CN108883139B - 包含细菌菌株的组合物 - Google Patents
包含细菌菌株的组合物 Download PDFInfo
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- CN108883139B CN108883139B CN201780014234.3A CN201780014234A CN108883139B CN 108883139 B CN108883139 B CN 108883139B CN 201780014234 A CN201780014234 A CN 201780014234A CN 108883139 B CN108883139 B CN 108883139B
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Abstract
本发明提供了包含一种或多种细菌菌株的组合物,所述组合物用于治疗或预防内脏高敏感性。
Description
发明领域
本发明属于包含从哺乳动物消化道分离的细菌菌株的组合物和此类组合物用于治疗疾病的用途的领域。
发明背景
虽然认为在子宫内人类肠道是无菌的,但在出生后其立刻暴露于大量的母体和环境微生物。此后,出现微生物定殖和演替的动态期,其受例如分娩模式、环境、饮食和宿主基因型等因素影响,所有因素都影响肠道微生物丛的组成,特别是在童年期间。随后,微生物丛稳定化并变成成人样[1]。人类肠道微生物丛含有超过1500个不同的种系型,其中两种主要细菌门(division)(门(phyla))的丰度占主导地位,即拟杆菌门(Bacteroidetes)和厚壁菌门(Firmicutes)[2-3]。由人类肠的细菌定殖产生的成功的共生关系产生多种代谢、结构、保护和其它有益功能。定殖肠部的增强的代谢活性确保降解以其它方式无法摄取的饮食组分,同时释放副产物,为宿主提供重要的营养物来源和另外的健康益处。类似地,充分认识到肠道微生物丛的免疫重要性,且在免疫***减弱的无菌动物中例示,其免疫***在引入共生细菌后在功能上复原[4-6]。
微生物丛组成的显著变化已经在例如炎性肠病(IBD)等肠胃病症中证明。举例来说,在IBD患者中梭菌属(Clostridium)XIVa簇和梭菌属XI簇(普拉梭菌(F.prausnitzii))细菌的水平降低,而大肠杆菌的数目增加,这表明肠内共生有机体与致病有机体的平衡的变化[7-11]。
认识到某些细菌菌株对动物肠可能具有潜在的积极作用,已经提议各种菌株用于治疗各种疾病(参见例如[12-15])。已经提议多种菌株,主要包括杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium)菌株,用于治疗各种肠病症(综述参见[16])。也已经提议布劳特氏菌(Blautia) 属的菌株可用于调节消化生态***的微生物平衡(WO 01/85187)。然而,对不同细菌菌株与不同疾病之间的关系和特定的细菌菌株对肠和在全身水平下和对任何特定类型的疾病的准确作用尚未很好地表征。
需要待表征的肠细菌的潜在作用,以便能够研发使用肠细菌的新疗法。
发明概要
本发明人已经研发出用于治疗并预防内脏高敏感性的新颖疗法。具体地说,本发明人已经确定来自布劳特氏菌属的细菌菌株可以有效降低内脏高敏感性。如实施例中所述,经口施用包含氢营养布劳特氏菌(Blautia hydrogenotrophica)的组合物可以降低内脏高敏感性和肠易激综合征(IBS)的大鼠模型的内脏高敏感性。因此,在第一实施方案中,本发明提供了包含布劳特氏菌属的细菌菌株的组合物,其用于治疗或预防内脏高敏感性的方法中。
在优选实施方案中,本发明提供了包含布劳特氏菌属的细菌菌株的组合物,其用于治疗或预防被诊断为患有克罗恩病(Crohn’s disease)、溃疡性结肠炎、功能性消化不良或更优选地IBS的受试者的内脏高敏感性的方法中。在其它优选实施方案中,本发明提供了包含布劳特氏菌属的细菌菌株的组合物,其用于治疗或预防被诊断为患有克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS的受试者的内脏高敏感性的方法中。
在其它优选实施方案中,本发明提供了包含布劳特氏菌属的细菌菌株的组合物,其用于治疗或预防腹部中、优选地胃肠道中且最优选地下胃肠道中的内脏高敏感性。在其它实施方案中,本发明的组合物用于治疗或预防盲肠、结肠或直肠中的内脏高敏感性。
在本发明的优选实施方案中,组合物中的细菌菌株属于氢营养布劳特氏菌。还可以使用紧密相关的菌株,例如具有与氢营养布劳特氏菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列的细菌菌株。优选地,细菌菌株具有与SEQ ID NO:5至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16srRNA序列。最优选地,组合物中的细菌菌株为以登记号DSM 10507/14294保藏的氢营养布劳特氏菌菌株。
在本发明的其它实施方案中,组合物中的细菌菌株属于粪便布劳特氏菌(Blautiastercoris)。还可以使用紧密相关的菌株,例如具有与粪便布劳特氏菌的细菌菌株的16srRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列的细菌菌株。优选地,细菌菌株具有与SEQ ID NO:1或3至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,序列同一性是针对SEQ ID NO:3。优选地,用于本发明的细菌菌株具有由SEQ ID NO:3表示的16s rRNA序列。
在本发明的其它实施方案中,组合物中的细菌菌株属于韦氏布劳特氏菌(Blautiawexlerae)。还可以使用紧密相关的菌株,例如具有与韦氏布劳特氏菌的细菌菌株的16srRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列的细菌菌株。优选地,细菌菌株具有与SEQ ID NO:2或4至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,序列同一性是针对SEQ ID NO:4。优选地,用于本发明的细菌菌株具有由SEQ ID NO:4表示的16s rRNA序列。
在某些实施方案中,本发明的组合物用于经口施用。经口施用本发明的菌株可以有效地治疗内脏高敏感性。此外,经口施用便于患者和开业医师且允许传递至肠和/或部分或全部定殖肠部。
在某些实施方案中,本发明的组合物包含一种或多种药学上可接受的赋形剂或载剂。
在某些实施方案中,本发明的组合物包含已冻干的细菌菌株。冻干是一项制备允许传递细菌的稳定组合物的有效和便利的技术,并在实施例中显示提供有效组合物。
在某些实施方案中,本发明提供了一种包含如上所述的组合物的食品。
在某些实施方案中,本发明提供了一种包含如上所述的组合物的疫苗组合物。
另外,本发明提供了一种治疗或预防内脏高敏感性的方法,其包括施用包含布劳特氏菌属的细菌菌株的组合物。
图示简单说明
图1:通过qPCR测量BH群体,其显示接受BH冻干物的动物在第14天和第28天时BH增加。
图2:BH培养物和冻干物对动物对扩张的反应的影响,其显示接受BH组合物的动物收缩减少。
图3:BH培养物对微生物丛的影响,其显示接受日剂量的BH 培养物的大鼠中SRB减少1log。
图4:BH冻干物对微生物丛的影响。
图5:BH冻干物对微生物丛发酵-短链脂肪酸的影响,其显示经 BH治疗的大鼠中乙酸盐产量增加。
图6:BH冻干物对微生物丛发酵-硫化物的影响,其显示硫化物产量减少。
图7:BH冻干物对动物对扩张的反应的影响。大鼠MIH IBS+ BH:CRD测试。
图8:BH冻干物对动物对扩张的反应的影响。大鼠MIH IBS+ BH:所有数据-CRD测试。
图9:BH冻干物对硫化物的影响。大鼠MIH IBS+BH:硫化物浓度(mg/L)。图9 A 显示每只大鼠在用BH冻干物或对照溶液处理后盲肠的硫化物浓度。图9 B 显示在IBS-微生物丛相关的大鼠中在用BH 冻干物或对照溶液处理后测量的盲肠的硫化物浓度的平均值+/-SEM。
图10:BH冻干物对硫化物的影响。大鼠MIH IBS+BH:所有数据-硫化物浓度(mg/L)。图10A 显示每只大鼠在用BH冻干物或对照溶液处理后盲肠的硫化物浓度。图10B 显示在IBS-微生物丛相关的大鼠中在用BH冻干物或对照溶液处理后测量的盲肠的硫化物浓度的平均值+/-SEM。
