CN101945589A - 用于改善肠道微生物群的非消化性碳水化合物的用途 - Google Patents
用于改善肠道微生物群的非消化性碳水化合物的用途 Download PDFInfo
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Abstract
提供了用于提供和/或维持最佳肠道微生物群的包含至少两种非消化性碳水化合物的组合物。该组合物特别适用于婴儿营养品。
Description
发明领域
本发明属于用于恢复或维持均衡的肠道微生物群的营养组合物领域。该组合物特别适合于婴儿和幼儿。
发明背景
婴儿在出生时没有肠道微生物群(microbiota)。出生后大肠被迅速拓殖而且其微生物群快速发育和增殖。母乳喂养的婴儿的肠道微生物群主要由属于双歧杆菌属(Bifidobacterium)的种类和其它的产乳酸细菌组成。配方奶喂养的婴儿的微生物群更为多样化,而且通常包含属于拟杆菌属(Bacteroides)、梭菌属(Clostridium)和肠杆菌科(Enterobacteriaceae)的更多种类。据称,微生物群组成方面的差异导致了有关免疫***、胃肠道屏障功能和抗病原功能的许多有利效应,从而使胃肠道感染在发病率和持续时间这两方面都更少,诸如食物过敏、异位性皮炎、过敏诱发的哮喘的特应性疾病更少,而且母乳喂养的婴儿便秘更少。
WO 2006/091103公开了用于对抗几种病症的包含益生菌和两种非消化性糖类的组合物。WO 00/08948公开了非消化性寡糖和多糖的混合物,以便改善肠道微生物群。
WO 2007/073194公开了用于预防肥胖和/或糖尿病的包含磷脂、鞘脂和胆固醇及任选地非消化性碳水化合物的组合物的用途。
发明概述
本发明基于包含至少两种非消化性寡糖的组合物对肠道微生物群的组成和/或活性的出乎意料的有利效应。出乎意料地发现,给予包含至少两种不同的非消化性碳水化合物的营养组合物导致厚壁菌门/拟杆菌门(Firmicutes/Bacteroidetes)比率降低和/或梭菌属/拟杆菌属比率降低。
本发明人认识到,在婴儿期形成的微生物群的组成会影响到以后生活中微生物群的组成。在婴儿期微生物群的发育差异被认为造成了至少7岁儿童中肠道微生物群的组成差别。因此在婴儿期均衡的微生物群的发育具有超越婴儿期延伸到儿童期、***和/或成年期的健康因果关系。
因此当在生活早期给予婴儿和/或年龄低于36个月的幼儿时,包含至少两种非消化性碳水化合物的组合物的使用,有利地影响与不均衡的肠道微生物群有关的病症的预防,时间的延伸超越给予组合物给时的时期,即超过36个月的年龄,诸如儿童期、***和/或成年期。
因此认为均衡的微生物区系,特别是具有低比率的厚壁菌/拟杆菌或梭菌/拟杆菌的微生物区系,影响脂肪细胞中脂肪储存和/或对肥胖具有预防和/或治疗作用。因此,本发明的组合物特别适用于治疗和/或预防肥胖。因为脂肪细胞,特别是内脏脂肪细胞,在婴儿期期间形成并增殖,所以本发明的组合物特别适用于给予年龄低于36个月的人个体,当所述人个体达到高于36个月的年龄时,用于预防肥胖。
发明的详细描述
本发明涉及,使人个体肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向健康体瘦个体中所发现的比率的方向,和/或向母乳喂养的婴儿中所发现的比率的方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低的方法,所述方法包括给予所述人个体包含至少两种非消化性碳水化合物的组合物,所述非消化性碳水化合物选自:低聚果糖(fructo-oligosaccharide)、低聚半乳糖(galacto-oligosaccharide)、葡聚寡糖(gluco-oligosaccharide)、***寡糖(arabino-oligosaccharide)、甘露寡糖(mannan-oligosaccharide)、低聚木糖(xylo-oligosaccharide)、岩藻寡糖(fuco-oligosaccharide)、***半乳寡糖(arabinogalacto-oligosaccharide)、葡糖甘露糖寡(glucomanno-oligosaccharide)、半乳甘露寡糖(galactomanno-oligosaccharide)、含有唾液酸的寡糖和糖醛酸寡糖。
也就是说,本发明涉及包含至少两种非消化性碳水化合物的营养组合物在制备组合物中的用途,所述组合物使人个体肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向健康体瘦个体中所发现的比率的方向,和/或向母乳喂养的婴儿中所发现的比率的方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低,所述非消化性碳水化合物选自:低聚果糖、低聚半乳糖、葡聚寡糖、***寡糖、甘露寡糖、低聚木糖、岩藻寡糖、***半乳寡糖、葡糖甘露寡糖、半乳甘露寡糖、含有唾液酸的寡糖和糖醛酸寡糖。
