CN108348536A - 治疗抗生素相关性并发症的合成组合物 - Google Patents
治疗抗生素相关性并发症的合成组合物 Download PDFInfo
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- CN108348536A CN108348536A CN201680067334.8A CN201680067334A CN108348536A CN 108348536 A CN108348536 A CN 108348536A CN 201680067334 A CN201680067334 A CN 201680067334A CN 108348536 A CN108348536 A CN 108348536A
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Abstract
本发明涉及包含人乳寡糖的合成组合物,其用于至少部分地恢复共生胃肠微生物群并预防或减轻抗生素相关的腹泻。
Description
技术领域
本发明涉及用于预防或治疗与抗生素治疗有关的副作用、例如预防或治疗艰难梭菌(C.difficile)感染的方法和组合物。
背景技术
人肠内含有据估计1013至1014个细菌细胞,并且细菌数量超过体内细胞总数10倍(Gill等人,Science 312,1355(2006))。人肠内的微生物群是一个复杂且非常动态的微生物生态系统,认为其可以为人类宿主提供许多重要功能,包括对病原体的防护、免疫调节功能的诱导、营养加工和代谢功能(Tojo等,World J.Gastroenterol.20,15163(2014))。
最近的研究已经能够将肠内微生物群中的失衡与肠内和肠外疾病联系起来(Guinane等,Ther.Adv.Gastroenterol.6,295(2013))。抗生素、特别是广谱抗生素,显著影响微生物群及其平衡,并且已经与许多健康状况的发病机理密切相关。鉴于抗生素的广泛使用,这具有巨大的健康和健康经济影响。例如,2010年对美国抗生素处方率的分析表明抗生素在儿童中的广泛使用(Hicks等,New Engl.J.Med.368,1461(2013))。美国的一名普通儿童在2岁前接受过近3次抗生素疗程,10岁前接受约10次疗程,20岁前接受约17次疗程。
过度使用抗生素的常见有害影响是致病菌抗生素耐药性的发展。然而,抗生素对肠内微生物群体通过导致肠内生态失调造成的有害影响可能是一个更重要的问题。腹泻是抗生素治疗中最重要的短期与生态失调相关的不良反应之一。当其连同抗生素使用发生时,在没有任何其它原因的情况下,其称为抗生素相关性腹泻(AAD)。AAD的范围从轻度症状性稀便到危及生命的结肠炎。AAD最常引用的机制是致病微生物的肠内过度生长,特别是艰难梭菌(Clostridium difficile)、大肠杆菌(Escherichia coli)、产气荚膜梭菌(Clostridium perfringens)、沙门氏菌(Salmonella)、金黄色葡萄球菌(Staphylococcusaureus)和克雷伯菌(Klebsiella),这是由抗生素特别是青霉素、头孢菌素和克林霉素诱导的肠道生态失调的结果(Song等,Korean J.Intern.Med.23,9(2008))。例如,艰难梭菌形成孢子,这有助于细菌抵抗抗生素治疗。在生态失调的肠内,孢子可以发育,艰难梭菌可以定殖并生长。定殖后,艰难梭菌通过两种毒素TcdA和TcdB介导其对疾病发展的作用。这些毒素导致渗透性和炎症增加。艰难梭菌感染是世界范围内不断增加的挑战。由于艰难梭菌引起的住院率从2000年到2005年翻了一倍。感染已证明难以控制,死亡率相对较高(估计在美国为1-25%),并且15-35%的患者在治疗结束后经历至少一次复发性艰难梭菌感染(Antharam等,J.Clin.Microb.51,2884(2013))。
然而,并非所有的AAD患者都表现出致病菌的迹象,并且还认为涉及其它机制。例如,各种抗生素(包括氨苄青霉素)可导致结肠中的糖分解的和蛋白水解的细菌失衡,导致难消化的碳水化合物发酵减少。结果,结肠中未发酵的碳水化合物增加,导致渗透性腹泻。此外,由于糖分解活性降低,已观察到细菌代谢物比如短链脂肪酸(SCFA)醋酸盐、丙酸盐和丁酸盐的缺乏。SCFA通常刺激结肠中的盐和水重吸收,因此缺乏SCFA可导致严重的腹泻。使用抗生素的肠内微生物群的失衡也显示增加肠通透性、减少杯状细胞中MUC2产生和使粘液层变薄,导致粘膜屏障功能的完整性受损。
此外,肠内微生物群不一定从抗生素治疗中恢复。在健康成年人服用抗生素5天的人体研究中,与抗生素治疗前相比,总的粪便细菌浓度以及双歧杆菌浓度显著降低。此外,暴露两个月后,在大多数受试者中,不能观察到双歧杆菌和总细菌的复原力(Mangin等,PLoS One7,e50257(2012))。健康志愿者服用抗生素10天后的另一项人体研究显示,持续一年对粪便微生物多样性和微生物组成变化的影响很大,一个月后微生物变化最明显(Rashid等,Clin.Infect.Dis.60,S77(2015))。总之,这些结果表明抗生素疗法诱导人肠内微生物群的短期和长期改变(Jernberg等Microbiology 156,3216(2010))。
除抗生素治疗的短期副作用外,存在对肠内微生物群的影响具有长期健康影响的担心。例如,过去六十年来西方国家自身免疫性疾病和代谢性疾病的发病率急剧增加。这些病症的上升促使人们推测20世纪40年代抗生素的出现、加上剖腹产的增加、饮食习惯和城市化的改变,可能改变了人类相关的微生物群,使个体更易患这些疾病。此外,抗生素介导的肠内微生物群的变化与哮喘、湿疹、特应性皮炎和其它过敏性致敏、自身免疫性脑炎、念珠菌病、霍乱和病原体诱导的结肠炎的发展有关。也认为它们增加了饮食诱导的肥胖症和对肝基因表达、代谢激素水平和内脏脂肪积累的影响(Blaser,Nature 476,393(2011);Nobel等,Nat.Commun.6:7486doi:10.1038/ncomms8486(2015))。
因此,通过减少或预防生态失调和恢复肠内微生物群,优选通过在抗生素治疗后促进有益的肠内微生物群组成,能够预防或减少抗生素治疗的损害后果,将是有利的。此外,预防或减少抗生素治疗对肠屏障功能的负面影响和/或恢复抗生素治疗后的肠屏障功能,将是有利的。
已经研究的一种方法是通过使用益生菌来最小化抗生素治疗的负面后果。分析了包括3,432名参与者的16项研究的综述表明,益生菌对于预防儿科AAD具有保护作用(Johnston等.Cochrane Database Syst.Rev.doi:10.1002/14651858.CD004827.pub3(2011))。然而,在肠内添加少量不同的益生菌不可能在抗生素治疗后完全恢复和促进有益的肠内微生物群组成。
