERIC-2反向引物
<400> 5
aagtaagtga ctggggtgag cg 22
<210> 6
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> (GTG)5正向/反向引物
<400> 6
gtggtggtgg tggtg 15
<210> 7
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 27F正向引物
<400> 7
agagtttgat cmtggctcag 20
<210> 8
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 1492R反向引物
<400> 8
ggttaccttg ttacgactt 19
Claims (10)
1.一种用于预防或治疗特应性疾病的药物组合物,其特征在于,包含保藏编号为KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株作为有效成分。
2.根据权利要求1所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,上述普氏栖粪杆菌EB-FPDK11菌株具有由序列1表示的16s核糖体脱氧核糖核酸序列。
3.根据权利要求1所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,上述药物组合物包含上述普氏栖粪杆菌EB-FPDK11菌株的活菌剂或者包含巴氏杀菌的菌株。
4.根据权利要求1所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,上述药物组合物还包含维生素或免疫抑制剂。
5.根据权利要求4所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,上述免疫抑制剂为选自由糖皮质激素、环孢菌素、他克莫司、吡美莫司、包含ISA(TX)247的钙调神经磷酸酶抑制剂、雷帕霉素、磷酸二酯酶4抑制剂、吗替麦考酚酯及地塞米松组成的组中的一种以上。
6.根据权利要求1所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,相对于组合物的总重量,上述用于预防或治疗特应性疾病的药物组合物包含108CFU至1012CFU的普氏栖粪杆菌EB-FPDK11菌株或者包含具有同等数量的活菌或巴氏杀菌体的培养物作为有效成分。
7.根据权利要求1所述的用于预防或治疗特应性疾病的药物组合物,其特征在于,上述特应性疾病为哮喘、过敏性鼻炎、荨麻疹、特应性皮炎、过敏性结膜炎、过敏性反应或食物过敏。
8.一种用于预防或改善特应性疾病的保健功能食品,其特征在于,包含保藏编号为KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株作为有效成分。
9.一种用于缓解或改善特应性皮炎的化妆品组合物,其特征在于,包含保藏编号为KCCM12621P的普氏栖粪杆菌EB-FPDK11菌株作为有效成分。
10.根据权利要求9所述的用于缓解或改善特应性皮炎的化妆品组合物,其特征在于,上述特应性皮炎为皮肤过敏、皮疹、特应性皮炎、银屑病或湿疹。
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PCT/KR2021/002433 WO2022045502A1 (en) | 2020-08-26 | 2021-02-26 | Pharmaceutical composition for preventing or treating atopic disease containing faecalibacterium prausnitzii strain |
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WO2014137211A1 (en) | 2013-03-05 | 2014-09-12 | Rijksuniversiteit Groningen | Use of faecali bacterium prausnitzii htf-f (dsm 26943) to suppress inflammation. |
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US11224622B2 (en) | 2017-06-16 | 2022-01-18 | Biofermin Pharmaceutical Co., Ltd. | Agent for preventing or treating fat-associated diseases and/or inflammation |
AU2019253714A1 (en) | 2018-04-10 | 2020-11-26 | Siolta Therapeutics, Inc. | Microbial consortia |
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US20230293600A1 (en) | 2020-08-14 | 2023-09-21 | Kobiolabs, Inc. | Faecalibacterium prausnitzii strain and uses there of |
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JP2023536414A (ja) | 2023-08-25 |
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