本发明也可以措词表达为,用于使人个体肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向健康体瘦个体中所发现的比率的方向,和/或向母乳喂养的婴儿中所发现的比率方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低的包含至少两种非消化性碳水化合物的营养组合物,所述非消化性碳水化合物选自:低聚果糖、低聚半乳糖、葡聚寡糖、***寡糖、甘露寡糖、低聚木糖、岩藻寡糖、***半乳寡糖、葡糖甘露寡糖、半乳甘露寡糖、包含唾液酸的寡糖和糖醛酸寡糖。
非消化性碳水化合物
本发明的组合物包含至少两种不同的非消化性碳水化合物。非消化性碳水化合物改善微生物群。非消化性碳水化合物刺激双歧杆菌的生长和/或活性。如实施例1中所示,发现给予至少两种非消化性碳水化合物,有利地降低了厚壁菌门/拟杆菌门即梭菌属/拟杆菌属的比率。
优选地,本发明组合物包含DP(聚合度)为2-250更优选为2-60的非消化性碳水化合物。非消化性碳水化合物为至少两种,选自:低聚果糖、低聚半乳糖、葡聚寡糖、***寡糖、甘露寡糖、低聚木糖、岩藻寡糖、***半乳寡糖(包括***树胶)、葡糖甘露寡糖、半乳甘露寡糖、含有唾液酸的寡糖和糖醛酸寡糖。本发明组合物优选包含低聚果糖、低聚半乳糖和/或半乳糖醛酸寡糖,更优选低聚半乳糖,最优选β-低聚半乳糖。低聚果糖组包括菊粉,低聚半乳糖组包括反式低聚半乳糖或β-低聚半乳糖,葡聚寡糖组包括龙胆寡糖(gentio-oligosaccharide)、黑曲寡糖(nigero-oligosaccharide)和环糊精寡糖(cyclodextrin-oligosaccharide)和聚葡萄糖,***半乳寡糖组包括***树胶,半乳甘露寡糖组包括部分水解的瓜尔豆胶(guar gum)。
本发明组合物优选包含低聚半乳糖。低聚半乳糖优先选自:β-低聚半乳糖、乳糖-N-四糖(LNT)、乳糖-N-新四糖(新LNT(neo-LNT))、岩藻糖基乳糖、岩藻糖苷LNT和岩藻糖苷新LNT。在特别优选的实施方案中,本发明组合物包含β-低聚半乳糖。本发明所用的β-低聚半乳糖指,基于单体亚单位,由超过50%,优选超过65%的半乳糖单位组成的低聚糖,其聚合度(DP)为2-20,其中至少50%,更优选至少75%,甚至更优选至少90%的半乳糖单位经由β-糖苷键,优选β-1,4糖苷键连结在一起。平均DP优选为3-6。葡萄糖单元可存在于半乳糖单元链的还原末端。有时β-低聚半乳糖也称为反式低聚半乳糖(TOS)。β-低聚半乳糖的合适来源为VivinalGOS(自Borculo Domo Ingredients,Zwolle,Netherlands商业性获取)。其它合适的来源为低聚半乳糖Oligomate(Yakult)、Cupoligo(Nissin)和Bi2muno(Classado)。
本发明组合物优选包含低聚果糖。本发明所用的低聚果糖指,基于单体亚单位,由超过50%,优选超过65%的果糖单位组成的碳水化合物,其中至少50%,更优选至少75%,甚至更优选至少90%的果糖单位经由β-糖苷键更优选β-2,1糖苷键连结在一起。葡萄糖单位可存在于半乳糖单元链的还原末端。低聚果糖优选具有2-250、更优选2-100甚至更优选10-60的DP或平均DP。低聚果糖包括果聚糖、水解的果聚糖、菊粉、水解的菊粉和合成的低聚果糖。该组合物优选包含平均聚合度(DP)为3-6的短链低聚果糖,更优选水解的菊粉或合成的低聚果糖。该组合物优选包含平均DP为20以上的长链低聚果糖,如RaftilinHP。该组合物优选包含短链和长链低聚果糖两者。适用于该组合物的低聚果糖也可容易地商业性获取,例如RaftilineHP(Orafti)。
本发明的组合物优选包含糖醛酸寡糖,更优选半乳糖醛酸寡糖。本发明所用半乳糖醛酸寡糖这一术语是指寡糖,其中存在于该寡糖中的至少50%的单糖单位为半乳糖醛酸。本发明所用的半乳糖醛酸寡糖优选由果胶、果胶酸盐/酯和/或聚半乳糖醛酸的降解制备。优选地,降解的果胶通过水果和/或蔬菜果胶,更优选苹果、柑橘和/或甜菜果胶,甚至更优选至少一种裂解酶所降解的苹果、柑橘和/或甜菜果胶的水解和/或β-消除制备。在优选的实施方案中,至少一个半乳糖醛酸寡糖的末端半乳糖醛酸单位具有双键。该双键有效地保护防御致病菌粘附到肠道上皮细胞上。优选地,一个末端半乳糖醛酸单元包含C4-C5双键。半乳糖醛酸寡糖可以衍生化。半乳糖醛酸寡糖可以甲氧基化和/或酰胺化。在一实施方案中,乳糖醛酸寡糖的特征在于,甲氧基化程度超过20%,优选超过50%,甚至更优选超过70%。
因此,在一实施方案中,按照本发明使用的组合物包含至少β-低聚半乳糖。在一实施方案中,按照本发明使用的组合物包含至少短链低聚果糖和/或长链低聚果糖,优选长链低聚果糖。在一实施方案中,按照本发明使用的组合物包含至少糖醛酸寡糖。在一实施方案中,按照本发明使用的组合物包含至少β-低聚半乳糖和至少短链低聚果糖或长链低聚果糖或这两者。在一实施方案中,按照本发明使用的组合物包含至少β-低聚半乳糖和至少糖醛酸寡糖。在一实施方案中,按照本发明使用的组合物包含至少短链低聚果糖和糖醛酸寡糖或长链低聚果糖和糖醛酸寡糖。在一实施方案中,按照本发明使用的组合物包含至少β-低聚半乳糖和短链低聚果糖和糖醛酸寡糖或至少β-低聚半乳糖和长链低聚果糖和糖醛酸寡糖。