另一种方法是使用益生元。已将益生元定义为:“选择性发酵的成分,其允许在胃肠微生物群的组成和/或活性两者中特定的变化,其赋予对宿主安宁和健康的益处”(Gibson等,Nutr.Res.Rev.17,259(2004))。例如,一项人体研究已显示,抗生素治疗期间每日共同施用12g低聚果糖将成功治疗的艰难梭菌相关性腹泻复发的发生率降低至8%,而对照组为34%(Lewis等,Aliment.Pharmacol.Ther.21,469(2005)),然而相同量的低聚果糖未能保护接受广谱抗生素的老年受试者免于AAD(Lewis等,Clin.Gastroenterol.Hepatol.3,442(2005))。
WO 2010/065652描述了使用人乳渗透物来治疗艰难梭菌相关性结肠炎这一长期广谱抗生素治疗的常见并发症。然而,使用人乳作为一般治疗选择在商业上并不现实。
WO 2013/032674描述了使用人乳寡糖(HMO)来治疗由于几种原因、包括抗生素治疗引起的胃肠损伤。
然而,仍然需要安全的选择用于在人类中预防或治疗抗生素治疗的不良后果,比如艰难梭菌感染、腹泻、生态失调、SCFA耗减和产肠毒素细菌产生的毒素水平的增加。
发明内容
本发明的第一方面涉及选自岩藻糖基化HMO和核心HMO的一种或多种HMO,优选一种或多种岩藻糖基化HMO与一种或多种核心HMO的混合物,它们用于:
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻,
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗下部胃肠道的生态失调,特别是在所述人类患者中增加双歧杆菌的丰度和/或减少变形菌(Proteobacteria)和/或产肠毒素细菌的丰度,和/或
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗原发性或复发性艰难梭菌感染,
其中将至少2g的一种或多种HMO每日施用于人。
本发明的第二方面是一种合成组合物,优选为单位剂型,该合成组合物用于:
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻,
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗下部胃肠道的生态失调,特别是在所述人类患者中增加双歧杆菌的丰度和/或减少变形菌和/或产肠毒素细菌的丰度,和/或
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗原发性或复发性艰难梭菌感染,
该合成组合物包含至少2g的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO与一种或多种核心HMO的混合物。优选地,该组合物每日施用。
本发明的第三方面是一种用于在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻的方法,该方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
本发明的第四方面是一种用于在正接受或已经接受抗生素疗法的人类患者的胃肠道中减少产肠毒素细菌产生的毒素的量的方法,该方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选地,减少的毒素选自来自艰难梭菌的毒素A和毒素B以及来自产气荚膜梭菌(Clostridium perfringens)、金黄色葡萄球菌(Staphylococcus aureus)、沙门氏菌(Salmonella)、绿脓假单胞菌(Pseudomonas aeruginosa)和大肠杆菌的毒素。
本发明的第五方面是一种用于在正接受或已经接受抗生素疗法的人类患者中增加双歧杆菌的丰度和/或减少变形菌和/或产肠毒素细菌的丰度的方法,该方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选地,双歧杆菌是青春双歧杆菌(B.adolescentis)系统发育组的双歧杆菌(Bifidobacterium),尤其是青春双歧杆菌(Bifidobacterium adolescentis)和/或假链状双歧杆菌(Bifidobacteriumpseudocatenulatum)。优选地,变形菌和/或产肠毒素细菌是大肠杆菌和/或艰难梭菌。
本发明的第六方面是一种用于减少与人类患者的抗生素治疗相关的长期健康风险的方法,该方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选地,减少以后的生活中自身免疫性和代谢性疾病的风险。
本发明的第七方面是一种用于在正接受或已经接受抗生素疗法的人类患者中初级预防艰难梭菌感染的方法,该方法包括每日向患者施用有效量的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选地,一种或多种HMO的有效量为至少2克。
本发明的第八方面是一种用于在正接受或已经接受抗生素疗法的人类患者中预防或治疗复发性艰难梭菌感染的方法,该方法包括每日向患者施用有效量的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选预防艰难梭菌复发的发生。优选地,一种或多种HMO的有效量为至少2克。
本发明的第九方面是一种用于在正接受或已经接受抗生素疗法的人类患者中刺激短链脂肪酸(SCFA)产生的方法,该方法包括每日向患者施用至少2克的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。优选地,SCFA是乙酸盐、丙酸盐和/或丁酸盐。
根据本发明的第三至第九方面,对患者优选施用纯形式的(即未稀释)或在给药之前用水稀释的一种或多种HMO、或者以合成组合物的形式施用,更优选以一种或多种更多单位剂型施用,甚至更优选以单一单位剂型施用。
根据本发明的第三至第九方面,优选在患者的抗生素治疗终止后对患者施用一种或多种HMO,持续至少14天。更优选地,每天对患者施用合成组合物,该合成组合物包含约2g至约10g、特别是约3.5g至约7.5g的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。可以对患者施用约5g至10g/天的初始较高治疗剂量至多约30天、例如约14天的时间。此后,可以对患者施用约2g至5g/天的较低维持剂量。维持剂量可以在长时间内长期施用。
根据本发明的第一至第九方面,选自岩藻糖基化HMO和核心HMO的一种或多种HMO优选为两种或多种HMO。在一个实施方式中,选自岩藻糖基化HMO和核心HMO的两种或多种HMO是包含岩藻糖基化HMO和核心HMO的混合物或由其组成的混合物。特别地,混合物包含选自2’-FL、3-FL、DFL、LNFP-I、LNFP-II、LNFP-III、LNFP-V、LNDFH-I、LNDFH-II、LNDFH-III、FLNH-I、FLNH-II、FLNnH、FpLNH-I和FpLNnH-II的岩藻糖基化HMO以及选自LNT、LNnT、LNH、LNnH、pLNH和pLNnH的核心HMO,或由其组成。在一个优选的实施方式中,混合物包含选自2’-FL、3-FL和DFL的岩藻糖基化HMO以及选自LNT和LNnT的核心HMO,或由其组成。在一些优选的实施方式中,混合物包含2’-FL和LNnT,或由其组成。
