CN103263443A - 用于尘螨***反应的双歧杆菌 - Google Patents
用于尘螨***反应的双歧杆菌 Download PDFInfo
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- CN103263443A CN103263443A CN2013101298013A CN201310129801A CN103263443A CN 103263443 A CN103263443 A CN 103263443A CN 2013101298013 A CN2013101298013 A CN 2013101298013A CN 201310129801 A CN201310129801 A CN 201310129801A CN 103263443 A CN103263443 A CN 103263443A
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Abstract
含有短双歧杆菌(Bifidobacterium breve)的组合物,其可用于改善患有尘螨***反应之人类患者的肺功能。
Description
本申请是申请号为200880124477.3的中国专利申请的分案申请,原申请是国际申请PCT/NL2008/050781的中国国家阶段申请。
技术领域
本发明涉及治疗和/或预防尘螨引起的呼吸功能不全的领域。
背景技术
屋尘螨(house dust mite)(尘螨属(Dermatophagoides))***反应是对存在于屋尘螨***物中蛋白质的过敏性反应,其可导致呼吸功能不全,例如气道阻塞和支气管高反应性。这种过敏性反应在本文中称为“尘螨引起的呼吸功能不全”。屋尘螨存在于几乎所有住宅中。对于对所述***物敏感的人以及危重患者来说,尘螨***物可构成严重的威胁。尘螨肉眼不可见,因而难以在房屋中被发现。
在Mihrishahi等人的研究中(J Allergy Clin Immunol,2003;111:162-8),未发现主动驱避屋尘螨对症状有益处。目前针对尘螨引起的呼吸功能不全,一种重要的治疗方法是通过施用例如支气管扩张剂来防止症状发生。
过去几年的一些研究提示,益生菌在控制婴儿的食物变应性疾病中具有作用。WO 2005/039319公开了含有非消化性寡糖的短双歧杆菌(B.breve)在使非母乳喂养婴儿中的双歧杆菌种群在物种水平上正常化的用途。
DE 102006005404公开了调节免疫的革兰氏阳性菌用于***反应的用途。
EP 1 230 932公开了经转化的乳杆菌属(Lactobacillus)或链球菌属(Streptococcus)细菌,所述细菌包含这样的DNA分子,其含有(1)编码蛋白质变应原的核苷酸序列和(2)与所述核苷酸序列有效连接之启动子。
WO 2007/105945公开了用于孕妇的食物或补充剂,其包含水溶性、非消化性的糖类,用以改善菌群和/或免疫***以及改善出生后婴儿的肠道菌群。
WO2006123230公开了免疫原性组合物,其至少包含抗原并至少包含选自双歧杆菌和乳酸菌的细菌佐剂,用以引发抗原特异性免疫耐受。
发明内容
现已出人意料地发现,包含短双歧杆菌(Bifidobacterium breve)的组合物有效地降低针对屋尘螨***物的***反应,特别是尘螨引起的呼吸功能不全。
已发现,本发明组合物对患有屋尘螨(HDM)IgE介导之变应性哮喘的成年患者中的呼气峰值流速(peak expiratory flow rate)产生有益影响。另外,在施用本发明组合物的成年患者中,屋尘螨引起的IL-5释放也得到了抑制。
具体实施方式
本发明涉及用于治疗和/或预防人的尘螨***反应和/或尘螨引起的呼吸功能不全的方法,所述方法包括向所述人对象施用含有未经遗传修饰的短双歧杆菌的组合物。换言之,本发明涉及未经遗传修饰的短双歧杆菌在制备用于治疗和/或预防人的尘螨***反应和/或尘螨引起的呼吸功能不全的组合物中的用途。本发明还可表述成为包含未经遗传修饰之短双歧杆菌的组合物,其用于治疗/或预防人的尘螨***反应和/或尘螨引起的呼吸功能不全。