在优选的实施方案中,组合物包含菊粉和低聚果糖的混合物。在优选的实施方案中,组合物包含低聚半乳糖和选自短链低聚果糖和菊粉的低聚果糖更优选菊粉的混合物。至少两种不同的非消化性碳水化合物的混合物比基于单个非消化性碳水化合物在更大程度上有利地刺激肠道微生物群的有益菌。优选地,两种不同的非消化性碳水化合物的混合物,优选低聚半乳糖和低聚果糖间的重量比为20-0.05,更优选20-1。低聚半乳糖更类似于人乳寡糖。优选地,本发明的组合物包含DP为2-10的低聚半乳糖和/或DP为2-60的低聚果糖。已发现这一组合物协同增加双歧杆菌和乳酸杆菌。优选地该组合物包含β-低聚半乳糖、低聚果糖和果胶降解产物。这三种非消化性低聚糖的存在,与低聚半乳糖和低聚果糖相比,甚至进一步地刺激双歧杆菌,同时降低拟杆菌和梭菌,而且甚至进一步地降低厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。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(12-7)∶1∶(1-3)。
优选地,每100ml组合物由80mg至2g,更优选150mg至1.50g,甚至更优选300mg至1g非消化性低聚糖组成。基于干重,组合物优选包含0.25wt.%至20wt.%,更优选0.5wt.%至10wt.%,甚至更优选1.5wt.%至7.5wt.%。较少量的非消化性低聚糖在刺激微生物群中的有益菌方面作用较小,然而过高的量又会导致肿胀和腹部不适的副作用。
脂质
在本文中,LA指的是亚油酸(18:2 n6);ALA指的是α-亚油酸(18:3n3);LC-PUFA指的是长链多不饱和脂肪酸和/或脂肪酰基链中包含至少20个碳原子且具有2个或更多不饱和键的酰基链;DHA指的是二十二碳六烯酸(22:6,n3);EPA指的是二十碳五烯酸(20:5 n3);ARA指的是花生四烯酸(20:4 n6);DPA指的是二十二碳五烯酸(22:5 n3)。
LA优选以充足的量存在,以便促进健康生长和发育,然而量还要尽可能地低,以预防以后生活中肥胖的发生。因此,基于总脂肪酸,组合物优选包含少于15wt.%,优选5-14.5wt.%,更优选6-12wt.%的LA。优选地ALA以足以促进健康生长和发育的量存在。因此,基于总脂肪酸,本发明组合物优选包含至少1.0wt.%的ALA。优选地,基于总脂肪酸,组合物包含至少1.6wt.%,更优选至少2.0wt.%的ALA。优选地,基于总脂肪酸,组合物包含少于10wt.%,更优选少于5.0wt.%的ALA。应该均衡LA/ALA的重量比,以预防肥胖,尤其是腹部肥胖(central obesity),而同时确保正常的生长和发育。因此,本发明组合物优选包含重量比为2-15,更优选2-7,更优选3-6,甚至更优选4-5.5,甚至更优选4-5的LA/ALA。
优选地本发明组合物包含LC-PUFA,因为LC-PUFA减少以后生活中的肥胖,更优选腹部肥胖。更优选,本发明的组合物包含n-3LC-PUFA,甚至更优选EPA、DPA和/或DHA,甚至更优选DHA。据发现,这些n-3LC-PUFA降低肥胖。因为低浓度的DHA、DPA和/或EPA已经是有效的,而且正常的生长和发育是重要的,所以n-3LC-PUFA在本发明组合物中的含量,优选不超过总脂肪酸含量的15wt.%,优选不超过10wt.%,甚至更优选不超过5wt.%。优选地,本发明的组合物包含至少总脂肪酸含量的0.2wt.%,优选至少0.5wt.%,更优选至少0.75wt.%的n-3LC-PUFA。在本发明的组合物中n-6LC-PUFA/n-3LC-PUFA重量比优选是低的,以便预防以后生活中的肥胖。优选地,组合物包含重量比低于1.5、更优选低于1.0、甚至更优选低于0.6的n-6LC-PUFA/n-3LC-PUFA。LC-PUFA具有其他优势,即它们促进有益菌的粘附,据此,进一步改善微生物群和/或维持均衡的微生物群。
本发明的组合物优选包含鞘磷脂和/或其某一降解产物。本发明所用鞘磷脂这一术语涉及一种鞘脂,其由经由酰胺键与一脂肪酸结合而且经由氧与包含磷酸盐(磷酸盐、磷酸胆碱、磷酸丝氨酸、磷酸乙醇胺、磷酸甘油或磷酸肌醇)的一个极性头基(heandgroup)结合的鞘氨基醇碱(sphingoid base)组成。在本发明的另一实施方案中,衍生于鞘磷脂的一降解产物,特别是神经酰胺、溶血鞘磷脂(lysosphingophospholipid)、鞘氨基醇磷酸盐和/或游离的鞘氨基醇碱,优选存在于该组合物中。本发明的鞘氨基醇碱优选为2-氨基-1,3-二羟基-链烷或具有(2S,3R)-赤型立体化学的烯烃,链长为14个原子或更高。鞘氨基醇碱可以包含3个而不是2个羟基基团。脂肪链可以是单不饱和的或多不饱和的(在顺式或反式构型中)或饱和的。脂肪链可以是分支的。鞘氨基醇碱包括鞘胺醇、二氢鞘胺醇(sphinganine)、植物鞘胺醇和二氢植物鞘胺醇。优选地,组合物包含鞘磷脂。鞘磷脂为神经酰胺磷酸胆碱。神经酰胺由经由酰胺键与脂肪酸联结的鞘氨基醇碱组成。
在口服的基础上,鞘磷脂和/或其降解产物,特别是溶血鞘脂(lysosphingolipid)、神经酰胺、鞘氨基醇磷酸盐和/或鞘氨基醇碱具有减少肠道微生物群内不利菌,诸如厚壁菌,特别是梭菌的作用。因同时具有有益菌的刺激剂和不利菌的抑制剂这两者,本发明将以更有效的方式改善微生物群的组成和/或维持微生物群均衡。