此外,混合物或合成组合物优选包含比核心HMO更多的岩藻糖基化HMO(按重量计),例如约1.5:1至约5:1、更优选约2:1至4:1的2’-FL:LNnT。而且,合成组合物可以包含谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的两种或多种的组合的来源。合成组合物可以包含能够代谢HMO的益生菌,例如双歧杆菌。
还根据本发明的第一至第九方面,人类患者优选是儿童,优选年龄在3至10岁之间,或者年龄在60岁以上的老年患者。
具体实施方式
根据本发明,以下术语优选具有以下含义:
“人乳寡糖”或“HMO”是指在人母乳中发现的复合碳水化合物(Urashima等:MilkOligosaccharides,Nova Biomedical Books,New York,2011,ChenAdv.Carbohydr.Chem.Biochem.72,113(2015))。HMO具有在还原末端包含乳糖单元的核心结构,其可以通过一个或多个β-N-乙酰基-乳糖氨基和/或一个或多个β-乳-N-二糖基单元延长,并且该核心结构可以由α-L-吡喃岩藻糖基(fucopyranosyl)和/或α-N-乙酰基-神经氨酸基(唾液酸基)部分取代。在这方面,非酸性(或中性)HMO不含唾液酸残基,而酸性HMO在其结构中具有至少一个唾液酸残基。非酸性(或中性)HMO可以是岩藻糖基化或非岩藻糖基化的(核心HMO)。
“核心人乳寡糖”或“核心HMO”是指其核心结构未被αL-吡喃岩藻糖基和/或α-N-乙酰基-神经氨酸基(唾液酸基)部分取代的HMO。核心HMO的实例包括乳-N-四糖(LNT)、乳-N-新四糖(LNnT)、乳-N-新六糖(LNnH)、对-乳-N-新六糖(pLNnH)、对-乳-N-六糖(pLNH)和乳-N-六糖(LNH)。
“岩藻糖基化人乳寡糖”或“岩藻糖基化核心HMO”是指其核心结构由αL-吡喃岩藻糖基部分取代的HMO。岩藻糖基化HMO的实例包括2’-岩藻糖基乳糖(2’-FL)、乳-N-岩藻五糖I(LNFP-I)、乳-N-二岩藻六糖I(LNDFH-I)、3-岩藻糖基乳糖(3-FL)、二岩藻糖基乳糖(DFL)、乳-N-岩藻五糖II(LNFP-II)、乳-N-岩藻五糖III(LNFP-III)、乳-N-二岩藻六糖III(LNDFH-III)、岩藻糖基-乳-N-六糖II(FLNH-II)、乳-N-岩藻五糖V(LNFP-V)、乳-N-二岩藻六糖II(LNDFH-II)、岩藻糖基-乳-N-六糖I(FLNH-I)、岩藻糖基-对-乳-N-六糖I(FpLNH-I)、岩藻糖基-对-乳-N-新六糖II(FpLNnH-II)和岩藻糖基-乳-N-新六糖(FLNnH)。“青春双歧杆菌系统发育组的双歧杆菌”是指选自青春双歧杆菌(Bifidobacterium adolescentis)、角形双歧杆菌(Bifidobacterium angulatum)、链状双歧杆菌(Bifidobacterium catenulatum)、假链状双歧杆菌(Bifidobacterium pseudocatenulatum)、Bifidobacteriumkashiwanohense、齿双歧杆菌(Bifidobacterium dentum)和Bifidobacterium stercoris的细菌(Duranti等Appl.Environ.Microbiol.79,336(2013),Bottacini等Microbial CellFact.13:S4(2014))。
“微生物群”、“微生物区系”和“微生物组”是指通常栖息于身体器官或部分、特别是非婴儿人类的胃肠器官的活微生物群体。胃肠微生物群的最主要成员包括以下的微生物,在门水平的厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、放线菌门(Actinobacteria)、变形菌门(Proteobacteria)、互养菌门(Synergistetes)、疣微菌门(Verrucomicrobia)、梭杆菌门(Fusobacteria)和广古菌门(Euryarchaeota);在属水平的拟杆菌属(Bacteroide)、栖粪杆菌属(Faecalibacterium)、双歧杆菌属(Bifidobacterium)、罗斯氏菌属(Roseburia)、Alistipes、柯林斯氏菌(Collinsella)、布劳特氏菌属(Blautia)、粪球菌属(Coprococcus)、瘤胃球菌属(Ruminococcus)、真杆菌属(Eubacterium)和多尔氏菌属(Dorea);在种水平的单形拟杆菌(Bacteroides uniformis)、Alistipes putredinis、Parabacteroides merdae、布氏瘤胃球菌(Ruminococcusbromii)、Dorea longicatena、粪拟杆菌(Bacteroides caccae)、多形拟杆菌(Bacteroidesthetaiotaomicron)、霍氏真杆菌(Eubacterium hallii)、扭链瘤胃球菌(Ruminococcustorques)、Faecalibacterium prausnitzii、酸奶瘤胃球菌(Ruminococcus lactaris)、产气柯林斯菌(Collinsella aerofaciens)、Dorea formicigenerans、普通拟杆菌(Bacteroides vulgatus)和罗斯拜瑞氏菌(Roseburia intestinalis)。胃肠微生物群包括位于或附着于覆盖胃肠道上皮的粘液层的粘膜-相关的微生物群、和在胃肠道腔中发现的腔(luminal)-相关的微生物群。
“变形菌”是一种革兰氏阴性菌门,并且包括各种病原菌,比如埃希氏菌属(Escherichia)、沙门氏菌属(Salmonella)、弧菌属(Vibrio)、螺杆菌属(Helicobacter)、耶尔森氏菌属(Yersinia)和许多其它值得注意的属。
“产肠毒素细菌”是指产生肠毒素的细菌。肠毒素是由靶向肠的微生物释放的蛋白质外毒素,比如由下列细菌产生的外毒素:霍乱弧菌(V.cholerae)、产肠毒素大肠杆菌(ETEC)、金黄色葡萄球菌(S.aureus)的一些菌株、副溶血性弧菌(V.parahaemolyticus)、小肠结肠炎耶尔森氏菌(Y.enterocolitica)、气单胞菌(Aeromonas)种和产气荚膜梭菌(C.perfringens)。
“下部胃肠道的生态失调”是指胃肠道中与微生物群受损相关的病症,其中通常主导的细菌种类代表性不足或由异常或致病种胜出。
“患者”是指诊断为患有疾病的3岁或以上的人,即儿童、青少年、成年人或老人。在一个优选的实施方式中,患者是60岁或以上的老人。
“预防”是指为预防疾病或病理状况的发生、包括减少对健康的风险或威胁而给予的治疗或采取的行动。病理状况的非限制性实例包括腹泻、短链脂肪酸的量减少或胃肠道中肠毒素的量增加、胃肠道生态失调等。
“原发性感染”是指宿主例如人类患者第一次暴露于病原体,例如致病菌,并且被该病原体感染,即病原体已经在宿主中完成静止或休眠期。本文中的“复发性感染”是在原发性感染治愈后的一段时间内由相同或相似病原体感染的第二次、第三次、第四次等。
