CN101420966B - 不可消化的糖用于在出生后给予婴儿最佳开始的用途 - Google Patents
不可消化的糖用于在出生后给予婴儿最佳开始的用途 Download PDFInfo
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Abstract
本发明涉及包含水溶性、不可消化的糖的用于孕妇的食品或添加剂。所述组合物用于改善孕妇的菌群和/或免疫系统，改善婴儿的免疫系统，以及改善出生后婴儿的肠道菌群。
Description
技术领域
本发明涉及一种组合物，其通过向孕妇施用而促进婴儿健康。
背景技术
对母亲而言，婴儿在妊娠期间发育良好以及在出生时获得最佳开始是尤其重要的。因此，孕妇通常摄取旨在改善未出生儿童的生长和发育的营养组合物。
长链多不饱和脂肪酸(LC-PUFA)已被描述为能够促进未出生儿童的大脑发育。据此，孕妇(以及哺乳期妇女)可摄取具有LC-P UFA的营养组合物。EP705539描述了这样的组合物。
EP1296694涉及对变态反应进行预防，并特别涉及通过在出生前和出生后，给处于患特应性疾病高风险的儿童施用益生菌、存在于健康肠道菌群中的有益微生物对特应性疾病进行一级预防。
发明概述
本发明人已发现，给孕妇施用水溶性、不可消化的糖能够改善未出生婴儿的免疫系统。发现未出生婴儿存在于肠细胞和单核细胞的细胞膜中的受体CD14和TLR2表达增强。
此外，还发现，与没有摄取本发明的糖的母亲所分娩的婴儿的肠道菌群发育情况相比，摄取了本发明的糖的母亲所分娩的婴儿的肠道菌群发育状况得以改善。
本发明人已发现，婴儿的肠道菌群发育之所以得到改善是源于摄取了本发明的糖的母亲的肠道和/或阴道菌群得到改善。摄取本发明的糖后，母亲胃肠道中的双歧杆菌和乳杆菌的生长受到促进。随后，通过交叉定植，母亲的阴道菌群也有益地朝向高含量和多样化的双歧杆菌和乳杆菌变化。出生期间，新生儿的肠道首先受到母体阴道和肠道微生物菌群的接种。因此，母亲有益的阴道和肠道菌群可导致婴儿在生命的第一阶段获得改善的菌群。
作为免疫系统被促进以及由双歧杆菌属(Bifidobacterium)和乳杆菌属(Lactobacillus)控制的最佳肠道菌群的结果，婴儿不仅发生免疫相关疾病(例如特应性疾病)的机会降低，而且发生胃肠道疾病(例如感染、肠道炎症、腹泻或便秘)的机会也降低。
另一方面，令人惊讶地发现施用这一不可消化的糖有益地影响了孕妇和/或婴儿的免疫系统。发现分娩前的儿童免疫系统在出生后经激发出现更快的Th1应答。结果，发生免疫相关疾病(例如特应性疾病)的机会被进一步降低。
优选实施方式的详细描述
本发明提供了水溶性、不可消化的糖用于制备用于
i)改善出生后婴儿的肠道菌群发育；
ii)加强出生前婴儿的免疫系统；和/或
iii)加强出生后婴儿的免疫系统和/或预防出生后婴儿的免疫系统相关疾病
的组合物的用途，其中将所述组合物施用给怀有所述婴儿的孕妇。
本发明还提供了水溶性、不可消化的糖用于制备用于
i)加强孕妇的免疫系统；
ii)改善孕妇的肠道菌群；和/或
iii)改善孕妇的阴道菌群；
的组合物的用途，其中将所述组合物施用给孕妇。
水溶性、不可消化的糖