图11:HIM大鼠中的给药研究-接受不同浓度的细菌物种的健康 HIM大鼠的粪便样品中氢营养布劳特氏菌(B.hydrogenotrophica)的 RT-PCR定量。
图12:将氢营养布劳特氏菌经口施用(109/天)于健康HIM大鼠后的传输时间。
图13:施用(以1010/天/大鼠施用氢营养布劳特氏菌)14天后,在健康HIM大鼠的粪便和盲肠样品中发现的氢营养布劳特氏菌水平的比较(RT-PCR定量)。
图14:氢营养布劳特氏菌(1010/天,14天)对健康HIM大鼠的盲肠内容物中的短链脂肪酸产量(RMN 1H)的作用。
图15:氢营养布劳特氏菌施用对IBS-HIM大鼠中的微生物群体的影响。
图16:经氢营养布劳特氏菌治疗(1010/天,14天)的IBS-HIM大鼠中的硫化物产量。对照大鼠未进行治疗。
图17:患者症状在I期临床试验的给药期间(第1-16天)的改变。
图18:患者症状在I期临床试验的洗脱期期间的改变。
图19:经或未经包含氢营养布劳特氏菌(BlautiX)的组合物治疗 28天的IBS-HMA大鼠的粪便样品中的氢营养布劳特氏菌群体的 qPCR评估。
图20:在经或未经氢营养布劳特氏菌(BlautiX)治疗28天的 IBS-HMA大鼠中和在未进行治疗的健康HMA大鼠中对结肠直肠扩张的腹腔反应。
图21:相对于对照溶液,氢营养布劳特氏菌(BlautiX)施用后,IBS HMA-大鼠粪便样品中的细菌计数。
图22:经或未经氢营养布劳特氏菌(Blautix)治疗28天的IBS HMA-大鼠的盲肠样品中的硫化物浓度。
图23:经或未经氢营养布劳特氏菌(Blautix)治疗28天的 IBS-HMA大鼠的盲肠样品中的短链脂肪酸(SCFA)浓度。图23A 显示总SCFA浓度。图23B 显示乙酸、丙酸和丁酸的浓度。
发明详述
细菌菌株
本发明的组合物包含布劳特氏菌属的细菌菌株。所述实施例证明此种属的细菌可用于治疗或预防内脏高敏感性。优选的细菌菌株属于氢营养布劳特氏菌、粪便布劳特氏菌和韦氏布劳特氏菌物种。用于本发明中的其它优选细菌菌株是产生性布劳特氏菌(Blautiaproducta)、球形布劳特氏菌(Blautia coccoides)和汉逊氏布劳特氏菌(Blautiahansenii)。
用于本发明的布劳特氏菌属菌株的实例包括氢营养布劳特氏菌、粪便布劳特氏菌、粪布劳特氏菌(B.faecis)、球形布劳特氏菌(B. coccoides)、格鲁氏布劳特氏菌(B.glucerasea)、汉逊氏布劳特氏菌(B. hansenii)、卢氏布劳特氏菌(B.luti)、产生性布劳特氏菌(B.producta)、史氏布劳特氏菌(B.schinkii)和韦氏布劳特氏菌。布劳特氏菌属物种是革兰氏反应呈阳性的不运动细菌,其可以是球形或椭圆形,并且都是产生乙酸作为葡萄糖发酵的主要最终产物的专性厌氧菌[17]。布劳特氏菌属可以从人肠道分离,不过产生性布劳特氏菌是从败血症样品分离。
已经从哺乳动物的肠道分离氢营养布劳特氏菌(先前称为氢营养瘤胃球菌(Ruminococcus hydrogenotrophicus)),其严格厌氧并将 H2/CO2代谢成对人类营养和健康来说具有重要意义的乙酸盐。氢营养布劳特氏菌的模式菌株是S5a33=DSM 10507=JCM14656。氢营养布劳特氏菌菌株S5a36的16S rRNA基因序列的GenBank登记号是 X95624.1(在本文中公开为SEQ ID NO:5)。此例示性氢营养布劳特氏菌菌株描述于[17]和[18]中。S5a33菌株和S5a36菌株对应于从健康受试者的粪便样品分离的菌株的两个亚克隆。其显示相同的形态、生理学和代谢并具有相同的16S rRNA序列。因此,在一些实施方案中,用于本发明中的氢营养布劳特氏菌具有SEQ ID NO:5的16S rRNA序列。
以登记号DSM 10507以及以登记号DSM 14294保藏的氢营养布劳特氏菌细菌在实施例中进行测试且在本文中又称为菌株BH。菌株 BH在1996年1月以登记号DSM 10507作为“氢营养瘤胃球菌”保藏于Deutsche Sammlung von Mikroorganismen[德国微生物保藏中心 (German Microorganism Collection)](Mascheroder Weg 1b,38124 Braunschweig,德国),以及在2001年5月10日以登记号DSM 14294 作为“S5a33”保藏。保藏者是法国INRALaboratoire de Microbiologie CR de Clermont-Ferrand/Theix 63122Saint GenèsChampanelle。保藏物的所有权已经通过受让的方式转给4D Pharma Plc。
粪便布劳特氏菌菌株GAM6-1T的16S rRNA基因序列的GenBank 登记号是HM626177(本文中公开为SEQ ID NO:1)。一种例示性粪便布劳特氏菌菌株描述于[19]中。韦氏布劳特氏菌的模式菌株是WAL 14507=ATCC BAA-1564=DSM 19850[17]。韦氏布劳特氏菌菌株WAL 14507T的16S rRNA基因序列的GenBank登记号是EF036467 (本文中公开为SEQ ID NO:2)。此例示性韦氏布劳特氏菌菌株描述于 [17]中。
优选的粪便布劳特氏菌菌株是以登记号NCIMB 42381保藏的菌株,其在本文中又称为菌株830。830菌株的16S rRNA序列提供于 SEQ ID NO:3中。菌株830由GT Biologics有限公司(Life Sciences Innovation Building,Aberdeen,AB25 2ZS,苏格兰)以“粪便布劳特氏菌830”在2015年3月12日保藏在国际保藏局NCIMB有限公司(Ferguson Building,Aberdeen,AB21 9YA,苏格兰)并分配登记号 NCIMB 42381。GT Biologics有限公司随后将其名称改为4D Pharma Research有限公司。
优选的韦氏布劳特氏菌菌株是以登记号NCIMB 42486保藏的菌株,其在本文中又称为菌株MRX008。MRX008菌株的16S rRNA序列提供于SEQ ID NO:4中。菌株MRX008由4DPharma Research有限公司(Life Sciences Innovation Building,Aberdeen,AB25 2ZS,苏格兰)以“布劳特氏菌属/瘤胃球菌属(Ruminococcus)MRx0008”在2015年 11月16日保藏在国际保藏局NCIMB有限公司(Ferguson Building, Aberdeen,AB21 9YA,苏格兰)并分配登记号NCIMB 42486。
还预期与实施例中测试的菌株紧密相关的细菌菌株有效治疗或预防内脏高敏感性。在某些实施方案中,用于本发明的细菌菌株具有与氢营养布劳特氏菌的细菌菌株的16srRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,用于本发明的细菌菌株具有与SEQ ID NO:5至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。
在某些实施方案中,用于本发明的细菌菌株具有与粪便布劳特氏菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,用于本发明的细菌菌株具有与SEQ ID NO:1或SEQ ID NO:3至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,序列同一性是针对SEQ ID NO:3。优选地,用于本发明的细菌菌株具有由SEQ ID NO:3表示的16s rRNA序列。在某些实施方案中,用于本发明的细菌菌株具有与韦氏布劳特氏菌的细菌菌株的16s rRNA序列至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA序列。优选地,用于本发明的细菌菌株具有与SEQ ID NO:2或SEQ ID NO:4 至少95%、96%、97%、98%、99%、99.5%或99.9%同一的16s rRNA 序列。优选地,序列同一性是针对SEQ ID NO:4。优选地,用于本发明的细菌菌株具有由SEQ ID NO:4表示的16s rRNA序列。