“治疗”是指为减轻或消除疾病的症状或病理状态而给予的治疗或采取的行动。
本文中的“下部胃肠道”包括小肠的空肠和回肠以及大肠。“肠内施用”是指导致组合物在胃肠道(包括胃部)中沉积的用于递送组合物的任何常规形式。肠内施用的方法包括通过鼻胃管或空肠(jujenum)管供给、口服、舌下和直肠。
“口服给药”是指通过口腔递送组合物的任何常规形式。因此,口服给药是肠内给药的一种形式。
“有效量”是指以足量提供HMO以给予期望的治疗结果的组合物的量。有效量可以以一个或多个剂量施用以实现期望的治疗结果。
“广谱抗生素”是指抗各种致病菌包括革兰氏阳性菌和革兰氏阴性菌的抗生素。广谱抗生素的实例是万古霉素、氨苄青霉素、阿莫西林、阿莫西林/克拉维酸、碳青霉烯类、哌拉西林/他佐巴坦、左氧氟沙星、加替沙星、莫西沙星、环丙沙星、链霉素、四环素、氯霉素、替卡西林。
“与抗生素治疗相关的长期健康风险”是指一种生理状况或疾病,其在先前已经接受抗生素作为治疗的一部分或接受抗生素作为其它治疗并且在第一次出现所述生理状况或疾病之前已经停止该治疗的患者中发展并得以诊断。与抗生素治疗相关的长期健康风险的实例包括但不限于自身免疫性或代谢性疾病、腹泻、溃疡性结肠炎、免疫功能受损、肥胖症、食物吸收、抑郁症、败血症、哮喘、过敏。
术语“以后的生活中(later in life)”是指在终止对该患者的抗生素治疗之后的一段时间之后,即在患者不服用抗生素作为治疗的一部分或其它治疗的一段时间之后,比如终止抗生素治疗后1-3个月,比如在终止抗生素治疗后3-6个月、或6-12个月、或1-2年、或2-5年、或5-10年、或甚至大于10年,在患者中首次观察和/或测量的效应。
根据本发明,已经发现将至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种核心HMO与一种或多种岩藻糖基化HMO的混合物,每日施用于正在接受或已经接受抗生素疗法的人类患者:
-至少部分恢复患者的共生胃肠微生物群,并且特别是增加双歧杆菌的丰度和/或减少患者胃肠道中的变形菌和/或产肠毒素细菌的丰度,和/或
-增加患者结肠中SCFA的产生,尤其是乙酸盐、丙酸盐和/或丁酸盐的产生,和/或
-降低肠毒素的产生,和/或
-预防或减轻患者中抗生素相关性腹泻。
单一HMO或HMO混合物可以选自本文所述的岩藻糖基化HMO和核心HMO。
这种治疗可以部分避免或甚至防止抗生素治疗的后果。这种后果可能会涉及到对患者的肠内微生物菌群的严重改变,这种变化在抗生素治疗完成时不一定会恢复到健康状态。由此产生的生态失调会对患者的健康产生不利影响。调节患者胃肠道中的微生物群以特异性增加双歧杆菌可预防或至少治疗生态失调,恢复SCFA水平并减少产肠毒素细菌及其毒素。特别地,双歧杆菌(例如青春双歧杆菌)丰度的增加可以减少产肠毒素细菌比如艰难梭菌、产气荚膜梭菌、金黄色葡萄球菌、沙门氏菌、绿脓假单胞菌和大肠杆菌对肠上皮细胞的粘附。产肠毒素细菌可能是抗生素抗性的。这种治疗还可以改善患者的肠道屏障功能。此外,治疗还可以在正接受或已经接受抗生素疗法的人类患者中减少发生艰难梭菌感染的风险、和/或在正接受或已经接受抗生素疗法以治疗艰难梭菌感染的人类患者中减少复发的风险。
岩藻糖基化HMO和核心HMO可以通过熟知的方法从哺乳动物分泌的乳中分离,哺乳动物包括但不限于人类、牛、绵羊、猪或山羊物种。这些HMO也可以通过熟知的方法使用微生物发酵、酶促过程、化学合成、或这些技术的组合来生产。作为实例,使用化学法,LNnT可以如WO 2011/100980和WO 2013/044928中所述制备,LNT可以如WO 2012/155916和WO 2013/044928中所述合成,LNT和LNnT的混合物可以如WO 2013/091660中所述制备,2’-FL可以如WO 2010/115934和WO 2010/115935中所述制备,3-FL可以如WO 2013/139344中所述制备,6’-SL及其盐可以如WO 2010/100979中所述制备,并且HMO的混合物可以如WO 2012/113405中所述制备。作为酶促生产的实例,岩藻糖基化HMO可以如WO 2012/127410中所述制备,并且有利地HMO的多种混合物可以如WO 2012/156897和WO 2012/156898中所述制备。关于生物技术方法,WO 01/04341、WO 2007/101862、WO 2015/032412和WO 2015/032413描述了如何使用基因修饰的大肠杆菌制备核心和岩藻糖基化HMO。
岩藻糖基化HMO和核心HMO优选作为混合物以合成组合物施用,合成组合物可以采取任何适当形式。术语“合成组合物”是指人工制备的组合物,并且优选是指包含至少一种化学地和/或生物学地,例如通过化学反应、酶促反应或重组方式,离体产生的化合物的组合物。在一些实施方式中,本发明的合成组合物可以与天然存在的组合物相同,但优选与之不同。例如,组合物可以是包含其它常量营养素比如蛋白质、脂质或其它碳水化合物或者微量营养素的营养组合物的形式。合成组合物也可以是单位剂型,如补充剂和药物组合物。
营养组合物
包含选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种核心HMO与一种或多种岩藻糖基化HMO的混合物的合成组合物可以是营养组合物。它可以包含一种或多种蛋白质、脂质和/或可消化的碳水化合物的来源,并且可以是粉末或液体形式。该组合物可以设计成营养的唯一来源或营养补充剂。
合适的蛋白质来源包括乳蛋白、大豆蛋白、大米蛋白、豌豆蛋白和燕麦蛋白、或其混合物。乳蛋白可以是乳蛋白浓缩物、乳蛋白分离物、乳清蛋白或酪蛋白或两者混合物的形式。蛋白质可以是全蛋白质或者部分水解或深度水解的水解蛋白质。水解蛋白质提供消化更容易的优点,这对于患有发炎胃肠道的非婴儿可以是重要的。蛋白质也能够以游离氨基酸的形式提供。蛋白质能够包括营养组合物的大约5%至大约30%的能量,通常为大约10%至20%。
蛋白质来源可以是谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的两种或多种组合的来源。谷氨酰胺来源可以是L-谷氨酰胺、谷氨酰胺二肽和/或富含谷氨酰胺的蛋白质。谷氨酰胺由于肠上皮细胞使用谷氨酰胺作为能量来源使用而能够包括在内。苏氨酸、丝氨酸和脯氨酸是产生粘蛋白的重要氨基酸。半胱氨酸是对于身体的抗氧化防御来说至关重要的谷胱甘肽的主要前体。
合适的可消化碳水化合物包括麦芽糖糊精、水解或改性的淀粉或玉米淀粉、葡萄糖聚合物、玉米糖浆、玉米糖浆固体、高果糖玉米糖浆、源自大米的碳水化合物、源自豌豆的碳水化合物、源自马铃薯的碳水化合物、木薯粉、蔗糖、葡萄糖、果糖、蔗糖、乳糖、蜂蜜、糖醇(例如麦芽糖醇、赤藓糖醇、山梨糖醇)、或其混合物。优选地,该组合物不含乳糖。通常,可消化碳水化合物提供大约营养组合物的大约35%至大约55%的能量。优选地,营养组合物乳糖不含乳糖。特别合适的可消化碳水化合物是低葡萄糖当量(DE)麦芽糖糊精。