优选地,每100ml组合物包含10-200mg鞘磷脂,更优选20mg-150mg,甚至更优选60mg-100mg。基于脂肪,组合物优选包含0.25wt%至5.5wt%,更优选0.5wt%至4wt%,甚至更优选1.5wt%至3wt%。基于干重,组合物优选包含0.07wt.%至1.5wt.%,更优选0.15wt.%至1.1wt.%,甚至更优选0.5wt.%至0.8wt.%。数量越低则效应越小,然而数量越高将会留给有利的必需和长链脂肪酸的空间越少。鞘磷脂的合适来源为乳脂,更合适的为酪乳脂或奶油乳清脂、蛋黄和/或大豆卵磷脂。
优选地,非消化性寡糖和鞘磷脂间的重量比为0.4-200,更优选1-75,甚至更优选3-15。组合物中具有这一比率的存在确保了对微生物群中有益菌的刺激作用和对微生物群中不利菌的减少作用之间的平衡。
优选地,本发明组合物包含胆固醇和/或胆固醇酯。鞘磷脂和胆固醇和/或胆固醇酯同时存在于组合物中可延缓鞘磷脂在小肠内的消化,从而增加到达大肠的鞘磷脂的数量及此后鞘磷脂和/或其降解产物对抗肠道微生物群中不利菌的活性。基于总脂肪,本发明组合物优选包含至少0.005wt%胆固醇和/或胆固醇酯,更优选至少0.01wt%,更优选至少0.05wt%,甚至更优选至少0.1wt%。优选地,基于总脂质,胆固醇和/或胆固醇酯的数量不超过10wt%,更优选不超过5wt%,甚至更优选不超过总脂质的1wt%。最优选胆固醇的数量基于总脂质为0.5-0.7wt%。
营养组合物
本发明组合物优选为口服给予的。本发明组合物优选为营养配方,优选为婴儿配方。包含至少两种非消化性碳水化合物的本发明组合物不是人乳。
本发明组合物能作为婴儿的全营养品有利地应用。本发明组合物优选包含脂质、蛋白和消化性碳水化合物,而且优选以液体形式给予。本发明包括干性食品(例如粉末),其附有关于所将上述干性食品与合适的液体(例如水)混合的说明书。
本发明有利地提供了其中的脂质提供5%-50%的总卡路里的组合物。本发明有利地提供了其中的蛋白提供5%-50%总卡路里的组合物。本发明有利地提供了其中的消化性碳水化合物提供15%-90%总卡路里的组合物。本发明有利地提供了这样一种组合物:在该组合物,脂质提供5%-50%的总卡路里,蛋白提供5%-50%的总卡路里,以及消化性碳水化合物提供15%-90%的总卡路里。优选地,在本发明组合物中,脂质提供35%-50%的总卡路里,蛋白提供7.5%-12.5%的总卡路里,以及消化性碳水化合物提供40%-55%的总卡路里。为计算蛋白占总卡路里的百分比,需要考虑蛋白、肽和氨基酸所提供的总能量。总卡路里涉及脂质、消化性碳水化合物和蛋白所提供的卡路里的总和。
营养制品中所用的蛋白优选选自非动物蛋白(优选乳蛋白)、植物性蛋白(优选大豆蛋白和/或大米蛋白)、游离氨基酸和其混合物。本发明组合物优选包含酪蛋白、乳清、水解的酪蛋白和/或水解的乳清蛋白。优选地蛋白包含完整的蛋白,更优选完整的牛乳清蛋白和/或完整的牛酪蛋白。由于本发明组合物适合用于减少婴儿过敏反应,因此蛋白优选选自水解的乳蛋白。
本发明组合物优选含有选自蔗糖、乳糖、葡萄糖、果糖、玉米糖浆干粉、淀粉和麦芽糊精的消化性碳水化合物,更优选乳糖。
优选地,本发明组合物包含核苷酸和/或核苷,更优选核苷酸。优选地,组合物包含胞嘧啶核苷5’-单磷酸、尿嘧啶核苷5’-单磷酸、腺嘌呤核苷5’-单磷酸、鸟嘌呤核苷5’-单磷酸和/或次黄嘌呤核苷5’-单磷酸,更优选胞嘧啶核苷5’-单磷酸、尿嘧啶核苷5’-单磷酸、腺嘌呤核苷5’-单磷酸、鸟嘌呤核苷5’-单磷酸和次黄嘌呤核苷5’-单磷酸。优选地,每100g组合物干重,该组合物包含5-100mg,更优选5-50mg,最优选10-50mg核苷酸和/或核苷。核苷酸和/或核苷的存在有利地增加了拟杆菌,从而降低硬壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。
核苷酸和/或核苷被认为与本发明组合物的其它成分协同作用。
排便不正常,例如排便困难、排便量不足、腹泻是婴儿的重要的问题。据发现,通过给予渗透压浓度为50-500mOsm/kg,更优选100-400mOsm/kg的液体形态的本发明组合物可以减少排便问题。排便不正常减少,增强了肠道健康微生物群的建群和发育。
根据上文所述,重要的是,流质食品没有过度的热量密度,却仍然提供喂养个体的足够的卡路里。因此,流质食品优选具有0.1-2.5kcal/ml的热量密度,甚至更优选0.5-1.5kcal/ml的热量密度,最优选0.6-0.8kcal/ml。
应用
包含至少两种非消化性碳水化合物的本发明组合物,特别适用于年龄在36个月以下的人个体,用于降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。本发明组合物特别适用于年龄在36个月以下的人个体,用于当所述人个体的年龄达到36个月以上时,降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。