还预期作为以登记号DSM 10507/14294保藏的细菌的生物型或以登记号NCIMB42381和NCIMB 42486保藏的细菌的生物型的细菌菌株有效治疗或预防内脏高敏感性。生物型是具有相同或极类似的生理和生物化学特性的紧密相关的菌株。
作为以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486 保藏的细菌的生物型且适用于本发明中的菌株可以通过对以登记号 DSM 10507/14294、NCIMB 42381或NCIMB42486保藏的细菌的其它核苷酸序列进行测序来鉴别。举例来说,基本上全基因组可以进行测序,且用于本发明的生物型菌株可以在其全基因组的至少80%上 (例如在至少85%、90%、95%或99%上或在其全基因组上)具有至少95%、96%、97%、98%、99%、99.5%或99.9%序列同一性。举例来说,在一些实施方案中,生物型菌株在其基因组的至少98%上具有至少98%序列同一性,或在其基因组的99%上具有至少99%序列同一性。用于鉴别生物型菌株的其它合适序列可以包括hsp60或重复序列,例如BOX、ERIC、(GTG)5或REP或[20]。生物型菌株可以具有与以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌的对应序列至少95%、96%、97%、98%、99%、99.5%或99.9%序列同一的序列。在一些实施方案中,生物型菌种具有与以DSM 10507/14294保藏的氢营养布劳特氏菌菌株的对应序列至少97%、98%、99%、99.5%或99.9%序列同一的序列,且包含与SEQ ID NO:5 至少99%同一(例如,至少99.5%或至少99.9%同一)的16S rRNA序列。在一些实施方案中,生物型菌种具有与以DSM 10507/14294保藏的氢营养布劳特氏菌菌株的对应序列至少97%、98%、99%、99.5%或99.9%序列同一的序列,且具有SEQ ID NO:5的16S rRNA序列。
可替代地,作为以登记号DSM 10507/14294、NCIMB 42381或 NCIMB 42486保藏的细菌的生物型且适用于本发明中的菌株可以通过使用登记号DSM 10507/14294保藏物、登记号NCIMB 42381保藏物或登记号NCIMB 42486保藏物和限制性片段分析和/或PCR分析,例如通过使用荧光扩增片段长度多态性(fluorescent amplified fragment lengthpolymorphism,FAFLP)和重复DNA组件(rep)-PCR指纹法,或蛋白质谱分析,或部分16S或23srDNA测序来鉴别。在优选实施方案中,此类技术可以用于鉴别其它氢营养布劳特氏菌、粪便布劳特氏菌或韦氏布劳特氏菌菌株。
在某些实施方案中,作为以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌的生物型且适用于本发明中的菌株是当通过扩增核糖体DNA限制性分析(amplified ribosomal DNA restriction analysis,ARDRA)进行分析时,例如当使用Sau3AI限制酶 (关于例示性方法和指导参见例如[21])时提供与以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌相同模式的菌株。可替代地,生物型菌株被确定是具有与以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌相同的碳水化合物发酵模式的菌株。
适用于本发明的组合物和方法的其它布劳特氏菌属菌株,例如以登记号DSM10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌的生物型可以使用任何适当方法或策略,包括实施例中描述的测定来鉴别。举例来说,用于本发明的菌株可以通过培养细菌并施用于大鼠中以在扩张测定中测试来鉴别。具体来说,具有与以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的细菌类似的生长模式、代谢类型和/或表面抗原的细菌菌株可用于本发明。适用的菌株将具有与DSM 10507/14294、NCIMB 42381或NCIMB 42486菌株相当的微生物丛调节活性。具体来说,生物型菌株将对内脏高敏感性模型引起与实施例中所示的作用相当的作用,其可以通过使用实施例中描述的培养和施用方案来鉴别。
本发明的一种尤其优选的菌株是以登记号DSM 10507/14294保藏的氢营养布劳特氏菌菌株。它是实施例中测试的例示性BH菌株并且展示有效治疗疾病。因此,本发明提供了以登记号DSM 10507/14294保藏的氢营养布劳特氏菌菌株或其衍生物的细胞,例如分离细胞,其用于治疗中,尤其用于本文中描述的疾病。
以登记号DSM 10507/14294、NCIMB 42381或NCIMB 42486保藏的菌株的衍生物可以是子代菌株(后代)或从原始菌株培养(亚克隆) 的菌株。本发明菌株的衍生物可以例如在基因水平下进行修饰,而不消除生物活性。具体来说,本发明的衍生菌株具治疗活性。衍生菌株将具有与原始DSM 10507/14294、NCIMB 42381或NCIMB 42486菌株相当的微生物丛调节活性。具体来说,衍生菌株将对内脏高敏感性模型引起与实施例中所示的作用相当的作用,其可以通过使用实施例中描述的培养和施用方案来鉴别。DSM 10507/14294菌株的衍生物一般将是DSM 10507/14294菌株的生物型。NCIMB 42381菌株的衍生物一般将是NCIMB42381菌株的生物型。NCIMB 42486菌株的衍生物一般将是NCIMB 42486菌株的生物型。
对以登记号DSM 10507/14294保藏的氢营养布劳特氏菌菌株的细胞的提及涵盖具有与以登记号DSM 10507/14294保藏的菌株相同的安全性和治疗功效特征的任何细胞,且本发明涵盖此类细胞。对以登记号NCIMB 42381保藏的粪便布劳特氏菌菌株的细胞的提及涵盖具有与以登记号NCIMB 42381保藏的菌株相同的安全性和治疗功效特性的任何细胞,且本发明涵盖此类细胞。对以登记号NCIMB 42486 保藏的韦氏布劳特氏菌菌株的细胞的提及涵盖具有与以登记号 NCIMB 42486保藏的菌株相同的安全性和治疗功效特性的任何细胞,且本发明涵盖此类细胞。
在优选实施方案中,本发明组合物中的细菌菌株是有活力的并能够部分或全部定殖肠部。
治疗用途
在优选实施方案中,本发明的组合物用于治疗内脏高敏感性。内脏高敏感性是一种特殊类型的疼痛,其特征为位于腹腔区域,由胸部、骨盆或腹腔内脏(器官)的疼痛感受器活化所致的主观疼痛感觉。内脏高敏感性通常弥漫且难以定位,因此与通常较剧烈并更集中的躯体性疼痛形成对比。而且,与躯体性疼痛不同,内脏高敏感性通常与特定的结构性病变无关联。内脏疼痛感受器在本质上不同于皮肤和大部分其它非内脏疼痛感受器[22]。
内脏高敏感性通常是在腹部感受到的,但并非所有的腹痛都是内脏高敏感性。相比之下,腹痛具有许多潜在的原因且腹痛可能是躯体性疼痛、牵涉痛或内脏疼痛。在腹部中,躯体性疼痛可能由发炎器官引起且通常剧烈而集中。腹痛可能由纤维肌痛引起,纤维肌痛是躯体 (皮肤和肌肉)高敏感性的病状。牵涉痛可以在远离患病器官的皮肤部位感受到。
内脏高敏感性通常与功能性消化不良和肠易激综合征(IBS)相关。然而,并非所有与功能性消化不良和IBS相关的疼痛都是内脏高敏感性。实际上,许多患有IBS的患者也展现众多种腹腔部位(背痛、胃灼热)和非腹腔部位(偏头痛、***困难、躯体定位上远离肠道的身体部位中的肌肉疼痛)中的躯体症状[23]。
在一些实施方案中,疾病或病状的发病机制影响肠。在一些实施方案中,疾病或病状的发病机制不影响肠。在一些实施方案中,疾病或病状的发病机制不局限于肠。在一些实施方案中,治疗或预防发生在除肠以外的部位。在一些实施方案中,治疗或预防发生在肠以及除肠以外的部位。在某些实施方案中,疾病或病状是全身性的。
内脏高敏感性又称为内脏疼痛,且这两个术语在本文中可以互换使用。
如实施例中所显示,本发明的细菌组合物可以有效降低内脏高敏感性。具体地说,本发明的细菌组合物可以减少对结肠直肠扩张的反应,所述反应是影响许多患者的内脏高敏感性的表现。在优选实施方案中,本发明的组合物用于治疗或预防腹部中、优选地胃肠道中且最优选地下胃肠道中的内脏高敏感性。在其它实施方案中,本发明的组合物用于治疗或预防盲肠、结肠或直肠中的内脏高敏感性。