在另一实施方案中,本发明涉及提高***反应和/或哮喘人对象之呼气峰值流速的方法,所述方法包括向所述人对象施用含有未经遗传修饰之短双歧杆菌的组合物。换言之,本发明涉及未经遗传修饰的短双歧杆菌在制备提高***反应和/或哮喘人对象之呼气峰值流速的组合物中的应用。本发明还可表述为包含未经遗传修饰的短双歧杆菌的组合物,其用以提高***反应和/或哮喘人对象之呼气峰值流速。
尘螨引起的呼吸功能不全
本发明中的术语“尘螨”是指属于尘螨属的屋尘螨或屋螨(housemite)或螨。本发明提供了治疗和/或预防尘螨***反应(特别是尘螨引起的呼吸功能不全,特别是尘螨***物引起的呼吸功能不全)的组合物和方法。尤其是可以治疗和/或预防尘螨引起的哮喘和尘螨引起的肺部炎性疾病。尘螨引起的哮喘可描述为发生支气管收缩的急性期,直至支气管嗜酸性粒细胞浸润和分泌过多的慢性期。尘螨引起的肺部炎性疾病的一个实例为尘螨引起的鼻炎。
尘螨引起的疾病(例如,尘螨引起的呼吸功能不全)有时也称为尘螨引起的***反应。可被合适地治疗和/或预防的尘螨引起之呼吸功能不全包括尘螨引起的呼吸困难、尘螨引起的呼吸粗重、尘螨引起的呼吸道感染、尘螨引起的肺部刺激、尘螨引起的肺部充血、尘螨引起的粘液过多产生、尘螨引起的呼吸暂停、尘螨引起的支气管炎、尘螨引起的细支气管炎、尘螨引起的气管炎、尘螨引起的肺炎、尘螨引起的鼻窦炎(sinusinitis)、尘螨引起的气流阻塞和/或尘螨引起的鼻炎。
呼气峰值流速(PEFR)是指呼气中产生的最大流量。PEFR通常在使用最大力量时并且在深吸气后开始测量。PEFR是一种测定肺部工作状况好坏的测试。合适的测量PEFR的方法描述于Quanjer等,1997,Eur.Respir.J10增刊24:2s-8s中。人对象中PEFR的增加是指:与治疗前的值相比,在接受本发明含短双歧杆菌之组合物的治疗后观察到PEFR统计学显著性增加。优选地,所述增加至少为5%,更优选地增加至少10%。
短双歧杆菌
细菌的免疫作用具有高度的物种和/或菌株特异性。因此,本发明人在鉴定用作尘螨***反应患者之饮食中的最有效且安全的益生菌菌种方面已进行了大量的临床前工作。与其它益生菌菌种相比,本发明选定的益生菌菌种对于卵白蛋白***反应小鼠模型中的支气管高反应性和支气管炎症具有优异的作用。此外,对本发明选定之益生菌进行多种有关安全性的体外测定和动物模型测试,发现其优于属于其它菌种的益生菌菌株。
本发明组合物包含未经遗传修饰的短双歧杆菌。短双歧杆菌是一种革兰氏阳性、厌氧、分支杆状细菌。与典型菌株短双歧杆菌ATCC 15700相比,本发明短双歧杆菌优选地具有至少95%的16S rRNA序列同一性,更优选地至少97%的同一性(Stackebrandt&Goebel,1994,Int.J.Syst.Bacteriol.44:846-849)。优选的短双歧杆菌菌株是从人乳喂养的健康婴儿的粪便中分离出来的。通常,它们可从乳酸菌生产商购得,但是亦可以直接从粪便中分离、鉴定、表征和生产。根据一个优选的实施方案,本发明组合物包含至少一种选自以下的短双歧杆菌:短双歧杆菌Bb-03(Rhodia/Danisco)、短双歧杆菌M-16V(Morinaga)、短双歧杆菌R0070(Institute Rosell,Lallemand)、短双歧杆菌BR03(Probiotical)、短双歧杆菌BR92(Cell Biotech)、DSM20091、LMG11613、YIT4065、FERM BP-6223和CNCM 1-2219。最优选地,所述短双歧杆菌选自短双歧杆菌M-16V和短双歧杆菌CNCM1-2219。