合适的脂类包括中链甘油三酯(MCT)和长链甘油三酯(LCT)。优选地,脂质是MCT和LCT的混合物。例如,MCT可以包含约30重量%至约70重量%的脂质,更具体地约50重量%至约60重量%。MCT提供易消化的优点,这对于患有发炎胃肠道的非婴儿可以是重要的。通常,脂质提供营养组合物的约35%至约50%的能量。脂质可以包含必需脂肪酸(ω-3和ω-6脂肪酸)。优选地,这些多不饱和脂肪酸提供小于脂质来源总能量的约30%。认为降低这些多不饱和脂肪酸的水平会降低对过氧化作用的敏感性;这对于患有炎症状况的非婴儿可以是有益的。
长链甘油三酯的合适来源是菜籽油、葵花籽油、棕榈油、大豆油、乳脂、玉米油、高油酸油和大豆卵磷脂。分馏椰子油是中链甘油三酯的合适来源。营养组合物的脂质特征优选设计为具有约4:1至约10:1的多不饱和脂肪酸ω-6(n-6)比ω-3(n-3)的比率。例如,n-6与n-3脂肪酸比率可以是约6:1至约9:1。
营养组合物优选地还包括维生素和矿物质。如果意在将营养组合物作为唯一的营养来源,其优选地包括完整的维生素和矿物质图谱。维生素的实例包括维生素A、B-复合维生素(例如B1、B2、B6和B12)、维生素C、D、E和K、烟酸和酸类维生素例如泛酸、叶酸和生物素。矿物质的实例包括钙、铁、锌、镁、碘、铜、磷、锰、钾、铬、钼、硒、镍、锡、硅、钒和硼。
营养组合物还能够包括类胡萝卜素,例如叶黄素、番茄红素、玉米黄质和β-胡萝卜素。包括的类胡萝卜素的总量能够从大约0.001μg/ml至大约10μg/ml变化。包括的叶黄素的量能够为大约0.001μg/ml至大约10μg/ml、优选大约0.044μg/ml至大约5μg/ml叶黄素。包括的番茄红素的量能够为大约0.001μg/ml至大约10μg/ml、优选大约0.0185μg/ml至大约5μg/ml番茄红素。包括的β-胡萝卜素能够为大约0.001μg/ml至大约10μg/ml、例如大约0.034μg/ml至大约5μg/ml的β-胡萝卜素。
营养组合物优选还包含降低浓度的钠;例如约300mg/l至约400mg/l。剩余的电解质可以以满足需要的浓度存在,而不会提供肾功能的过度肾溶质负担。例如,钾优选以约1180至约1300mg/l的范围存在;并且氯化物优选以约680至约800mg/l的范围存在。
营养组合物还可以包含各种其它常规成分,比如防腐剂、乳化剂、增稠剂、缓冲剂、纤维和益生元(例如低聚果糖、低聚半乳糖)、益生菌(例如动物双歧杆菌乳双歧亚种(B.animalis subsp.lactis)BB-12、乳双歧杆菌(B.lactis)HN019、乳双歧杆菌Bi07、婴儿双歧杆菌(B.infantis)ATCC 15697、鼠李糖乳杆菌(L.rhamnosus)GG、鼠李糖乳杆菌HNOOl、嗜酸乳杆菌(L.acidophilus)LA-5、嗜酸乳杆菌NCFM、发酵乳杆菌(L.fermentum)CECT5716、长双歧杆菌(B.longum)BB536、长双歧杆菌AH1205、长双歧杆菌AH1206、短双歧杆菌(B.breve)M-16V、罗伊氏乳杆菌(L.reuteri)ATCC 55730、罗伊氏乳杆菌ATCC PTA-6485、罗伊氏乳杆菌DSM 17938)、包括生育酚、类胡萝卜素、抗坏血酸/维生素C、抗坏血酸棕榈酸酯、多酚、谷胱甘肽和超氧化物歧化酶(甜瓜)的抗氧化剂/抗炎化合物、其它生物活性因子(例如生长激素、细胞因子、TFG-β)、着色剂、香料、和稳定剂、润滑剂等等。益生菌优选包含双歧杆菌(Bifidobacterium)。
营养组合物可以是可溶性粉末、液体浓缩物或即用型剂型的形式。组合物可以经由鼻胃管或口服供应给患者。各种香料、纤维和其它添加剂也可以存在。
营养组合物可以通过用于制备固体或液体形式的营养组合物的任何常用制造技术来制备。例如,组合物可以通过组合各种供给溶液来制备。脂肪包蛋白质供给溶液可以通过加热和混合脂质来源、然后在加热和搅拌的同时添加乳化剂(例如卵磷脂)、脂溶性维生素和蛋白质来源的至少一部分来制备。然后碳水化合物供给溶液通过在加热和搅拌的同时向水中加入矿物质、痕量和超痕量矿物质、增稠剂或悬浮剂来制备。在加入碳水化合物(例如HMO和可消化的碳水化合物来源)之前,持续加热和搅拌所得溶液保持10分钟。然后将所得的供给溶液在加热和搅拌的同时混合在一起,并将pH调节至6.6-7.0,然后将组合物进行高温短时加工,在此期间将组合物热处理、乳化并均化,然后允许冷却。加入水溶性维生素和抗坏血酸,如果需要将pH调节至所需范围,加入香料,并加入水以达到所需的总固体水平。
对于液体产品,然后可以将所得溶液无菌包装以形成无菌包装的营养组合物。以这种形式,营养组合物可以是即食型或浓缩型液体形式。或者,该组合物可以喷雾干燥并作为可重构粉末加工和包装。
当营养产品是即食型营养液时,以液体重量计,液体中HMO的总浓度为约0.2%至约4.0%,包括约0.4%至约3%、包括约0.8%至约2.0%。当营养产品是浓缩型营养液时,以液体重量计,液体中HMO的总浓度为约0.4%至约8.0%,包括约0.8%至约6.0%、包括约1.6%到约4.0%。当以固体形式在液体中重构时,固体中HMO的量将取决于推荐的重构水平。优选地,以不超过约1升的重构液体、更优选约250ml的重构液体递送2g剂量的HMO。
单位剂型
优选地,包含选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种核心HMO与一种或多种岩藻糖基化HMO的混合物的合成组合物为单位剂型,比如胶囊剂,片剂或小袋(sachet)。在每个单位剂量中,合成组合物包含约2g至约10g、优选约3.5g至约7.5g的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选岩藻糖基化和核心HMO的混合物。
单位剂型还可以包含营养上或药学上可接受的载体、稀释剂、赋形剂、润滑剂、着色剂、粘合剂和崩解剂。合适的载体、稀释剂、赋形剂、润滑剂、着色剂、粘合剂和崩解剂包括磷酸盐缓冲盐溶液、乙醇在水中的混合物、水和乳液比如油/水或水/油乳液、聚乙烯、聚氯乙烯、乙基纤维素、丙烯酸酯聚合物及其共聚物、羟乙基-纤维素、羟丙基甲基-纤维素(HPMC)、羧甲基纤维素钠、聚甲基丙烯酸羟乙酯(PHEMA)、聚乙烯醇(PVA)、聚乙烯基吡咯烷酮(PVP)、聚氧乙烯(PEO)或聚丙烯酰胺(PA)、角叉菜胶、海藻酸钠、聚卡波非、聚丙烯酸、黄芪胶、甲基纤维素、果胶、天然树胶、黄原胶、瓜尔豆胶、刺梧桐胶(karaya gum)、羟丙甲纤维素、硬脂酸镁、微晶纤维素和胶体二氧化硅。单位剂型还可以包括合适的抗氧化剂,比如维生素A、类胡萝卜素、维生素C、维生素E、硒、类黄酮、多酚、番茄红素、叶黄素、木质素、辅酶Q10(“CoQ10”)和谷胱甘肽。
单位剂型还可以包括治疗剂,比如抗病毒剂、抗生素、益生菌、镇痛剂和抗炎剂。
单位剂型,尤其是小袋形式的单位剂型还可以包含各种常量营养素或微量营养素。例如可以包括谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的两种或多种组合。
单位剂型可以制成口服施用,例如作为包含预定量的片剂、胶囊或小丸,或者作为包含预定浓度的粉末或颗粒剂,或包含预定浓度的以含水液体或无水液体的凝胶、糊剂、溶液剂、悬浮剂、乳剂、糖浆剂、丸剂(bolus)、干药糖剂、或膏剂。口服施用形式可以包括粘合剂、润滑剂、惰性稀释剂、调味剂和湿润剂。口服施用形式比如片剂可以任选地进行包衣并且可以进行配制以提供HMO的持续、延迟或控制释放。