在优选实施方案中,本发明的组合物用于治疗或预防与克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS相关的内脏高敏感性。在优选实施方案中,本发明的组合物用于治疗或预防被诊断为患有克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS的受试者的内脏高敏感性。在优选实施方案中,本发明的组合物用于在克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS的治疗中治疗或预防内脏高敏感性。
在优选实施方案中,本发明的组合物用于治疗或预防与克罗恩病、溃疡性结肠炎、功能性消化不良或更优选地IBS相关的内脏高敏感性。在优选实施方案中,本发明的组合物用于治疗或预防被诊断为患有克罗恩病、溃疡性结肠炎、功能性消化不良或更优选地IBS的受试者的内脏高敏感性。在优选实施方案中,本发明的组合物用于在克罗恩病、溃疡性结肠炎、功能性消化不良或更优选地IBS的治疗中治疗或预防内脏高敏感性。在某些实施方案中,本发明的组合物用于治疗遭受胃肠道、特别是结肠或直肠中胀痛的患者的内脏高敏感性。
与IBS和其它肠病状相关的不适和痛苦的某些方面可能由胃肠道中气体的过量产生和这些累积气体的巨大体积引起。例如,不同气体的体积增加可能导致肠胃气胀。如实施例中所示,本发明的细菌组合物可以有效治疗IBS和其它肠病状的特定方面-内脏高敏感性。不希望受限于任何理论,所观察到的本发明的细菌组合物对内脏高敏感性的作用可能与细菌对特定气体(H2S)的作用和其对在肠道中合成 H2S的硫酸盐还原细菌(SRB)的作用相关。H2S可能作为疼痛信号传导分子起重要作用且在实施例中所观察到的本发明组合物对内脏高敏感性的作用可能与肠中H2S产量的减少有关,所述H2S的产生可能通过影响疼痛信号传导引起内脏高敏感性,与涉及气体体积的任何气胀效应无关。实施例显示本发明的细菌组合物可以有效减少SRB 并减少H2S。在一些实施方案中,本发明的细菌组合物在盲肠中减少 SRB和/或减少H2S。SRB是利用硫酸盐还原作用产生能量的厌氧细菌且SRB的实例包括脱硫弧菌属(Desulfovibrio)的成员,且特别是懒惰脱硫弧菌(Desulfovibrio piger,其是最丰富的物种),以及脱硫杆菌属(Desulfobacter)、脱硫葱状菌属(Desulfobulbus)和脱硫肠状菌属 (Desulfotomaculum)的成员。
在某些实施方案中,本发明的组合物用于在内脏高敏感性的治疗中减少SRB在胃肠道中的定殖。在这些实施方案中,组合物可以优选呈细菌培养物的形式。在这些实施方案中,组合物可以优选是冻干物。在某些实施方案中,本发明的组合物用于在内脏高敏感性的治疗中降低胃肠道中H2S水平或预防H2S水平升高。在这些实施方案中,组合物可以优选是冻干物。
在某些实施方案中,本发明的组合物用于在内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、群落和/或种群水平。在某些实施方案中,本发明的组合物用于在内脏高敏感性的治疗中减少SRB在盲肠中的定殖、群落和/或种群水平。
在优选实施方案中,本发明的组合物用于在与IBS相关的内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、降低H2S水平或预防 H2S水平升高。在其它实施方案中,本发明的组合物用于在与克罗恩病、溃疡性结肠炎、功能性消化不良或婴儿肠绞痛相关的内脏高敏感性的治疗中、例如在与克罗恩病、溃疡性结肠炎或功能性消化不良相关的内脏高敏感性的治疗中,减少SRB在胃肠道中的定殖、降低H2S 水平或预防H2S水平升高。
在优选实施方案中,本发明的组合物用于在与IBS相关的内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、群落和/或种群水平,降低H2S水平或预防H2S水平升高。在其它实施方案中,本发明的组合物用于在与克罗恩病、溃疡性结肠炎、功能性消化不良或婴儿肠绞痛相关的内脏高敏感性的治疗中、例如在与克罗恩病、溃疡性结肠炎或功能性消化不良相关的内脏高敏感性的治疗中,减少SRB在胃肠道中的定殖、群落和/或种群水平,降低H2S水平或预防H2S水平升高。
在优选实施方案中,本发明的组合物用于在腹部中,优选地胃肠道中,更优选地下胃肠道中、盲肠中、结肠中或直肠中的内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、降低H2S水平或预防H2S 水平升高。在优选实施方案中,本发明的组合物用于在腹部中,优选地胃肠道中,更优选地下胃肠道中、盲肠中、结肠中或直肠中的内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、群落和/或种群水平,降低H2S水平或预防H2S水平升高。
在某些实施方案中,本发明的组合物用于治疗、预防或减少SRB 在胃肠道中的定殖的方法中。在某些实施方案中,本发明的组合物用于治疗、预防或减少SRB在胃肠道中的定殖、群落和/或种群水平的方法中。在某些实施方案中,本发明的组合物用于降低胃肠道中的 H2S水平或预防H2S水平升高的方法中。
在某些实施方案中,本发明的组合物用于治疗(例如)当与健康受试者或健康受试者的群体相比时,展现或预期会展现胃肠道中的SRB 和/或H2S水平增加的患者。
在某些实施方案中,本发明的组合物用于预防正在接受或已经接受抗生素治疗或正在遭受或已经遭受细菌性胃肠炎的受试者的内脏高敏感性。抗生素治疗和细菌性胃肠炎引起肠道微生物丛的改变,所述微生物丛改变可能引发内脏高敏感性且可以通过本发明的组合物预防。本发明的组合物可以与抗生素治疗同时施用。
在优选实施方案中,利用本发明的组合物治疗降低内脏高敏感性、减少SRB定殖和/或降低H2S水平。
内脏高敏感性的治疗或预防可以指例如缓和症状严重性或降低恶化频率或缩小对患者来说成问题的触发因素的范围。举例来说,在一些实施方案中,本发明的组合物用于治疗或预防严重的内脏高敏感性。在一些实施方案中,患有重度内脏高敏感性的受试者是被诊断为患有克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS的受试者。在一些实施方案中,患有重度内脏高敏感性的受试者是被诊断为患有克罗恩病、溃疡性结肠炎、功能性消化不良或更优选地IBS的受试者。
施用模式
优选地,本发明的组合物待施用于胃肠道,以便能够传递至肠和 /或使本发明的细菌菌株部分或全部定殖肠部。一般地,虽然本发明的组合物经口施用,但其可以经直肠、鼻内或经颊或舌下途径施用。
在某些实施方案中,本发明的组合物可以呈泡沫、喷雾或凝胶形式施用。
在某些实施方案中,本发明的组合物可以呈栓剂,例如直肠栓剂,例如呈可可豆油(可可脂)、合成硬脂(例如suppocire、witepsol)、甘油基-明胶、聚乙二醇或肥皂甘油组合物的形式施用。
在某些实施方案中,本发明的组合物经由管,例如鼻饲管、口胃管、胃管、空肠造口管(J型管)、经皮内窥镜胃造口术(percutaneous endoscopic gastrostomy,PEG)或端口,例如通向胃、空肠和其它适合进入端口的胸壁端口施用于胃肠道。
本发明的组合物可以施用一次,或其可以作为治疗方案的一部分相继施用。在某些实施方案中,本发明的组合物将每天施用。实施例显示,每天施用在内脏高敏感性的大鼠模型中成功地提供定殖和临床益处。
实施例还显示,BH施用不会导致肠中的永久定殖,故定期长时间施用可以提供较大的治疗益处。因此,实施例显示在每天施用后本发明的细菌菌株成功地传递至结肠。
因此,在某些实施方案中,本发明的组合物定期(例如,每天、每两天或每周)长时间(例如,至少一周、两周、一个月、两个月、六个月或一年)施用。
在一些实施方案中,本发明的组合物施用7天、14天、16天、 21天或28天或不多于7天、14天、16天、21天或28天。举例来说,在一些实施方案中,本发明的组合物施用16天。
在本发明的某些实施方案中,根据本发明的治疗伴随有患者肠道微生物丛的评估。如果未实现本发明的菌株传递和/或部分或全部定殖,从而未观察到功效,那么可以重复治疗,如果传递和/或部分或全部定殖成功且观察到功效,那么可以停止治疗。
在某些实施方案中,本发明的组合物可以施用于怀孕动物,例如哺乳动物,例如人类,以预防内脏高敏感性在其子女中在出生前和/ 或出生后出现。