本发明组合物优选地在每克干重本发明组合物中包含102~1013个菌落形成单位(colony forming unit,cfu)的短双歧杆菌,优选地为104~1012个菌落形成单位的短双歧杆菌,更优选地为105~1010个菌落形成单位的短双歧杆菌,最优选地为每克干重本发明组合物中包含105~1×109个菌落形成单位的短双歧杆菌。本发明短双歧杆菌的剂量优选地以每天102~1013个菌落形成单位(cfu)的剂量来施用,更优选地以105~1012个菌落形成单位的剂量来施用,最优选地以108~5×1010个菌落形成单位的剂量来施用。
本发明组合物优选地包含活的短双歧杆菌。或者,本发明组合物优选地包含等同于上述CFU量的非活短双歧杆菌。cfu的等同可通过如下方式来确定:使用WO 2005/039319中公开的短双歧杆菌探针和引物,在含有非活短双歧杆菌的产品(例如婴儿配方食品)中进行5′核酸酶测定,并将此结果与从可比产品(如标准婴儿配方食品)获得的标准曲线进行比较,其中所述可比产品中加入了已知量的干燥的活短双歧杆菌cfu。所述干燥的活双歧杆菌可如上所述购得。短双歧杆菌细胞可通过本领域已知的方法进行灭活,包括热处理步骤(包括灭菌、巴氏消毒和UHT(超高温)处理)、辐射(UV)、氧处理、杀菌剂(例如乙醇)处理、超声处理、施加超高压、高压匀浆以及使用细胞破碎仪。优选地,短双歧杆菌经热灭活。非活短双歧杆菌的存在有利地提供了诸多产品技术优势,包括延长货架期、减少细菌污染的发生率、降低产品的后酸化、改善剂量控制以及提高重构的便利性。
本发明的短双歧杆菌是未经遗传修饰的。遗传修饰在安全性和消费者接受度方面是一个缺点。此外,遗传修饰非常昂贵且通常对菌株生长特性有负面影响。因此,本发明不包括通过本领域已知的重组技术获得的表达尘螨抗原的短双歧杆菌菌株。
非消化性寡糖
本发明组合物优选地包含非消化性寡糖,其可被发酵成有机酸(优选为乳酸、丁酸、丙酸和/或乙酸)并刺激肠中产乳酸细菌的生长(下文称为“非消化性糖类”)。优选地,刺激双歧杆菌和/或乳杆菌的生长,更优选地刺激双歧杆菌的生长,最优选地刺激短双歧杆菌的生长。双歧杆菌和/或乳杆菌含量的增加刺激健康肠道菌群的形成。所述非消化性寡糖还增强本发明组合物中短双歧杆菌的效力,因为非消化性寡糖与短双歧杆菌的共施用选择性地刺激胃肠道中短双歧杆菌的生长和/或增强产品中短双歧杆菌的存活力。
优选地,非消化性寡糖在肠中不被人的上消化道(小肠和胃)中存在的酸或消化酶所消化或仅被部分地消化,而是通过人肠道菌群进行发酵。例如,蔗糖、乳糖、麦芽糖和麦芽糊精被认为是可消化的。
本发明组合物优选地包含非消化性寡糖。优选地,本发明组合物包含的非消化性寡糖具有2~250、更优选地2~60的DP(聚合度)。优选地,所述非消化性寡糖优选地选自以下的至少一种、更优选至少两种:低聚果糖(包括菊粉)、低聚半乳糖(包括反式低聚半乳糖)、低聚木糖、低聚***糖、低聚***半乳糖、低聚葡萄糖(包括环糊精、低聚龙胆糖(gentio-oligosaccharide)、黑曲霉寡糖(nigero-oligosaccharide)和非消化性聚右旋糖)、低聚壳聚糖、低聚葡萄甘露糖、低聚半乳甘露糖(包括部分水解的瓜尔胶)、低聚甘露糖、低聚岩藻糖、含唾液酸的寡糖、糖醛酸寡糖(包括半乳糖醛酸寡糖和果胶降解产物)。更优选地,本发明组合物包含低聚果糖、低聚半乳糖和/或半乳糖醛酸寡糖,更优选地包含低聚半乳糖,最优选地包含反式低聚半乳糖。在一个优选的实施方案中,所述组合物包含菊粉和低聚果糖的混合物。在一个优选的实施方案中,所述组合物包含低聚半乳糖和/或低聚果糖。在一个优选的实施方案中,所述组合物包含低聚半乳糖和低聚果糖(其选自短链低聚果糖和菊粉,更优选地为菊粉)的混合物。至少两种不同的非消化性寡糖的混合物更有利地刺激肠道微生物群中的有益细菌。优选地,两种不同的非消化性寡糖(优选低聚半乳糖与低聚寡糖)的混合物中的重量比为25~0.05,更优选地为20~1。低聚半乳糖能够更强地刺激双歧杆菌。优选地,本发明组合物包含DP为2~10的低聚半乳糖和/或DP为2~60的低聚果糖。