单位剂型还可以通过直肠栓剂、气雾剂管、鼻胃管或直接输注到胃肠道或胃中来施用。
给药
需要在合成组合物中施用于患者的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物的量将取决于因素比如患者的年龄、体重、饮食、和其它正在服用的药物。然而,所需的量可由医师容易地设定并且通常在每天约2g至约20g的范围内,在某些实施方式中为每天约3g至约15g、每天约4g至约10g,在某些实施方式中为每天约5g至约10g,在某些实施方式中为每天约6g至约7.5g。合适的剂量可以基于几种因素来确定,包括例如年龄、体重、其它不适和/或疾病、副作用的发生率和/或严重程度以及给药方式。合适的剂量范围可以通过本领域技术人员已知的方法确定。在初始治疗阶段期间,服量可以更高(例如每天3g至20g、优选每天3g至15g、更优选每天5g至10g,在某些实施方式中为每天6g至7.5g)。在维持阶段期间,可以减少服量(例如,每天2g至10g、优选每天3g mg至7.5g、更优选每天3g至5g)。
虽然已经参照优选实施方式描述本发明,但是应当理解,在本发明的范围内可以进行各种修改。
实施例
实施例1
总共招募100名男性和女性健康成年人参加研究。经筛查访视和磨合期(run-in)1-2周后,选择参与者并随机分为十组,每组10名受试者。一组每天施用含有2克葡萄糖的安慰剂产品。其余9组每天施用含有下列之一的治疗产品:a)20g的2’-FL、b)10g的2’-FL、c)5g的2’-FL、d)20g的LNnT、e)10g的LNnT、f)5g的LNnT、g)20g的2’-FL和LNnT的2:1混合物、h)10g的2’-FL和LNnT的2:1混合物,和i)5g的2’-FL和LNnT的2:1混合物,持续2周。安慰剂和治疗产品在单位剂量容器中呈粉末形式。
如果健康成年人的年龄在18-60岁,则他们有资格参加。所有招募的参加者都能够并愿意了解并遵守研究程序。如果有以下情况,则将参加者排除:患者在筛查访视前一个月内已经参加了临床研究;患者在筛查测试中具有在临床上与参加研究有关的异常结果;患者正患有严重的疾病,如恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经系统疾病或严重的精神疾病或任何可能混淆研究结果的病症;在研究前使用高剂量的益生菌补充剂(允许使用酸奶)3个月;他们在研究前服用抗生素药物6个月;他们在研究前2周内定期服用任何可能已干扰症状评估的药物;以及怀孕或泌乳。
在筛查访视时,登记病史和伴随药物,并收集血液样本用于安全性分析。分发粪便样本试剂盒。要求参加者将样本保存在冰箱中,直到下一次访视。
在第二次访视时,检查资格标准,并且将合格的受试者随机分配到试验中的十组(arm)(治疗组和安慰剂组)。收集粪便样本并分发用于新样本的装置。让参加者熟悉交互式互联网支持系统(interactive internet enabled system),每天记录数据,并提供以治疗或对照产品。提醒受试者在研究过程中不要改变他们惯常的饮食。收集血液样本用于生物标志物研究。将粪便样本储存在-80℃直到分析。
该研究进行2周,参加者每天服用安慰剂或治疗产品。参加者被指示在早晨与早餐一起服用产品。通过交互式互联网支持系统监控依从性(compliance)。
参与者还使用该系统记录:
·Bristol粪便性状量表(Bristol Stool Form Scale)(BSFS)信息。
·症状信息如腹痛、腹部不适、腹部绞痛、腹胀和腹部饱胀感。
·额外的胃肠症状评分量表(Gastrointestinal Symptom Rating Scale)(GSRS)信息。
该调查问卷包括15个项目,覆盖五个维度(腹痛、消化不良、反流、腹泻、便秘),并使用七级Likert量表。
在研究结束时,每名病人都有医疗团队的退出访问。收集粪便样本和血液样本。
血液样本在电化学发光平台上以多路格式同时进行分析。以下分析物包括在控制板中:BUN、LDL胆固醇、HDL胆固醇、铁、甘油三酯、ApoA1、ApoB、胰岛素、FFA、胰高血糖素、IL-10、IL-6和TNF-α。
为了评估微生物群特征,使用96孔PowerSoil DNA分离试剂盒(MO-BIO)从粪便样本中提取DNA。在PCR期间每个板最少一个样本-孔保持为空,以用作阴性对照。使用附带的Illumina适配器用正向引物S-D-Bact-0341-b-S-17和反向引物S-D-Bact-0785-a-A-21进行PCR。这些是靶向V3-V4区域的通用细菌16S rDNA引物。使用以下PCR程序:98℃进行30秒,25×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证扩增。在使用Nextera Index Kit V2(Illumina)的巢式PCR中加入条形码(barcode),使用以下PCR程序:98℃进行30秒,8×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证引物的附着。使用SequalPrep Normalization Plate试剂盒对来自巢式PCR的产物进行标准化和合并。通过蒸发将合并的基因库浓缩,并使用Qubit High Sensitivity Assay试剂盒(ThermoFisher Scientific)在Qubit荧光计上测量所合并的基因库的DNA浓度。使用用于2×300bp配对末端测序的MiSeq Reagent试剂盒V3(Illumina)在MiSeq桌面测序仪上进行测序。使用64位版本的USEARCH(Edgar,2013)用于序列数据的生物信息学分析。
为了评估双歧杆菌群落,根据Milani等,FEMS Microbiol.Ecol.90,493(2014)进行DNA样本的ITS分析(prolifing)。下表1示出,如从粪便分析所测定的,与在服用HMO后在人粪便中鉴定的其它双歧杆菌物种相比,具有与青春双歧杆菌高度序列相似性的双歧杆菌物种的百分比增加。此外,双歧杆菌群体分析的结果显示,当服用单一HMO时,主要是青春双歧杆菌的丰度增加,而当服用两种HMO的混合物时,主要是假链状双歧杆菌的丰度增加。青春双歧杆菌和假链状双歧杆菌都是青春双歧杆菌系统发育组的成员。可以看出,HMO的口服摄取明显地增加健康成年人的微生物群中的青春双歧杆菌和/或假链状双歧杆菌的丰度、以及其与其它双歧杆菌属物种的总数相比的相对丰度。
表1
与安慰剂相比,所有组中变形菌的丰度均减少。
实施例2
总共招募40名5至10岁的儿童参加研究。儿童正在开始由医生针对感染性疾病开出处方的广谱抗生素治疗。所有招募的儿童和他们的看护者都能够并愿意理解并遵守研究程序。如果有以下情况,则将该儿童排除:患者在筛查访视前一个月已经参加了临床研究;患者正患有严重的疾病,比如胃肠疾病、恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经系统疾病或严重的精神疾病或任何可能混淆研究结果的病症;在研究前使用高剂量的益生菌补充剂(允许使用酸奶)3个月;在研究前服用抗生素药物3个月,以及在研究前2周内定期服用任何可能干扰症状评估的药物。