本发明的组合物可以施用于被诊断为患有内脏高敏感性或与内脏高敏感性相关的疾病或病状或已经被鉴别为处于内脏高敏感性风险中的患者。组合物也可以作为预防措施施用以预防健康患者中出现内脏高敏感性。
本发明的组合物可以施用于已经被鉴别为具有异常肠道微生物丛的患者。举例来说,患者可以具有减少或缺乏的布劳特氏菌属和特别是氢营养布劳特氏菌、粪便布劳特氏菌或韦氏布劳特氏菌的定殖。
本发明的组合物可以作为食品,例如营养增补剂施用。
一般地,本发明的组合物用于治疗人类,不过其可以用于治疗动物,包括单胃哺乳动物,例如家禽、猪、猫、犬、马或兔。本发明的组合物可用于增强动物的生长和性能。如果施用于动物,那么可以使用经口管饲法。
在一些实施方案中,有待施用组合物的受试者是成年人。在一些实施方案中,有待施用组合物的受试者是人类婴儿。
组合物
一般地,本发明的组合物包含细菌。在本发明的优选实施方案中,组合物呈冻干形式配制。举例来说,本发明的组合物可以包含含有本发明的细菌菌株的颗粒或明胶胶囊,例如硬明胶胶囊。
优选地,本发明的组合物包含冻干细菌。细菌冻干是一种成熟的程序且相关指导可于例如参考文献[24-26]中获得。实施例显示,冻干物组合物尤其有效。在优选实施方案中,本发明的组合物包含冻干细菌且用于治疗与IBS相关的内脏高敏感性、优选用于在与IBS相关的内脏高敏感性的治疗中降低H2S水平或预防H2S水平升高。在其它优选实施方案中,本发明的组合物包含冻干细菌且用于治疗与IBS相关的内脏高敏感性、优选用于在内脏高敏感性的治疗中减少SRB在胃肠道中的定殖。在其它优选实施方案中,本发明的组合物包含冻干细菌且用于治疗与IBS相关的内脏高敏感性、优选地用于在内脏高敏感性的治疗中减少SRB在胃肠道中的定殖、群落和/或种群水平。
可替代地,本发明的组合物可以包含活的活性细菌培养物。实施例显示,本发明的细菌的培养物是治疗上有效的。
在一些实施方案中,本发明组合物中的细菌菌株尚未被灭活,例如尚未被热灭活。在一些实施方案中,本发明组合物中的细菌菌株尚未被杀死,例如尚未被热杀死。在一些实施方案中,本发明组合物中的细菌菌株尚未被减毒,例如尚未被热减毒。举例来说,在一些实施方案中,本发明组合物中的细菌菌株尚未被杀死、灭活和/或减毒。举例来说,在一些实施方案中,本发明组合物中的细菌菌株是活的。举例来说,在一些实施方案中,本发明组合物中的细菌菌株是有活力的。举例来说,在一些实施方案中,本发明组合物中的细菌菌株能够部分或完全定殖肠部。举例来说,在一些实施方案中,本发明组合物中的细菌菌株是有活力的并能够部分或完全定殖肠部。
在一些实施方案中,组合物包含活的细菌菌株与已经杀死的细菌菌株的混合物。
在优选实施方案中,本发明的组合物被囊封成能够传递细菌菌株至肠。囊封保护组合物免于降解,直到通过例如用化学或物理刺激,例如压力、酶活性或物理性崩解(其可以通过pH值改变而触发)进行破裂而在目标位置传递。可以使用任何适当囊封法。例示性囊封技术包括截留在多孔基质内、附着或吸附在固体载体表面上、通过絮凝或利用交联剂而自我凝聚以及机械密封在微孔膜或微胶囊后。关于可用于制备本发明的组合物的囊封的指导可以于例如参考文献[27-28]中获得。
组合物可以经口施用且可以呈片剂、胶囊或散剂形式。囊封产品是优选的,因为布劳特氏菌属是厌氧菌。其它成分(例如维生素C)可以作为除氧剂和益生元基质而包括以改良体内传递和/或部分或全部定殖和存活。可替代地,本发明的益生组合物可以作为食品或营养产品,例如基于牛奶或乳清的发酵乳制品,或作为药品经口施用。
组合物可以被配制为益生菌。
本发明的组合物包括治疗有效量的本发明的细菌菌株。治疗有效量的细菌菌株足以对患者发挥有益作用。治疗有效量的细菌菌株可以足够传递至患者肠部和/或部分或全部定殖患者肠部。
例如适合于成年人的细菌日剂量可以是约1×103至约1×1011菌落形成单位(colony forming unit,CFU);例如约1×107至约1×1010CFU;在另一实例中,约1×106至约1×1010CFU;在另一实例中,约1×107至约1×1011CFU;在另一实例中,约1×108至约1×1010CFU;在另一实例中,约1×108至约1×1011CFU。
在某些实施方案中,细菌的剂量是至少109个细胞/天,例如至少 1010个细胞/天、至少1011个细胞/天或至少1012个细胞/天。
在某些实施方案中,组合物含有相对于组合物的重量,约1×106至约1×1011CFU/g,例如约1×108至约1×1010CFU/g的量的细菌菌株。剂量可以是例如1g、3g、5g和10g。
通常,益生菌,例如本发明的组合物,任选地与至少一种合适的益生元化合物组合。益生元化合物通常是不易消化的碳水化合物,例如寡糖或多糖,或糖醇,其在上消化道中不降解或吸收。已知的益生元包括商业产品,例如菊糖和反式半乳寡糖。
在某些实施方案中,本发明的益生菌组合物包括相对于组合物总重量,约1至约30重量%(例如5至20重量%)的量的益生元化合物。碳水化合物可以选自由以下组成的组:果寡糖(或FOS)、短链果寡糖、菊糖、异麦芽寡糖、果胶、木寡糖(或XOS)、几丁寡糖(或COS)、β-葡聚糖、***胶改性和抗性淀粉、聚葡萄糖、D-塔格糖、***胶纤维、角豆树、燕麦和柑桔纤维。在一个方面中,益生元是短链果寡糖(下文中简单起见展示为FOSs-c.c);所述FOSs-c.c是不易消化的碳水化合物,一般由甜菜糖转变获得并且包括三个葡萄糖分子键结的蔗糖分子。
本发明的组合物可以包含药学上可接受的赋形剂或载剂。此类合适赋形剂的实例可以见于参考文献[29]中。用于治疗用途的可接受的载剂或稀释剂是医药技术中众所周知的并且描述于例如参考文献[30] 中。合适载剂的实例包括乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露糖醇、山梨糖醇等等。合适稀释剂的实例包括乙醇、甘油和水。医药载剂、赋形剂或稀释剂的选择可以针对预期施用途径和标准医药实践来选择。药物组合物可以包含任何合适的粘合剂、润滑剂、悬浮剂、包被剂、增溶剂作为载剂、赋形剂或稀释剂或除载剂、赋形剂或稀释剂之外可以包含所述物质。合适粘合剂的实例包括淀粉、明胶、天然糖(例如葡萄糖、无水乳糖、自由流动乳糖、β-乳糖、玉米甜味剂)、天然和合成胶(例如***胶、黄蓍胶或海藻酸钠)、羧甲基纤维素和聚乙二醇。合适润滑剂的实例包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等等。防腐剂、稳定剂、染料和甚至调味剂可以提供于药物组合物中。防腐剂的实例包括苯甲酸钠、山梨酸、半胱氨酸和对羟基苯甲酸酯,例如,在一些实施方案中,防腐剂选自苯甲酸钠、山梨酸和对羟基苯甲酸酯。还可以使用抗氧化剂和悬浮剂。合适载剂的另一实例是蔗糖。防腐剂的另一实例是半胱氨酸。
本发明的组合物可以被配制为食品。举例来说,除本发明的治疗作用之外,食品可以提供营养益处,例如在营养增补剂中。类似地,食品可以被配制成增强本发明组合物的口味,或通过使其更类似于常见食品而非药物组合物而使得组合物食用起来更具吸引力。在某些实施方案中,本发明的组合物被配制成基于牛奶的产品。术语“基于牛奶的产品”意指具有变化脂肪含量的任何基于牛奶或乳清的液体或半固体产品。基于牛奶的产品可以是例如奶牛奶、山羊奶、绵羊奶、脱脂乳、全脂奶、无任何加工下由奶粉与乳清重组而来的牛奶或加工产品,例如酸乳酪、奶酪、凝乳、酸牛奶、酸全脂奶、白脱牛奶和其它酸牛奶产品。另一重要组包括乳制饮料,例如乳清饮料、发酵牛奶、炼乳、婴儿或婴孩牛奶;风味奶、冰淇淋;含牛奶的食品,例如甜点。
在一些实施方案中,本发明的组合物包含布劳特氏菌属的一种或多种细菌菌株且不含有来自任何其它种属的细菌,或其仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌。
在某些实施方案中,本发明的组合物含有单一细菌菌株或物种且不含有任何其它细菌菌株或物种。此类组合物可以仅仅包含最低限度量或生物学上不相关量的其它细菌菌株或物种。此类组合物可以是基本上不含其它生物体物种的培养物。在一些实施方案中,此类组合物可以是基本上不含其它生物体物种的冻干物。
在某些实施方案中,本发明的组合物包含布劳特氏菌属(例如,氢营养布劳特氏菌)的一种或多种细菌菌株且不含有任何其它细菌种属,或其仅仅包含最低限度量或生物学上不相干量的来自另一种属的细菌。在某些实施方案中,本发明的组合物包含布劳特氏菌的单一物种(例如,氢营养布劳特氏菌)且不含有任何其它细菌物种,或其仅仅包含最低限度量或生物学上不相干量的来自另一物种的细菌。在某些实施方案中,本发明的组合物包含布劳特氏菌(例如,氢营养布劳特氏菌)的单一菌株且不含有任何其它细菌菌株或细菌物种,或其仅仅包含最低限度量或生物学上不相干量的来自另一菌株或物种的细菌。