所述低聚半乳糖优选地选自反式低聚半乳糖、乳糖-N-四糖(lacto-N-tetraose,LNT)、乳糖-N-新四糖(lacto-N-neotetraose,neo-LNT)、岩藻糖基乳糖、岩藻糖基化的LNT和岩藻糖基化的neo-LNT。在一个特别优选的实施方案中,本发明组合物包含反式低聚半乳糖([半乳糖]n-葡萄糖;其中n是介于1至60之间的整数,即2、3、4、5、6、....、59、60;优选地,n选自2、3、4、5、6、7、8、9或10),其中,半乳糖单元通过β键连接在一起。例如,反式低聚半乳糖(TOS)以商标Vivinal(TM)出售(Borculo Domo Ingredients,Netherlands)。优选地,反式低聚半乳糖中的糖通过β键进行连接。低聚果糖是NDO(非消化性寡糖),其包含DP或平均DP为2~250、更优选地2~100、更优选地10~60的β连接之果糖单元的链。低聚果糖包括菊粉、果聚糖(levan)和/或混合型的多聚果糖(polyfructan)。尤其优选的低聚果糖是菊粉。适用于本发明组合物中的低聚果糖也可购得,例如Raftiline(R)HP(Orafti)。糖醛酸寡糖优选地从果胶降解产物中获得。因此,本发明组合物优选地包含DP为2~100的果胶降解产物。优选地,果胶降解产物从苹果果胶、甜菜果胶和/或柑橘果胶制备。优选地,所述组合物包含反式低聚半乳糖、低聚果糖和果胶降解产物。反式低聚半乳糖∶低聚果糖∶果胶降解产物的重量比优选为(20~2)∶1∶(1~20),更优选为(20~2)∶1∶(1~10),更优选为(20~2)∶1∶(1~3),更优选为(12~7)∶1∶(1~2)。
优选地,所述组合物包含每100毫升80mg~2g的非消化性寡糖,更优选地每100毫升150mg~1.50g,更优选地每100毫升300mg~1g的非消化性寡糖。基于干重,所述组合物优选地包含0.25wt%~5.5wt%的非消化性寡糖,更优选地0.5wt%~4wt%,更优选地1.5wt%~3wt%。更低量的非消化性寡糖刺激微生物群中有益细菌的效力较低,而过高的量则会导致腹胀和腹部不适的副作用。
优选地,本发明组合物在每克总的非消化性寡糖中包含104~1012个菌落形成单位(cfu)的短双歧杆菌,更优选地为105~1011个菌落形成单位的短双歧杆菌,最优选地为107~5×1010个菌落形成单位的短双歧杆菌。
对象
本发明组合物特别适用于治疗和/或预防0~10岁儿童(优选地0~4岁的婴幼儿)的尘螨***反应和/或尘螨引起的呼吸功能不全。本发明组合物特别适用于治疗和/或预防成年人的尘螨***反应和/或尘螨引起的呼吸功能不全。本发明组合物特别适用于治疗和/或预防人对象中尘螨引起的呼吸功能不全。本发明组合物特别适合增加患有***反应和/或哮喘(更特别地尘螨***反应和/或尘螨引起的哮喘)的0~10岁儿童(优选0~4岁的婴幼儿)中的呼气峰值流速。本发明组合物特别适合增加患有尘螨***反应和/或尘螨引起的哮喘(更特别地尘螨***反应和/或尘螨引起的哮喘)的成年人中的呼气峰值流速。
此外,本发明组合物可有利地用于可能发生呼吸道感染疾病的患者,特别是被人类免疫缺陷病毒(HIV)感染的患者和/或患有以下一种或多种疾病的患者:肾病综合征、多发性骨髓瘤、淋巴瘤、霍奇金病;进行过器官移植的人;患有心脏、肾脏或肺慢性病(尤其是慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)、肺气肿、结节病、囊性纤维化、支气管扩张、肺癌、肺不张(atelectasis)、呼吸衰竭、职业性肺疾病、哮喘、嗜酸性粒细胞增多症(eosinophily))、糖尿病、酒精中毒、吞咽困难和胃食管反流病(gastro-oesophagal refluxdisease)的人。
在一个更优选的实施方案中,本发明包括向患者施用本发明的组合物,特别是向使用呼吸机或人工呼吸设备的患者以及在重症监护病房中的患者。这些患者对炎性疾病和感染特别易感。