在筛查访视时,登记病史和伴随药物。此外,检查资格标准,并将合格的受试者随机分为两组,每组20名儿童。治疗期(6周)分为两段,如下:
·第1阶段(2周):第1组(安慰剂),第2组(治疗产品)。
·第2阶段(4周):第1组(安慰剂),第2组(治疗产品)。
治疗产品包含5克的2’-FL和LNnT(2:1质量比)的组合,而安慰剂产品包含5克的葡萄糖。这两种产品都在小袋中呈粉末形式。产品各自在早餐时每天以食团施用,并且饮食不受控制;但要求参加者在研究过程中不改变他们的正常饮食。
在最初访视时,分发粪便样本试剂盒和治疗或安慰剂产品。对每名儿童的看护者进行指导以将粪便样本保存在冰箱中,直到下次访视。提醒儿童和看护者在研究期间不改变儿童的日常饮食。在这次访视时收集粪便样本并储存在-80℃直到分析。
该研究进行二加四周,儿童每天服用安慰剂和/或治疗产品。通过交互式互联网支持系统监控依从性。
参与者还使用该系统记录:
·Bristol粪便性状量表(BSFS)信息
·胃肠症状评分量表(GSRS)信息。
该调查问卷包括15个项目,覆盖五个维度(腹痛、消化不良、反流、腹泻、便秘),并使用七级Likert量表。
在第1阶段结束时,收集粪便样本并分发新的治疗或安慰剂产品。在第2阶段结束时(退出访视),每名儿童都有医疗团队的访视,并收集粪便样本。6个月后,在随访时收集粪便样本。
为了评估微生物群特征,使用96孔PowerSoil DNA分离试剂盒(MO-BIO)从粪便样本中提取DNA。在PCR期间每个板最少一个样本-孔保持为空,以用作阴性对照。使用附带的Illumina适配器用正向引物S-D-Bact-0341-b-S-17和反向引物S-D-Bact-0785-a-A-21(Klindworth等人,Nucleic Acids Res.41,e1(2013))进行PCR。这些是靶向V3-V4区域的通用细菌16S rDNA引物。使用以下PCR程序:98℃进行30秒,25×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证扩增。在使用Nextera Index Kit V2(Illumina)的巢式PCR中加入条形码(barcode),使用以下PCR程序:98℃进行30秒,8×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证引物的附着。
使用SequalPrep Normalization Plate试剂盒对来自巢式PCR的产物进行标准化和合并。通过蒸发将合并的基因库浓缩,并使用Qubit High Sensitivity Assay试剂盒(Thermo Fisher Scientific)在Qubit荧光计上测量所合并的基因库的DNA浓度。使用用于2×300bp配对末端测序的MiSeq Reagent试剂盒V3(Illumina)在MiSeq桌面测序仪上进行测序。使用64位版本的USEARCH(Edgar,2013)用于序列数据的生物信息学分析。
粪便分析显示,HMO能够在抗生素疗法期间和之后通过增加双歧杆菌、优选青春双歧杆菌系统发育组中的双歧杆菌、并且尤其是青春双歧杆菌和/或假链状双歧杆菌的丰度,来防止抗生素减轻的生态失调并且增强有利的微生物群组成。儿童的变形菌的丰度减少,并且产肠毒素细菌及其毒素的水平降低,并且腹泻和腹痛的发生率降低。
实施例3
使用体外肠系统来模拟感染艰难梭菌的人结肠区域。对模拟结肠区域(近端、横向和远端)的反应器接种来自年龄大于65岁的健康个体的新鲜粪便样本。在稳定和控制期后,将抗生素给药至系统以诱导结肠反应器中的生态失调。停止抗生素疗法后,将艰难梭菌孢子加入结肠反应器以形成艰难梭菌感染。一旦获得稳定的艰难梭菌感染,则开始治疗。两种不同的治疗(A和B)平行进行2周。A:2’-FL和LNnT(比例4:1)加抗生素治疗7天,并且2’-FL和LNnT(比例4:1)单独用于接下来的7天,B:抗生素治疗7天,并且接下来的七天没有治疗。在两周治疗期后,该模型作为随访进行两周以评估是否感染会复发。在几个时间点(在对照、治疗和随访期),分别使用16S测序和气相色谱法测量微生物群落和细菌代谢物。另外,测量孢子和活的艰难梭菌。
微生物群分析表明,即使在抗生素存在下,HMO也能够增加双歧杆菌的水平,并且可以在抗生素治疗停止后,将包括代谢物在内的微生物群体改变为更平衡的特征。另外,HMO抑制孢子和活的艰难梭菌,减少感染的复发。
实施例4-营养组合物
即食型营养组合物由水、麦芽糖糊精、玉米糖浆、糖、乳蛋白浓缩物、植物油(油菜、高油酸向日葵和玉米)、大豆蛋白分离物、阿拉伯树胶、香料、HMO、柠檬酸钾、磷酸镁、纤维素凝胶和树胶、碳酸钙、抗坏血酸钠、大豆卵磷脂、胆碱酒石酸氢盐、磷酸钙、α-生育酚乙酸酯、抗坏血酸、角叉菜胶、焦磷酸铁、香料、甜味剂(甜叶菊)、维生素A棕榈酸酯、烟酰胺、维生素D3、泛酸钙、硫酸锰、硫酸铜、盐酸吡哆醇、盐酸硫胺素、β-胡萝卜素、核黄素、氯化铬、叶酸、生物素、碘化钾、植物甲萘醌、亚硒酸钠、钼酸钠、维生素B12进行制备。
该组合物提供营养补充剂,其是蛋白质、低脂肪、维生素、矿物质和抗氧化剂的良好来源,并且符合FODMAP标准。此外,该组合物包含一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物,其能够促进有益肠道细菌的生长,调节慢性炎症,改善粘膜屏障完整性并减少焦虑和抑郁。
实施例5-胶囊组合物
通过使用填充机将约2g的一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物填充到000明胶胶囊中来制备胶囊。然后封闭胶囊。
Claims (36)
1.一种或多种人乳寡糖(HMO),其选自岩藻糖基化HMO和核心HMO,所述一种或多种人乳寡糖用于:
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻,
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗下部胃肠道的生态失调,特别是在所述人类患者中增加双歧杆菌的丰度和/或减少变形菌和/或产肠毒素细菌的丰度,和/或
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗原发性或复发性艰难梭菌感染,
其中将至少2g的一种或多种HMO每日施用于人。
2.根据权利要求1所述的一种或多种人乳寡糖(HMO),其中所述岩藻糖基化HMO选自2’-FL和DFL,并且所述核心HMO选自LNT和LNnT。
3.根据权利要求1或2所述的多种HMO,其为一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物形式。
4.根据权利要求3所述的混合物,其由岩藻糖基化HMO和核心HMO组成。
5.根据权利要求4所述的混合物,其由2’-FL和LNnT组成。
6.根据权利要求3至5所述的混合物,其包含按重量计约1.5:1至约5:1的2’-FL:LNnT。
7.一种合成组合物,其用于以下:
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻,