在目前年龄在36个月以下的人个体中降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率涉及,使肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向年龄在36个月以下的健康人乳喂养的人个体肠道微生物群中所发现的比率方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低。
当所述的人个体的年龄达到36个月以上时,在年龄为36个月以下的人个体中用于降低肠道微生物群中的厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率的用途涉及,使肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向同一年龄的、年龄36个月以下时进行人乳喂养的健康个体的肠道微生物群中所发现的比率的方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低。
包含至少两种非消化性碳水化合物的本发明组合物,特别适用于年龄在36个月以上的人个体,用于降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。在年龄在36个月以上的人个体中降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率涉及,使肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向正常体重的人个体肠道微生物群中所发现的比率的方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低。
包含至少两种非消化性碳水化合物的本发明组合物,特别适用于肥胖的人个体,用于降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。在肥胖的人个体中降低肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率涉及,使肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率向体重正常的人个体肠道微生物群中所发现的比率的方向,和/或相对于摄食本发明组合物之前人个体内存在的比率,和/或相对于未服用本发明组合物的对照组降低。
优选地,厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率降低至少25%,更优选至少33%,甚至更优选至少40%。优选地,厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率,与人个体中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属相比,或与未服用本发明组合物的对照组相比,向健康体瘦个体和/或母乳喂养的婴儿中所发现的比率的方向和/或相对于摄食本发明组合物之前人体内存在的比率降低。
肠道微生物群特别涉及结肠微生物群的组成。能够通过本领域中已知的方法,包括FISH、实时PCR和微阵列,利用本领域中已知的特异探针和/或引物,在门、纲、科、属和/或种水平上确定肠道微生物群的组成。
本发明的组合物对医院内出生的婴儿特别有利,因为他们处于被来自于医院环境的不利菌“拓殖”的风险中。本发明的组合物甚至对经由剖腹产分娩的婴儿更有利,因为这些婴儿未适当接种来自于母亲的有益菌而同时他们处于被来自于医院环境的不利菌“拓殖”的风险中。
因为如上文所述,给予年龄在36个月以下的人个体本发明组合物,对微生物群具有有利效应,所以本发明组合物优选随后用于预防和/或治疗肥胖和/或肥胖症,更优选内脏性肥胖,更优选当所述人个体的年龄达到36个月以上时。随后,本发明组合物优选用于预防当所述的人个体的年龄达到36个月以上时由内脏性肥胖导致的继发性病症,如2型糖尿病、空腹高血糖症(fasting hyperglycaemia)、胰岛素抵抗、内脏性肥胖症、高胰岛素血症、高血压、心血管疾病、脑血管疾病、动脉粥样硬化、血脂异常、高尿酸血症、脂肪肝、骨关节炎和睡眠呼吸暂停。在一实施方案中,肥胖、肥胖症和内脏性肥胖指的是作为肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属比率失衡后果的所述状况。
本发明旨在降低优选年龄在36个月以上、优选年龄在8岁以上、更优选年龄在15岁以上、最优选年龄在18岁以上的人个体肠道微生物群中厚壁菌门/拟杆菌门和/或梭菌属/拟杆菌属的比率。
在本说明书及其权利要求书中,动词“包含(to comprise)”及其词形变化以其非限制性意思使用,表示该词语后的条目都包括在内,但是并不排斥未特别提及的条目。另外,不定冠词“a”或“an”所提及的要素并不排除多于一个要素存在的可能性,除非上下文清楚地要求有且仅有一个要素。因此不定冠词“a”或“an”通常表示“至少一个”。
实施例
实施例1