在一些实施方案中,本发明的组合物包含超过一种细菌菌株或物种。举例来说,在一些实施方案中,本发明的组合物包含超过一种来自同一个物种内的菌株(例如,超过1种、2种、3种、4种、5种、6 种、7种、8种、9种、10种、15种、20种、25种、30种、35种、 40种或45种菌株),且任选地不含有来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含少于50种来自同一个物种内的菌株(例如,少于45种、40种、35种、30种、25种、20种、15种、12种、10种、9种、8种、7种、6种、5种、4种或3种菌株),且任选地不含有来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含1-40种、1-30种、1-20种、1-19种、1-18种、1-15种、 1-10种、1-9种、1-8种、1-7种、1-6种、1-5种、1-4种、1-3种、1-2 种、2-50种、2-40种、2-30种、2-20种、2-15种、2-10种、2-5种、 6-30种、6-15种、16-25种或31-50种来自同一个物种内的菌株,且任选地不含有来自任何其它物种的细菌。在一些实施方案中,本发明的组合物包含超过一种来自同一种属内的物种(例如,1个、2个、3 个、4个、5个、6个、7个、8个、9个、10个、12个、15个、17 个、20个、23个、25个、30个、35个或40个以上物种),且任选地不含有来自任何其它种属的细菌。在一些实施方案中,本发明的组合物包含少于50个来自同一种属内的物种(例如,少于50个、45个、 40个、35个、30个、25个、20个、15个、12个、10个、8个、7个、6个、5个、4个或3个物种),且任选地不含有来自任何其它种属的细菌。在一些实施方案中,本发明的组合物包含1-50个、1-40 个、1-30个、1-20个、1-15个、1-10个、1-9个、1-8个、1-7个、1-6 个、1-5个、1-4个、1-3个、1-2个、2-50个、2-40个、2-30个、2-20 个、2-15个、2-10个、2-5个、6-30个、6-15个、16-25个或31-50 个来自同一种属内的物种,且任选地不含有来自任何其它种属的细菌。本发明包含上述每一种细菌的任一组合。
在一些实施方案中,组合物包含微生物菌群。举例来说,在一些实施方案中,组合物包含布劳特氏菌属细菌菌株作为微生物菌群的一部分。举例来说,在一些实施方案中,布劳特氏菌属细菌菌株与一种或多种(例如,至少2种、3种、4种、5种、10种、15种或20种) 来自可在体内共生生存的其它种属的其它细菌菌株组合存于肠部。举例来说,在一些实施方案中,组合物包含氢营养布劳特氏菌的细菌菌株与来自不同种属的细菌菌株的组合。在一些实施方案中,微生物菌群包含两个或更多个从例如人等单一生物体的粪便样品获得的细菌菌株。在一些实施方案中,微生物菌群在自然界中未一起发现。举例来说,在一些实施方案中,微生物菌群包含从至少两个不同生物体的粪便样品获得的细菌菌株。在一些实施方案中,所述两个不同生物体来自同一物种,例如两个不同人。在一些实施方案中,两个不同生物体是人类婴儿和成年人。在一些实施方案中,两个不同生物体是人和非人哺乳动物。
在一些实施方案中,本发明的组合物另外包含具有与以登记号 DSM 10507/14294保藏的氢营养布劳特氏菌菌株相同的安全性和治疗功效特征的细菌菌株,但其不是以登记号DSM 10507/14294保藏的氢营养布劳特氏菌菌株,或其不是氢营养布劳特氏菌或其不是布劳特氏菌属。
在本发明的组合物包含超过一个细菌菌株、物种或种属的一些实施方案中,个别的细菌菌株、物种或种属可以分开、同时或相继施用。举例来说,组合物可以包含超过一个细菌菌株、物种或种属全部,或细菌菌株、物种或种属可以分开存储并且分开、同时或相继施用。在一些实施方案中,超过一个细菌菌株、物种或种属分开存储,但是在使用前混合在一起。
在一些实施方案中,从成人粪便获得用于本发明的细菌菌株。在本发明的组合物包含超过一个细菌菌株的一些实施方案中,从成人粪便获得所有细菌菌株,或者如果存在其它细菌菌株,那么其仅仅以最低限度量存在。细菌可以在从成人粪便获得并且用于本发明的组合物后进行培养。
在一些实施方案中,一个或多个布劳特氏菌属细菌菌株是本发明的组合物中的唯一治疗活性剂。在一些实施方案中,组合物中的细菌菌株是本发明的组合物中的唯一治疗活性剂。
根据本发明使用的组合物可能需要或可能不需要上市批准。
在某些实施方案中,本发明提供了以上药物组合物,其中所述细菌菌株是冻干的。在某些实施方案中,本发明提供了以上药物组合物,其中所述细菌菌株进行喷雾干燥。在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其是活的。在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其是有活力的。在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其能够部分或完全定殖肠部。在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株是冻干的或喷雾干燥并且其中其是有活力的并能够部分或完全定殖肠部。
在一些情况下,冻干或喷雾干燥的细菌菌株在施用之前复原。在一些情况下,复原是通过使用本文中描述的稀释剂。
本发明的组合物可以包含药学上可接受的赋形剂、稀释剂或载剂。
在某些实施方案中,本发明提供了药物组合物,其包含:本发明的细菌菌株;和药学上可接受的赋形剂、载剂或稀释剂;其中细菌菌株的量在施用于有需要的受试者时足以治疗病症;且其中病症是内脏高敏感性,例如与克罗恩病、溃疡性结肠炎、功能性消化不良、婴儿肠绞痛或更优选地IBS相关的内脏高敏感性。
在某些实施方案中,本发明提供了一种药物组合物,其包含:本发明的细菌菌株;和药学上可接受的赋形剂、载剂或稀释剂;其中细菌菌株的量在施用于有需要的受试者时足以治疗病症;并且其中病症是内脏高敏感性,例如与克罗恩病、溃疡性结肠炎、功能性消化不良或更优选地IBS相关的内脏高敏感性。
在某些实施方案中,本发明提供了以上药物组合物,其中细菌菌株的量是相对于组合物的重量每克约1×103至约1×1011菌落形成单位。
在某些实施方案中,本发明提供了以上药物组合物,其中组合物以1g、3g、5g或10g的剂量施用。
在某些实施方案中,本发明提供了以上药物组合物,其中组合物通过选自由口腔、直肠、皮下、鼻、颊和舌下组成的组的方法施用。
在某些实施方案中,本发明提供了以上药物组合物,其包含选自由乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露糖醇和山梨糖醇组成的组的载剂。
在某些实施方案中,本发明提供了以上药物组合物,其包含选自由乙醇、甘油和水组成的组的稀释剂。
在某些实施方案中,本发明提供了以上药物组合物,其包含选自由以下组成的组的赋形剂:淀粉、明胶、葡萄糖、无水乳糖、自由流动的乳糖、β-乳糖、玉米甜味剂、***胶、黄蓍胶、海藻酸钠、羧甲基纤维素、聚乙二醇、油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠和氯化钠。
在某些实施方案中,本发明提供了以上药物组合物,其进一步包含防腐剂、抗氧化剂和稳定剂中的至少一种。
在某些实施方案中,本发明提供了以上药物组合物,其包含选自由苯甲酸钠、山梨酸和对羟基苯甲酸酯组成的组的防腐剂。
在某些实施方案中,本发明提供了以上药物组合物,其中所述细菌菌株是冻干的。
在某些实施方案中,本发明提供了以上药物组合物,其中当组合物存储在密封容器中约4℃或约25℃下并且将容器置于具有50%相对湿度的气氛中时,如以菌落形成单位所测量,在至少约1个月、3 个月、6个月、1年、1.5年、2年、2.5年或3年时期后,至少80%细菌菌株残留。
在一些实施方案中,本发明的组合物提供于包含如本文描述的组合物的密封容器中。在一些实施方案中,密封容器是小袋或瓶子。在一些实施方案中,本发明的组合物提供于包含如本文描述的组合物的注射器中。
在一些实施方案中,本发明的组合物可以呈药物制剂提供。举例来说,组合物可以呈片剂或胶囊提供。在一些实施方案中,胶囊是明胶胶囊(“gel-cap”)。