现有技术的结果主要来自于婴幼儿,他们的菌群和免疫***更容易操控,而成年人的菌群和免疫***已经成型,所以不容易改变。出人意料地发现,短双歧杆菌通过减少Th2型细胞因子IL-4、IL-5和/或IL-13的全身性产生从而在已患哮喘的***反应患者中降低变应原所引起的应答。本发明的组合物通过减少Th2型细胞因子IL-4、IL-5和/或IL-13的全身性产生来降低***反应患者中变应原所引起的应答。本发明的组合物减少IL-4和/或IL-5和/或IL-13。
营养组合物及施用方式
本发明方法中使用的组合物优选经肠施用,更优选口服施用。
在一个优选的实施方案中,本发明的组合物作为营养基质来施用,或包含在其中,所述营养基质优选地含有脂质、蛋白质和碳水化合物成分。这对于尚无法吞咽胶囊的婴幼儿来说是特别重要的。因此,对于0~4岁的婴幼儿,本发明的短双歧杆菌优选地掺入含有脂肪、碳水化合物和蛋白质的营养组合物中。在一个优选的实施方案中,本发明的营养组合物满足喂养婴儿的需要,或者本发明的方法包括施用满足喂养婴儿之需要的营养组合物,特别是含有10~60en-%脂质、5~50en-%蛋白质、15~90en-%碳水化合物的营养组合物。更优选地,所述营养组合物含有7.5~12.5en-%蛋白质、40~55en-%碳水化合物以及35~50en-%脂肪。(en-%是能量百分数的缩写,其代表各成分占制剂总热量值的相对量)。
本发明营养组合物优选地包含占总脂肪含量至少0.1wt.%、优选地至少0.25wt.%、更优选地0.5wt.%、更优选地0.75wt.%的具有20和22个碳原子的LC-PUFA。本发明组合物中具有20和22碳原子的LC-PUFA的含量优选地不超过总脂肪含量的15wt.%,更优选地不超过10wt.%,更优选地不超过5wt.%。LC-PUFA对尘螨***反应和/或尘螨引起的呼吸功能不全具有有利的影响。
根据一个更优选的实施方案,本发明的组合物采用粉末剂、胶囊剂、丸剂或片剂(以下称为“单位剂量”)的形式或摄入形式。这样的优点是不必改变对象的饮食,可在正常饮食之外摄取包含短双歧杆菌的补充剂。此外,通过选择扁囊(sachet)或胶囊作为施用短双歧杆菌的形式可使其适当地避开空气和水分,这对于细菌的存活力和/或产品货架期是有益的。所述单位剂量优选地为每单位0.1~15克。所述单位剂量优选地包含至少1×108cfu的短双歧杆菌。
实施例
实施例1含有合生素(synbiotics)的扁囊
扁囊,其包含10克的以下成分:
A.0.1克短双歧杆菌M-16V菌株(Morinaga),1×1010cfu;
B.4g GOS/FOS混合物(重量比为9/1),使用Vivinal GOS(DOMOBorculo)作为GOS的来源,使用RaftilinHP(Tiense)作为FOS的来源;
C.其余为麦芽糊精。
实施例2对患有屋尘螨(HDM)IgE介导之变应性哮喘的成年患者进行益生菌口服治疗的效果
包括一组30位成年患者,他们患有轻度至中度哮喘以及已知的针对屋尘螨的HDM IgE介导之***反应(根据美国胸腔学会标准)。在双盲平行实验设计中,患者随机接受实施例1中的补充剂(A组)或接受包含麦芽糊精的安慰剂补充剂(B组),每日两次,为期4周。扁囊被溶于冷饮、酸奶或蛋奶糊中。
在进入研究时以及干预四周以后,进行变应原攻击,历时3天。第1天,抽取血液样品,之后进行组胺激发试验(histamine provocationtest),在组胺激发试验后,收集痰液。第2天,进行变应原激发试验,其间收集痰液和血液样品。第3天,抽取血液样品,之后进行组胺激发试验,在组胺激发试验后,收集痰液。在整个4周研究期间,对象使用便携式PEF计(呼气峰值流量计)每天早晚各一次自行测量呼气峰值流速(PEFR)。
利用所收集的痰液(嗜酸性粒细胞、嗜中性粒细胞、嗜酸性粒细胞阳离子蛋白(Eosinophil cationic protein,ECP)、髓过氧物酶(Myeloperoxydase,MPO))来确定支气管炎症。