每天给予9-10个月龄婴儿500ml的包含1.2gβ-低聚半乳糖加上长链菊粉的配方奶,持续1个月(A组)。对照组接受没有β-低聚半乳糖和长链菊粉的配方奶(B组)。总计138名儿童参与了该研究。通过FISH分析在这一时期前后对粪便菌群进行检测。如之前所述,通过FISH分析,在12和13个月检查粪便菌群((Haarman et al.Appl.Environ.Microbiol.2005.May;71(5):2318-24)。用一组7种探针计算儿童的主要粪便菌群。这些探针为(i)检测双歧杆菌属的Bif164,(ii)针对直肠真杆菌(Eubacteria rectale)/球形梭菌(Clostridium coccoides)的Erec482,(iii)针对拟杆菌属/普氏菌属(Prevotella)群的Bac303,(iv)Chis150,其检测以艰难梭菌(C.difficile)作为主要种类的溶组织梭菌(Clostridium histolyticum)群,(v)Clit135,其检测以产气荚膜梭菌(C.perfringens)作为主要种类的象牙海岸梭菌(C.lituseburense)群,(vi)针对乳酸杆菌和肠球菌的Lab158,和(vii)针对E.coli(大肠杆菌)和相关种类的Ec1531。Eub338探针作为一种阳性对照使用,因为它靶向几乎所有的细菌。有关所用探针的更多细节,参见Harmsen,HJM et al.2002,AEM.68:2982-2990,Franks AH et al.1998.AEM.64:3336-3334。为测定厚壁菌门,使用Erec482、Chis150、Cli135和Lab158的集合。为测定梭菌属,使用Chis150和Clit的集合。为测定拟杆菌门或拟杆菌属,使用Bac303探针。
在干预时间后,A组中双歧杆菌/全部细菌的比率显著高于B组。而且A组中梭菌属/全部细菌的比率显著低于B组。厚壁菌门/拟杆菌门的比率在开始时在A组中为42而在B组中为39,在1个月干预后,在B组中降低为32而在A组中降低为16。梭菌属/拟杆菌属的比率也降低了。直肠真杆菌+球形梭菌/全部细菌的比率也显著降低了。肠杆菌Enterobacterium/全部细菌的比率也降低了。这些数据也显示于表1中。
表1:在12和13个月时,作为全部细菌(Eub338探针)的平均数百分比的、接受带有β-低聚半乳糖和长链菊粉配方(A)或对照配方(B)儿童的儿童粪便中不同细菌群的百分比和标准误差。
探针 | A前 | B前 | A后 | B后 |
Erec482 | 18.9(2.1) | 31.1(2.3) | 22.9(2.5) | 29.4(2.8) |
Chis150+Clit135 | 2.9(0.5) | 5.6(0.8) | 3.9(0.5) | 4.7(0.6) |
Lab158 | 1.5(0.5) | 1.6(0.8) | 1.9(0.9) | 1.7(0.8) |
厚壁菌门 | 23.3 | 38.3 | 27.0 | 35.8 |
Bac303 | 0.56(0.29) | 0.98(0.64) | 1.65(0.48) | 1.13(0.35) |
C/Ba比率 | 5.2 | 5.7 | 2.4 | 4.2 |
F/Bb比率 | 42 | 39 | 16 | 32 |
Bif164 | 18.9(2.1) | 31.1(2.3) | 41.1(3.4) | 31.0(3.5) |
Ec1531 | 0.14(0.09) | 0.17(0.35) | 0.32(0.14) | 0.60(0.43) |
a:C/B为梭菌属/拟杆菌属的比率,(Chis150+Clit135)/Bac303。
b:F/B为厚壁菌门/拟杆菌门的比率,(Erec482+Chis150+Clit135+Lab158)/Bac303。
实施例2
从4-5名健康成年人获取的混合的新鲜粪便用于进行发酵研究,如WO 2004/000340的Appendix I(附录I)所述。进行该实验,一式两份(in duplo)。这些粪便,以1∶5稀释到McBain和Farlane培养基中,被放入到透析管中并在缺氧状况下悬浮在带有缓冲液的瓶中,而且出于适应的目的,在按照以下表1在t=0时用底物接种它们之前,首先在37℃下孵育16小时。
这些测试底物每天添加一次(在t=0、24和48小时时)。缓冲液每天更新一次。在t=0和t=72时进行取样。因为细菌群体中的变化与所形成的短链酸类中的变化相比相对缓慢,所以使用这一相对长的时期。
表2:包含稀释粪便的透析管的添加物
作为低聚葡萄糖GOS的来源,使用Vivinal GOS(Borculo Domo,The Netherlands)。作为菊粉的来源,使用RaftilineHP(Orafti,Belgium)。
将D-鞘氨醇而不是鞘磷脂,诸如鞘磷脂,添加到透析管,因为鞘磷脂在小肠内降解产生D-鞘氨醇。作为D-鞘氨醇的来源,使用来源于牛脑(Fluka Sigma Aldrich Chemie)的D-鞘氨醇。
将鞘氨醇溶解于乙醇(储备液10mg/ml)中。将30μl 10mg/ml的储备液添加到透析管。