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗下部胃肠道的生态失调,特别是在所述人类患者中增加双歧杆菌的丰度和/或减少变形菌和/或产肠毒素细菌的丰度,和/或
-在正接受或已经接受抗生素疗法的人类患者中预防或治疗原发性或复发性艰难梭菌感染,
其中所述合成组合物
-包含至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO,并且
-每日施用。
8.根据权利要求7所述的合成组合物,其中所述岩藻糖基化HMO选自2’-FL和DFL,并且所述核心HMO选自LNT和LNnT。
9.根据权利要求7或8所述的合成组合物,其包含一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
10.根据权利要求9所述的合成组合物,其包含由岩藻糖基化HMO和核心HMO组成的混合物、优选由2-FL和LNnT组成的混合物。
11.根据权利要求9或10所述的合成组合物,其包含按重量计约1.5:1至约5:1的2’-FL:LNnT。
12.根据权利要求7至11所述的合成组合物,其还包含谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的两种或多种的组合。
13.根据权利要求7至12中任一项所述的合成组合物,其为包含约2g至约10g、优选约3.5g至约7.5g的HMO的单位剂型。
14.根据前述权利要求中任一项所述的一种或多种人乳寡糖(HMO)或合成组合物,其中在抗生素疗法终止后,每日施用一种或多种HMO或所述组合物,持续至少14天。
15.根据前述权利要求中任一项所述的一种或多种人乳寡糖(HMO)或合成组合物,用于刺激短链脂肪酸产生和/或抑制患者的胃肠道的细菌合成毒素。
16.一种用于在正接受或已经接受抗生素疗法的人类患者中预防或治疗抗生素相关性腹泻的方法,所述方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO。
17.一种用于在正接受或已经接受抗生素疗法的人类患者的胃肠道中减少产肠毒素细菌产生的毒素的量的方法,所述方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO。
18.一种方法,其用于在正接受或已经接受抗生素疗法的人类患者中
-增加双歧杆菌的丰度,和/或
-减少变形菌和/或产肠毒素细菌的丰度,
所述方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO。
19.根据权利要求18所述的方法,其中,
-青春双歧杆菌系统发育组的双歧杆菌的丰度,特别是青春双歧杆菌和/或假链状双歧杆菌的丰度增加,
-变形菌中的致病菌、尤其是大肠杆菌的丰度降低,和/或
-艰难梭菌的丰度降低。
20.一种用于降低与人类患者的抗生素治疗相关的长期健康风险的方法,所述方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
21.根据权利要求20所述的方法,其中以后生活中的自身免疫性和代谢性疾病的风险降低。
22.一种用于在正接受或已经接受抗生素疗法的人类患者中预防或治疗原发性或复发性艰难梭菌感染的方法,所述方法包括每日向患者施用有效量的选自岩藻糖基化HMO和核心HMO的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
23.根据权利要求22所述的方法,其中每日对所述患者施用至少2g所述一种或多种HMO。
24.一种用于在正接受或已经接受抗生素疗法的人类患者中刺激短链脂肪酸(SCFA),优选乙酸盐、丙酸盐和/或丁酸盐产生的方法,所述方法包括每日向患者施用至少2g选自岩藻糖基化HMO和核心HMO的一种或多种HMO。
25.根据权利要求16至24所述的方法,其中所述岩藻糖基化HMO选自2’-FL和DFL,并且所述核心HMO选自LNT和LNnT。
26.根据权利要求16或25所述的方法,其包括施用一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
27.根据权利要求26所述的方法,其包括施用由岩藻糖基化HMO和核心HMO、优选2-FL和LNnT组成的混合物。
28.根据权利要求26或27所述的方法,其包括施用按重量计约1.5:1至约5:1的2’-FL:LNnT的混合物。
29.根据权利要求16至28所述的方法,其中将所述一种或多种HMO以纯的形式、用水稀释、或以合成组合物的形式以一个或多个单位剂型施用、优选以单一单位剂型施用。
30.根据权利要求29所述的方法,其中每日施用约2g至约10g、优选约3.5g至约7.5g的一种或多种HMO,优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物。
31.根据权利要求29或30所述的方法,其中所述合成组合物以包含约2g至约10g、优选约3.5g至约7.5g的一种或多种HMO优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物的单位剂型施用。
32.根据权利要求16至31所述的方法,其中对所述患者另外施用谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的两种或多种的组合。
33.根据权利要求16至32所述的方法,其中在抗生素疗法终止后,对所述患者施用日剂量为至少2g的一种或多种HMO、优选一种或多种岩藻糖基化HMO和一种或多种核心HMO的混合物,持续至少14天。
34.根据权利要求16至33中任一项所述的方法,其中对所述患者另外施用双歧杆菌。
35.根据权利要求16至34中任一项所述的方法,其中所述患者是3岁以上的儿童或者60岁以上的老人。
36.根据前述权利要求中任一项所述的选自岩藻糖基化HMO和核心HMO的一种或多种人乳寡糖(HMO)、或合成组合物、或方法,其中所述抗生素是广谱抗生素。
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ES2975018T3 (es) | 2024-07-02 |
EP3377071B1 (en) | 2024-01-10 |
EP3377071A1 (en) | 2018-09-26 |
EP3377071A4 (en) | 2019-08-14 |
US10864224B2 (en) | 2020-12-15 |
US20180325929A1 (en) | 2018-11-15 |
PL3377071T3 (pl) | 2024-06-24 |
CN108348536B (zh) | 2021-09-24 |
US20210100822A1 (en) | 2021-04-08 |
WO2017084673A1 (en) | 2017-05-26 |
US11998558B2 (en) | 2024-06-04 |
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