测定血液样品中的免疫学参数(嗜酸性粒细胞的数目、IL-5、总的IgE和Der p1特异性IgE、IgG1和IgG4、Treg细胞(CD4/CD25/CD103/GITR/FoxP3)、IL-4、IL-5、IL-10、IFN-γ、MIG、IP-10、IL-12p70、IL-13、TGF-β和IL-18的酶联免疫斑点测定:基于IL-4和IFN-γ或基于IL-4和IL-13的Th1/Th2比值)。
通过测量肺功能、对变应原和组胺的反应能力以及呼气峰值流速来确定支气管反应性。
针对参数数据使用t-检验以及针对非参数数据使用Mann-Whitney检验来评估所述两个配方组的结果。使用卡方分析来评估二元数据和分类数据。
支气管接触屋尘螨(HDM)导致所有对象的FEV1下降至少20%。大多数对象还在吸入最后一剂HDM后数小时经历了迟发的哮喘反应(late asthmatic reaction,LAR)。在干预后的两个处理组中观察到LAR期间肺功能的微小差异。攻击后2~6小时的平均AUC差异为:B组为+2.3,A组处理后为-3.5。
呼气流量的结果示于表1中。与安慰剂组相比,在施用短双歧杆菌的组中观察到统计学显著的呼气峰值流速增加(早晨测量,p=0.003;晚间测量,p=0.011)。针对IL-5的结果示于表2中。与对照组相比,在干预后,在变应原刺激后释放的IL-5被统计学显著性抑制(6小时后,p=0.06,24小时后,p=0.019)。干预前,两组中由变应原刺激引起的IL-5释放是相同的。
与IL-5产生的变化一致地,我们发现,与B组相反,A组中HDM刺激之PBMC产生的Th2细胞因子(IL-4和IL-13)的量并未显着增加(针对总Th2细胞因子,p=0.046),参见表3。
表1:在早晨或晚上测量的呼气峰值流速(升/分钟),经基线值校正。
a:第1周的值作为基线值
表2:干预后,用HDM抗原进行变应原刺激过程中的IL-5效应(pg/ml)
表3:干预后,用5μg/ml HDM抗原进行变应原刺激过程中的IL-4和IL-13(pg/ml)效应
变应原攻击后的第6小时和第24小时,观察到诱导后痰液样品中嗜酸性粒细胞量和ECP的量均有显著增加。在变应原攻击后的这两个时间点,痰液中嗜中性粒细胞数和MBO的水平也有所增加。在干预后6小时(t=6),与B组相比,A组在LAR期间的痰液炎症参数的增加略有降低。参见表4。24小时(t=24)的水平又恢复到干预前24小时观察到的数值(数据未显示)。
表4:干预后痰液的炎症参数。
数值表示为每克痰液的几何平均值(SE)。ECP=嗜酸性粒细胞阳离子蛋白,MPO=髓过氧化物酶。
这些结果表明,包含短双歧杆菌的组合物对患有尘螨***反应和/或尘螨引起之呼吸功能不全的患者具有有益的作用。这些结果表明,包含短双歧杆菌的组合物对患有哮喘和/或***反应之患者的肺功能具有有益的作用。
由于IL-4和IL-13在将B细胞类别转换为产生变应原特异性IgE中是重要的Th2介导物,所述IgE结合肥大细胞、嗜碱性粒细胞和活化嗜酸性粒细胞上的IgE高亲和力受体,而IL-5指导招募以及活化嗜酸性粒细胞,因此用短双歧杆菌处理导致的这些细胞因子的减少最终导致了变应性炎性应答的降低。
与一些表明在益生菌处理后调节性细胞因子(IL-10)或调节性T细胞增加的人类研究相反,本发明未发现短双歧杆菌的免疫调节作用由调节特性的引起或改变所介导。因此,短双歧杆菌似乎不影响变应原本身的致敏作用,而是可能调节从致敏作用到临床疾病的途径;在这种情况下,通过减少Th2型细胞因子的产生,接触变应原后的变应性应答会随时间降低。最终,在长时间治疗后以及由此导致的Th2应答长时间的降低,同时气道中的变应性炎症会减少,从而改善肺功能。在本研究中,在A组中已观察到PEF的改善。
本研究首次揭示了短双歧杆菌通过减少Th2型细胞因子IL-4、IL-5和IL-13的全身性产生从而降低患有变应性哮喘之患者中变应原引起的应答。