在一些实施方案中,本发明的组合物经口施用。经口施用可能涉及吞咽,以便化合物进入胃肠道,和/或经颊、经舌或舌下施用,从而化合物直接从口腔进入血流。
适合于经口施用的药物制剂包括固体塞、固体微粒、半固体和液体(包括多相或分散***),例如片剂;含有微米粒子或纳米粒子的软胶囊或硬胶囊、液体(例如水溶液)、乳液或散剂;糖锭(包括填充液体);咀嚼片;凝胶;快速分散的剂型;薄膜;卵形囊剂;喷雾;和经颊/ 粘膜粘着贴片。
在一些实施方案中,药物制剂是肠制剂,即适合于通过经口施用传递本发明的组合物至肠的抗胃制剂(例如对胃pH值有抗性)。当细菌或组合物的另一组分对酸敏感,例如在胃条件下倾向于降解时,肠制剂可能特别有用。
在一些实施方案中,肠制剂包含肠衣。在一些实施方案中,制剂是肠衣剂型。举例来说,制剂可以是肠衣片剂或肠衣胶囊等等。肠衣可以是常规肠衣,例如用于片剂、胶囊等等进行经口传递的常规包衣。制剂可以包含膜衣,例如肠聚合物、例如酸不溶性聚合物的薄膜层。
在一些实施方案中,肠制剂本质上是肠溶性的,例如对胃具有抗性,无需肠衣。因此,在一些实施方案中,制剂是不包含肠衣的肠制剂。在一些实施方案中,制剂是由热胶凝材料制成的胶囊。在一些实施方案中,热胶凝材料是纤维素材料,例如甲基纤维素、羟甲基纤维素或羟丙基甲基纤维素(HPMC)。在一些实施方案中,胶囊包含不含任何成膜聚合物的壳。在一些实施方案中,胶囊包含壳并且壳包含羟丙基甲基纤维素且不包含任何成膜聚合物(例如参见[31])。在一些实施方案中,制剂是本质上肠胶囊(例如来自Capsugel的)。
在一些实施方案中,制剂是软胶囊。软胶囊是由于添加例如丙三醇、山梨糖醇、麦芽糖醇和聚乙二醇等在胶囊壳中存在的软化剂而具有一定弹性和柔软度的胶囊。软胶囊可以例如基于明胶或淀粉产生。基于明胶的软胶囊从多个供应商购得。取决于施用方法,例如经口或经直肠,软胶囊可以具有多种形状,其可以例如是圆形、卵形、长方形或鱼雷形状。软胶囊可以通过常规方法产生,例如通过谢勒法 (Scherer process)、阿可法(Accogelprocess)或液滴或吹制法产生。
培养方法
用于本发明的细菌菌株可以使用如例如参考文献[32-34]中详述的标准微生物学技术培养。
用于培养的固体或液体培养基可以例如是YCFA琼脂或YCFA 培养基。YCFA培养基可以包括(每100ml,近似值):酪胨(1.0g)、酵母提取物(0.25g)、NaHCO3(0.4g)、半胱氨酸(0.1g)、K2HPO4(0.045 g)、KH2PO4(0.045g)、NaCl(0.09g)、(NH4)2SO4(0.09g)、MgSO4·7H2O(0.009g)、CaCl2(0.009g)、刃天青(0.1mg)、氯化血红素(1mg)、生物素(1μg)、钴胺素(1μg)、对氨基苯甲酸(3μg)、叶酸(5μg)和吡哆胺(15 μg)。
通则
除非另外指明,否则本发明的实施将采用在本领域技能内的常规化学、生物化学、分子生物学、免疫学和药理学方法。此类技术在文献中予以充分解释。参见例如参考文献[35-42]等。
术语“包含”涵盖“包括”以及“由……组成”,例如“包含”X的组合物可以仅仅由X组成,或可以包括其它某物,例如X+Y。
关于数值x的术语“约”是任选选用的并且意指例如x±10%。
词语“基本上”不排除“完全”,例如“基本上不含”Y的组合物可以完全不含Y。必要时,本发明的定义中可以省略词语“基本上”。
提及两种核苷酸序列之间的序列同一性百分比意指在比对时,比较两种序列中相同的核苷酸百分比。此比对和同源性或序列同一性百分比可以使用本领域中已知的软件程序,例如参考文献[43]的部分 7.7.18中描述的软件程序确定。优选比对通过Smith-Waterman同源性搜索算法,使用仿射空位搜索(其中开放空位罚分是12且空位延伸罚分是2,BLOSUM 62矩阵)来确定。Smith-Waterman同源性搜索算法在参考文献[44]中公开。
除非特别陈述,否则包括多个步骤的工艺或方法可以在方法开始或结束时包括额外步骤,或可以包括额外***步骤。此外,适当时步骤可以组合,省去或以替代次序进行。
本文中描述本发明的多个实施方案。应了解每个实施方案中说明的特征都可以与其它所说明的特征进行组合以提供其它实施方案。具体来说,本文中强调为适合、典型或优选的实施方案可以彼此进行组合(除非其互斥时)。
用于进行本发明的模式
实施例1-细菌接种物在内脏高敏感性的大鼠模型中的功效
概述
用来自展现内脏高敏感性的人类IBS受试者的粪便微生物丛接种大鼠。然后将包含根据本发明的细菌菌株的组合物施用于大鼠且然后使用扩张测定进行测试以测量内脏高敏感性。发现本发明的组合物减少大鼠对扩张的反应,此表面内脏高敏感性降低。
菌株
氢营养布劳特氏菌(BH)菌株DSM 10507/14294。
组合物和施用
BH培养物(16H)或冻干物-通过经口管饲法施用
通过经口管饲法施用的对照溶液
大鼠
用来自IBS受试者的人类肠道微生物丛接种。
研究设计
第-14天-用来自IBS受试者的人类肠道微生物丛接种大鼠
第0天至第28天-每天给与BH培养物或冻干物或对照溶液
第0天、第14天和第28天-粪便样品中BH群体的qPCR
第14天与第28天之间-用以将电极植入腹部中(用于扩张测定)
第28天-扩张测定,收集盲肠样品用于硫化物和短链脂肪酸 (SCFA)分析,计数选择性培养基上粪便样品中的微生物丛
结果
图1呈现来自施用对照溶液(IBS)或BH冻干物(IBS+BH)的大鼠的粪便样品中BH群体的qPCR分析的结果。第14天和第28天时在接受BH冻干物的大鼠中观察到BH群体增加,此证实定殖成功。
图2呈现扩张测定的结果。使大鼠经受结肠直肠扩张并记录每分钟的收缩次数作为内脏高敏感性的特定量度。经本发明组合物治疗的大鼠展现减少的收缩和降低的内脏高敏感性。
图3和图4报告施用BH培养物和冻干物对粪便样品中的微生物丛的作用。施用BH培养物使硫酸盐还原细菌(SRB)显著减少(1log)。
图5报告施用BH冻干物对微生物丛发酵的影响,如通过盲肠样品中的短链脂肪酸浓度所测量。施用BH冻干物使乙酸盐产量增加。
图6报告施用BH冻干物对微生物丛发酵的影响,如通过盲肠样品中的硫化物(H2S)浓度所测量。施用BH使硫化物产量减少。
结论
施用包含氢营养布劳特氏菌的组合物实现成功定殖和内脏高敏感性显著降低,如使用扩张测定所测量。当将氢营养布劳特氏菌作为培养物和作为冻干物施用时观察到此作用。施用氢营养布劳特氏菌也对微生物丛构成和发酵具有显著的作用,其中观察到SRB和硫化物产量减少。这些数据表明氢营养布劳特氏菌可用于降低内脏高敏感性,特别是用于降低与IBS相关的内脏高敏感性。内脏高敏感性的降低可能与所观察到的SRB和硫化物产量的减少相关。
实施例2-细菌冻干物在内脏高敏感性的大鼠模型中的功效
实施例1的观察在使用氢营养布劳特氏菌(BH)菌株DSM 10507/14294的冻干物和IBS的大鼠模型的进一步实验中得到证实。如图7和图8中所显示,施用BH冻干物使因对扩张反应而产生的腹腔收缩的次数在统计学上显著减少,此表明内脏高敏感性降低。在图 7中,来自一名IBS受试者的粪便样品用于接种大鼠。在图8中,来自三名IBS受试者的粪便样品用于接种大鼠,其中这些IBS受试者中的一名与图7中所用的IBS受试者相同。此外,如图9和图10中所显示,施用BH冻干物使硫化物在统计学上显著减少。在图9中,来自一名IBS受试者的粪便样品用于接种大鼠。在图10中,来自三名 IBS受试者的粪便样品用于接种大鼠,其中这些IBS受试者中的一名与图9中所用的IBS受试者相同。
实施例3-细菌冻干物对健康大鼠的作用
研究施用氢营养布劳特氏菌(BH)菌株DSM 10507/14294的冻干物对健康HIM大鼠的作用且结果报告于图11-14中。关于实验的其它细节提供于以上对图的描述中。图11显示在大鼠中BH的适当剂量是109个细胞/天或更多。图12显示在这些实验中,BH并未永久地定殖于大鼠消化道。图13显示BH主要在盲肠中发现。图14显示施用BH诱导乙酸盐以及丁酸盐产量增加。
实施例4-细菌冻干物在内脏高敏感性的大鼠模型中的功效
进一步研究施用氢营养布劳特氏菌(BH)菌株DSM 10507/14294 的冻干物对IBS的大鼠模型的作用。用来自C-IBS(患便秘)或U-IBS (未定型)患者的粪便样品接种无菌大鼠。大多数实验利用来自显示内脏高敏感性(利用恒压器测量的VH)的IBS患者的粪便样品进行。结果报告于图15和图16中且关于实验的其它细节提供于以上对图的描述中。图15证实施用BH冻干物引起硫酸盐还原细菌统计学上显著减少。如所预期,还观察到BH增加。图16显示BH施用诱导由IBS HIM大鼠所产生的H2S的量统计学上显著减少。肠道微生物丛产生过多盲肠H2S与内脏高敏感性相关。