通过如Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345中所述的荧光原位杂交(Fluorescene In Situ Hybridisation,FISH)分析样品。为测定拟杆菌属-普氏菌属群,使用Bac303探针(Manz,W.,et al.,Microbiology,1996.142(Pt 5):p.1097-106)。为测定梭菌,使用Chis150和Clit135探针(Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345)。为测定直肠真杆菌和球形梭菌群,使用Erec482探针(Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345)。为测定双歧杆菌,使用Bif164探针(Langendijk,P.,et al.,Appl.Environ.Microbiol.,1995.61(8):p.3069-3075)。为测定乳酸杆菌和肠球菌,使用Lab158探针(Harmsen,H.J.M.,et al.,Microbial Ecology in Health and Disease,1999.Volume 11:p.3-12)。为测定肠细菌,使用Ec1531探针(Poulsen,L.K.,et al.,Infect Immun,1994.62(11):p.5191-4)。通过DAPI染色测定细菌总数。将厚壁菌门/拟杆菌门Firmicutes/Bacteroidetes比率设置为以Bac303探针所检测的细菌的百分比除Chis150、Clit135、Erec482和Lab158探针所检测的细菌百分比。通过Erec482所检测到的细菌通常为人肠道内厚壁菌门的最大群体。
结果:
Bac303、Chis150、Clit135、Ec1351和Lab158探针全部显示出低于FISH检测极限的信号,为每克样品<106细胞或在1000细胞中相对丰度低于1(0.1%)。就Bac303而言,样品储存在恶劣状况下,但是在添加了GOS和菊粉的样品中可观察到微弱信号。Bif164和Erec482探针的FISH结果显示于表3中。
表3:Bif164和Erec482探针的FISH结果
这些结果表示,当非消化性碳水化合物更具体为GOS和/或菊粉发酵时双歧杆菌增加,而且当鞘氨醇存在时(其为鞘磷脂在小肠消化后的降解产物)双歧杆菌进一步增加,而且当这两种成分都存在时,甚至以协同作用的方式进一步增加。
这些结果表示,梭菌和真细菌,作为肠道厚壁菌门的最大群体,当非消化性碳水化合物更具体而言GOS和/或菊粉发酵时减少。当鞘氨醇也存在时,观察到进一步改善的效应。
这些结果表示,基于非消化性碳水化合物,尤其是GOS和/或菊粉的消耗,改善大肠微生物群中厚壁菌门/拟杆菌门比率的降低和梭菌属/拟杆菌属比率的降低,且通过消耗鞘磷脂,获得进一步改善。
实施例3
包含提供48%总卡路里的脂质、提供8%总卡路里的蛋白和提供44%总卡路里的消化性碳水化合物的婴儿营养品:
(i)脂质,其基于全部脂质包含约1.4wt.%的鞘磷脂和约4wt.%的胆固醇;
(ii)消化性碳水化合物,其包含50.9g乳糖/100g粉末,而且每100g粉末还包含作为非消化性碳水化合物的5.22g DP为2-6的β-低聚半乳糖和0.58g DP为7-60的低聚果糖;
(iii)蛋白,其包含牛乳蛋白,包括酪蛋白在内。
按照欧盟指令,组合物包含维生素、痕量元素和矿物质。该婴儿营养品包装的标签表明,该营养品旨在降低厚壁菌门/拟杆菌门的比率和/或力求获取导致肥胖减少的微生物群。
Claims (13)
1.包含至少两种非消化性碳水化合物的营养组合物在制备组合物中的用途,所述组合物用于使人个体中厚壁菌门/拟杆菌门(Firmicutes/Bacteroidetes)和/或梭菌属/拟杆菌属(Clostridium/Bacteroides)的比率向健康体瘦人个体中所发现的比率的方向、和/或向母乳喂养的婴儿中所发现的比率的方向、和/或相对于摄食所述组合物之前所述人个体内存在的比率、和/或相对于未服用所述组合物的对照组降低,所述非消化性碳水化合物选自:低聚果糖、低聚半乳糖、葡聚寡糖、***寡糖、甘露寡糖、低聚木糖、岩藻寡糖、***半乳寡糖、葡糖甘露寡糖、半乳甘露寡糖、含有唾液酸的寡糖和糖醛酸寡糖。
2.包含至少两种非消化性碳水化合物的营养组合物在制备组合物中的用途,所述组合物用于使人个体中厚壁菌门/拟杆菌门(Firmicutes/Bacteroidetes)和/或梭菌属/拟杆菌属(Clostridium/Bacteroides)的比率以健康体瘦人个体中所发现的比率、和/或向母乳喂养的婴儿中所发现的比率的方向、和/或相对于摄食所述组合物之前所述人个体内存在的比率、和/或相对于未服用所述组合物的对照组维持,所述非消化性碳水化合物选自:低聚果糖、低聚半乳糖、葡聚寡糖、***寡糖、甘露寡糖、低聚木糖、岩藻寡糖、***半乳寡糖、葡糖甘露寡糖、半乳甘露寡糖、含有唾液酸的寡糖和糖醛酸寡糖。
3.如权利要求1或2所述的用途,其中所述人个体的年龄在36个月以下。
4.如权利要求3所述的用途,其中当所述人个体的年龄达到36个月以上时,所述比率仍然降低或维持在低水平上。
5.如权利要求1、3或4所述的用途,其中所述比率降低至少25%。
6.如上述权利要求中任一项所述的用途,用于预防肥胖和/或肥胖症。
7.如权利要求6所述的用途,用于年龄在36个月以下的人个体中,且当所述人个体的年龄达到36个月以上时,用于预防肥胖和/或肥胖症。