以下内容对应于母案申请中的原始权利要求书,现作为说明书的一部分并入此处:
1.包含未经遗传修饰的短双歧杆菌(Bifidobacterium breve)的组合物,其用于治疗和/或预防人的尘螨***反应和/或尘螨引起的呼吸功能不全。
2.包含未经遗传修饰的短双歧杆菌的组合物,其用于增加患有***反应和/或哮喘的人对象中的呼气峰值流速。
3.根据前述项中任一项的组合物,其用于成人。
4.根据前述项中任一项的组合物,其用于减少IL-4和/或IL-5和/或IL-13。
5.根据前述项中任一项的组合物,其中所述组合物采用包含粉末之扁囊剂、胶囊剂、丸剂或片剂的形式。
6.根据前述项中任一项的组合物,其还包含非消化性寡糖。
7.根据项6的组合物,其包含选自以下的至少一种、更优选地至少两种非消化性寡糖:低聚果糖(包括菊粉)、低聚半乳糖(包括反式低聚半乳糖)、低聚木糖、低聚***糖、低聚***半乳糖、低聚葡萄糖(包括环糊精、低聚龙胆糖、黑曲霉寡糖和非消化性聚右旋糖)、低聚壳聚糖、低聚葡萄甘露糖、低聚半乳甘露糖(包括部分水解的瓜尔胶)、低聚甘露糖、低聚岩藻糖、含唾液酸的寡糖、糖醛酸寡糖(包括半乳糖醛酸寡糖和果胶降解产物)。
8.根据项6或7的组合物,其包含低聚半乳糖和/或低聚果糖。
9.根据项6至8中任一项的组合物,其包含重量比为25~0.05的低聚半乳糖和低聚果糖。
10.根据前述项中任一项的组合物,其包含基于所述组合物干重为每克至少1×104cfu的短双歧杆菌。
11.根据前述项中任一项的组合物,其中所述短双歧杆菌选自短双歧杆菌Bb-03、短双歧杆菌M-16V、短双歧杆菌R0070、短双歧杆菌BR03、短双歧杆菌BR92、DSM20091、LMG11613、YIT4065、FERM BP-6223和CNCM1-2219。
Claims (13)
1.未经遗传修饰的短双歧杆菌(Bifidobacterium breve)在制备用于治疗和/或预防人的尘螨***反应和/或尘螨引起的呼吸功能不全的组合物中的用途。
2.未经遗传修饰的短双歧杆菌在制备用于增加患有***反应和/或哮喘的人对象中的呼气峰值流速的组合物中的用途。
3.根据权利要求1或2的用途,其中所述人是0至10岁的儿童。
4.根据权利要求3的用途,其中所述人是0至4岁的儿童。
5.根据权利要求1或2的用途,其中所述人是成人。
6.根据权利要求1或2的用途,其用于减少IL-4和/或IL-5和/或IL-13。
7.根据权利要求1或2的用途,其中所述组合物采用包含粉末之扁囊剂、胶囊剂、丸剂或片剂的形式。
8.根据权利要求1或2的用途,其中所述组合物还包含非消化性寡糖。
9.根据权利要求8的用途,其中所述非消化性寡糖包含选自以下的至少一种、更优选地至少两种非消化性寡糖:低聚果糖(包括菊粉)、低聚半乳糖(包括反式低聚半乳糖)、低聚木糖、低聚***糖、低聚***半乳糖、低聚葡萄糖(包括环糊精、低聚龙胆糖、黑曲霉寡糖和非消化性聚右旋糖)、低聚壳聚糖、低聚葡萄甘露糖、低聚半乳甘露糖(包括部分水解的瓜尔胶)、低聚甘露糖、低聚岩藻糖、含唾液酸的寡糖、糖醛酸寡糖(包括半乳糖醛酸寡糖和果胶降解产物)。
10.根据权利要求9的用途,其中所述非消化性寡糖包含低聚半乳糖和/或低聚果糖。
11.根据权利要求9的用途,其中所述非消化性寡糖包含重量比为25~0.05的低聚半乳糖和低聚果糖。
12.根据权利要求1或2的用途,其中所述组合物包含基于所述组合物干重为每克至少1×104cfu的短双歧杆菌。
13.根据权利要求1或2或12的用途,其中所述短双歧杆菌选自短双歧杆菌Bb-03、短双歧杆菌M-16V、短双歧杆菌R0070、短双歧杆菌BR03、短双歧杆菌BR92、DSM20091、LMG11613、YIT4065、FERM BP-6223和CNCM1-2219。
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