实施例5-在I期临床试验期间患者症状的改变
进行I期临床试验,其中将氢营养布劳特氏菌(“Blautix”,以登记号DSM 10507以及以登记号DSM 14294保藏的菌株)施用于患有肠易激综合征(IBS)的人类患者。在给药期间(第1-16天)将Blautix施用于患者,且洗脱期是第19-23天。发现Blautix安全且耐受良好。监测到四种症状,其中之一是腹痛。本研究记录患者经历这些症状中的每一种的改善、不变还是恶化。将来自施用Blautix的患者的结果与使用施用安慰剂的患者所得的结果比较。在三个时间点监测症状:第1 天、第15/16天和研究结束时。结果显示于图17和图18中。
当将患者在第16天报告的症状与第1天的基线比较时,17名接受Blautix的IBS患者中有82%报告症状改善(图17)。症状(其中之一是腹痛)的改善支持使用Blautix治疗或预防内脏高敏感性。值得注意的是,在研究开始时都具有严重腹痛的患者3.02、3.17和3.24在第 15/16天分别具有轻微、轻微和无腹痛。
50%的接受安慰剂的患者报告症状改善(图17)。高安慰剂反应率是在IBS临床研究中已确定的现象。最近基于小得多的相对于安慰剂的改善批准利福昔明(Xifaxan)治疗IBS[45]。
基于本文呈现的教示,预期与给药完成时(第16天)所呈现的症状相比,在研究完成时(第19-23天)症状恶化。在I期临床试验中观察到此症状恶化:41%的IBS患者在Blautix给药停止后报告症状恶化(图18)。因此,症状(其中之一是腹痛)在Blautix给药停止后的恶化也支持使用Blautix治疗或预防内脏高敏感性。
实施例6-在人类微生物丛相关大鼠(HMA大鼠)模型中研究的氢营养布劳特氏菌对内脏高敏感性的功效
概述
用来自人类IBS受试者的粪便微生物丛接种16只无菌大鼠(包含对照组中的8只大鼠和治疗组中的8只大鼠)的组(IBS-HMA大鼠)。使用来自3名不同IBS患者的粪便样品进行三次连续实验。用健康受试者(n=2名受试者;2组健康-HMA大鼠)的粪便样品接种另两组大鼠 (n=10),作为内脏敏感性对照组。因此,有24只IBS-微生物丛相关大鼠(对照组)、用Blautix治疗的24只IBS-微生物丛相关大鼠和20 只健康微生物丛相关大鼠。然后将包含根据本发明的氢营养布劳特氏菌的细菌菌株的组合物施用于一半IBS-HMA大鼠28天,而另一半动物接受对照溶液。施用28天后,使用结肠扩张测定测试所有HMA- 大鼠以测量内脏敏感性。发现本发明的组合物减少IBS-HMA大鼠对扩张的反应,此表明内脏高敏感性降低,达到如在健康-HMA大鼠中所观察到的正常敏感性。
菌株
氢营养布劳特氏菌(BH)菌株DSM 10507T/14294。
组合物和施用
使BH冻干物悬浮于无菌矿物溶液中至1010个细菌/ml的浓度。通过经口管饲法每天将2ml此悬浮液施用于每只IBS-HMA大鼠,历时28天的时间。
对照溶液是无菌矿物溶液,通过经口管饲法将其每天施用(2ml/ 大鼠)于对照组的IBS-HMA大鼠。
大鼠
用来自IBS受试者的人类粪便微生物丛接种无菌雄性Fisher大鼠 (10周龄)(IBS-HMA大鼠)。利用相同的人类粪便接种物接种16只大鼠。利用来自3名不同IBS受试者的粪便样品进行3次连续实验。用来自2名健康受试者的粪便样品接种另2组10只大鼠(正常敏感性对照组)。
研究设计
第-14天-利用人类粪便微生物丛接种无菌大鼠。
第0天至第28天-通过经口管饲法每天给与BH冻干物(测定组) 或对照溶液(对照组)。
第14天与第22天之间-用以将电极植入腹部中(用于扩张测定)。
第22-28天-使大鼠适应以避免与扩张测试相关的压力。
第28天-扩张测定并将动物安乐死以收集盲肠样品用于硫化物和短链脂肪酸(SCFA)分析。
第0、14和28天-收集粪便样品用于微生物分析:qPCR用于评估BH群体和其它共生微生物群,且使用选择性培养基和严格厌氧法计数功能性微生物群。
结果
图19呈现来自接受对照溶液或BH冻干物的IBS-HMA大鼠的粪便样品中氢营养布劳特氏菌群体的qPCR分析的结果。在施用时期结束时(第28天)在接受BH冻干物的大鼠中观察到BH群体显著增加,此证实BH成功传递于结肠中。
图20呈现扩张测定的结果。使大鼠经受结肠直肠扩张并记录每 5分钟的收缩次数作为内脏高敏感性的特定量度。经本发明组合物治疗的IBS-HMA大鼠展现减少的收缩,此反映了内脏高敏感性的降低。氢营养布劳特氏菌治疗后,与在健康HMA大鼠中所测量的内脏敏感性相比,IBS-HMA大鼠显示正常内脏敏感性。
图21报告施用氢营养布劳特氏菌对来自粪便微生物丛的一些微生物群的作用,先前发现这些微生物群在IBS患者中受到影响。施用 BH使硫酸盐还原细菌(SRB)显著减少。
图22报告施用BH对IBS-HMA大鼠的盲肠样品中硫化物(H2S) 浓度的影响。施用BH使硫化物产量显著减少。图22中的数据与图 10中相同,但规模不同。
图23报告施用BH对IBS-HMA大鼠的盲肠样品中的主要发酵代谢物短链脂肪酸的影响。施用BH使乙酸盐浓度显著增加以及丁酸盐浓度显著增加(图23B )。
结论
施用包含氢营养布劳特氏菌的组合物引起内脏高敏感性显著降低,如使用扩张测定所测量。治疗后,发现IBS-HMA大鼠的内脏敏感性与在健康-HMA大鼠中所测量的内脏敏感性相似。施用包含氢营养布劳特氏菌的组合物可以使IBS-HMA动物的内脏敏感性恢复至正常。施用氢营养布劳特氏菌也对微生物丛构成和发酵具有显著作用,且尤其诱导SRB和硫化物产量显著减少。这些数据表明氢营养布劳特氏菌可用于降低内脏高敏感性,特别是用于降低与IBS相关的内脏高敏感性。内脏高敏感性的降低可能与所观察到的SRB和硫化物产量的减少相关。
实施例7-稳定性测试
将含有至少一种本文中描述的细菌菌株的本文中描述的组合物存储在密封容器中25℃或4℃下并且将容器置于具有30%、40%、 50%、60%、70%、75%、80%、90%或95%相对湿度的气氛中。如以通过标准方案测定的菌落形成单位所测量,在1个月、2个月、3个月、6个月、1年、1.5年、2年、2.5年或3年后,至少50%、60%、 70%、80%或90%的细菌菌株应残留。
序列
SEQ ID NO:1(粪便布劳特氏菌菌株GAM6-1 16S核糖体RNA基因,部分序列-HM626177)
SEQ ID NO:2(韦氏布劳特氏菌菌株WAL 14507 16S核糖体RNA 基因,部分序列-EF036467)
SEQ ID NO:3(粪便布劳特氏菌菌株830的共有16S rRNA序列)
SEQ ID NO:4(韦氏布劳特氏菌菌株MRX008的共有16S rRNA 序列)
SEQ ID NO:5(氢营养布劳特氏菌S5a36 16S核糖体RNA基因,部分序列-X95624.1)
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Claims (8)
1.以登记号DSM 10507保藏的氢营养布劳特氏菌(Blautia hydrogenotrophica)细菌菌株在制备用于治疗或预防肠易激综合征(IBS)相关的内脏高敏感性的药物中的用途。
2.如权利要求1所述的用途,其中所述药物用于:
(i) 在内脏高敏感性的所述治疗或预防中减少硫酸盐还原细菌(SRB)在胃肠道中的定殖;或
(ii) 在内脏高敏感性的所述治疗或预防中降低胃肠道中H2S水平或预防H2S水平升高;或
(iii) 治疗或预防遭受胃肠道、特别是结肠或直肠中胀痛的患者的内脏高敏感性。
3.如权利要求1所述的用途,其中所述药物用于治疗或预防被诊断为患有IBS的受试者的内脏高敏感性。
4.如权利要求1或2所述的用途,其中所述药物用于经口施用。
5.如权利要求1或2所述的用途,其中所述药物包含一种或多种药学上可接受的赋形剂或载剂。
6.如权利要求1或2所述的用途,其中所述细菌菌株是冻干的或是有活力的。
7.如权利要求1或2所述的用途,其中所述药物包含所述氢营养布劳特氏菌细菌菌株作为单一菌株。
8.如权利要求1或2所述的用途,其中所述药物包含所述氢营养布劳特氏菌细菌菌株作为微生物菌群的一部分。
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2021
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