8.如权利要求6或7所述的用途,用于预防选自2型糖尿病、空腹高血糖症、胰岛素抵抗、内脏性肥胖症、高胰岛素血症、高血压、心血管疾病、脑血管疾病、动脉粥样硬化、血脂异常、高尿酸血症、脂肪肝、骨关节炎和睡眠呼吸暂停的病症。
9.如上述权利要求中任一项所述的用途,其中所述组合物基于所述组合物干重包含至少0.25wt.%g的非消化性碳水化合物。
10.如上述权利要求中任一项所述的用途,其中所述组合物包含基于总卡路里提供35%-50%卡路里的脂质、基于总卡路里提供40%-55%卡路里的消化性碳水化合物和基于总卡路里提供7.5%-12.5%卡路里的蛋白。
11.如上述权利要求中任一项所述的用途,其中所述组合物包含至少β-低聚半乳糖。
12.如上述权利要求中任一项所述的用途,其中所述组合物包含至少短链低聚果糖和/或长链低聚果糖,优选长链低聚果糖。
13.如上述权利要求中任一项所述的用途,其中所述组合物包含至少糖醛酸寡糖。
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Cited By (9)
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CN104168778A (zh) * | 2012-02-10 | 2014-11-26 | N·V·努特里奇亚 | 增强婴儿免疫***的母体补充物 |
CN104168778B (zh) * | 2012-02-10 | 2017-06-16 | N·V·努特里奇亚 | 增强婴儿免疫***的母体补充物 |
CN104968216A (zh) * | 2012-12-10 | 2015-10-07 | N·V·努特里奇亚 | 含有非消化性寡糖的营养组合物 |
CN109561723A (zh) * | 2016-08-04 | 2019-04-02 | 雀巢产品技术援助有限公司 | 用于预防、治疗非轮状病毒相关性腹泻或降低其严重程度的包含低聚糖和任选地乳双歧杆菌的混合物的营养组合物和婴儿配方食品 |
CN109419816A (zh) * | 2017-08-29 | 2019-03-05 | 深圳华大生命科学研究院 | 解纤维素拟杆菌在预防和/或治疗心脏疾病方面的应用 |
WO2019041141A1 (zh) * | 2017-08-29 | 2019-03-07 | 深圳华大基因研究院 | 解纤维素拟杆菌在制备预防和/或治疗脂质代谢相关疾病制剂中的应用 |
US11273186B2 (en) | 2017-08-29 | 2022-03-15 | Bgi Shenzhen | Application of bacteroides cellulosityticus in preparing a preparation for preventing and/or treating lipid metabolism related diseases |
CN109419816B (zh) * | 2017-08-29 | 2022-12-30 | 深圳华大生命科学研究院 | 解纤维素拟杆菌在预防和/或治疗心脏疾病方面的应用 |
WO2023284778A1 (zh) * | 2021-07-13 | 2023-01-19 | 量子高科(广东)生物有限公司 | 一种益生元组合物及其应用 |
Also Published As
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ES2611203T3 (es) | 2017-05-05 |
CN101951794A (zh) | 2011-01-19 |
EP2589302B1 (en) | 2016-11-23 |
RU2010130468A (ru) | 2012-01-27 |
RU2012155333A (ru) | 2014-06-27 |
WO2009082214A1 (en) | 2009-07-02 |
PL2589302T3 (pl) | 2017-05-31 |
EP2229063A1 (en) | 2010-09-22 |
EP2234505A1 (en) | 2010-10-06 |
CN101951794B (zh) | 2016-11-02 |
US20110034407A1 (en) | 2011-02-10 |
US20110009359A1 (en) | 2011-01-13 |
RU2478309C2 (ru) | 2013-04-10 |
RU2608215C2 (ru) | 2017-01-17 |
PL2234505T3 (pl) | 2013-06-28 |
WO2009082216A1 (en) | 2009-07-02 |
AR077520A1 (es) | 2011-09-07 |
AR071550A1 (es) | 2010-06-30 |
EP2589302A1 (en) | 2013-05-08 |
ES2402687T3 (es) | 2013-05-07 |
EP2234505B1 (en) | 2013-01-30 |
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