用于本发明的方法中的组合物包含水溶性、不可消化的糖。本发明中所用术语“不可消化的”指通过存在于人上消化道(小肠和胃)中的酸或消化酶的作用在肠中不会被消化，但却可被人的肠道菌群发酵的糖。单糖和双糖(例如葡萄糖、半乳糖、果糖、蔗糖和乳糖)是可消化的。本申请中所用术语“可发酵的”指通过胃肠道下部(例如，结肠)中的微生物能够被转化成较小分子(尤其是短链脂肪酸和乳酸)的能力。本发明的糖是水溶性的，其可采用L.Prosky et al，J.Assoc.Anal.Chem71：1017-1023，1988所公开的方法进行确定。
优选地，本发明的糖具有至少2个且优选低于100个单糖单位，优选低于60，更优选低于40，最优选低于10的聚合度(DP)。优选地，本发明的水溶性、不可消化的糖是包含半乳糖的糖。具有相对较低聚合度的糖具有改良的乳杆菌和/或双歧杆菌发酵能力，且不表现出增加粘性的技术劣势。
包含水溶性、不可消化的半乳糖的糖
优选地，本发明的糖为含有水溶性、不可消化的半乳糖的糖(下文中称作“GAL-oligo”)，其优选地包含占所述糖的单糖单位总数至少50％的半乳糖单位。与其他水溶性、不可消化的糖相比，GAL-oligo具有改善的双歧杆菌产生效应(bifidogenic effect)。人母乳同样包含高浓度的GAL-oligo，且喂食人母乳的婴儿的肠道菌群在双歧杆菌方面比喂食标准婴儿配方奶的婴儿更加丰富。优选地，本发明的GAL-oligo含有占存在于所述糖中的单糖单位总数至少60％(更优选至少65％)的半乳糖单位。
优选地，本发明的GAL-oligo包含至少两个末端糖单位，其中至少一个末端糖单位选自葡萄糖和半乳糖；且至少一个末端糖单位选自半乳糖和岩藻糖。优选地，GAL-oligo中至少75％(优选100％)的糖是β-连接的。
术语“末端糖”指结合于另一糖单位的糖(例如，半乳糖、葡萄糖、果糖或岩藻糖)。本发明的GAL-oligo优选地含有不超过4个末端糖，优选不超过2个。在一个优选的实施方式中，所述GAL-oligo包含至少一个末端半乳糖和选自至少末端葡萄糖和一个末端岩藻糖的糖。更优选地，本发明的GAL-oligo包含至少一个末端半乳糖和至少一个末端葡萄糖。优选地，本发明的Gal-oligo含有2个末端糖单位且具有2-60的聚合度(DP)。
优选地，所述GAL-oligo选自反式半乳糖寡糖、半乳糖寡糖、乳-N-四糖(lacto-N-tetraose(LNT))、乳-N-新四糖(lacto-N-neotetraose(neoLNT))、岩藻糖基乳糖、岩藻糖化LNT以及岩藻糖化neoLNT。优选地，所述GAL-oligo是唾液酸化的。优选地，所述GAL-oligo选自唾液酸乳糖、唾液酸岩藻糖基乳糖、唾液酸乳糖胺以及唾液酸化-LNT和唾液酸化-neo-LNT，更优选唾液酸乳糖。在一个特别优选的实施方式中，本发明的方法包括施用反式半乳糖寡糖([半乳糖]n-葡萄糖；其中n是介于1和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)。优选地，所述反式半乳糖寡糖的糖是β-连接的。反式半乳糖寡糖(TOS)例如存在于以商标VivinalTM(Borculo Domo Ingredients，荷兰)进行销售的组合物中。其它适当的TOC来源是Cup-oligo和Bi2muno。
不同的水溶性、不可消化的糖
为了获得关于肠道菌群和/或婴儿免疫系统或肠道菌群(的改善)，孕妇阴道菌群和/或免疫系统(的改善)的更佳效果，本发明的组合物优选地包含两种在结构上互不相同的，不同的水溶性、不可消化的糖。每一种水溶性、不可消化的糖都可用肠道和/或阴道菌群和/或肠道不同位置中的不同种类的微生物进行发酵，从而导致菌群的改善和细菌更加多样化。
本发明提供了优选地包含水溶性、不可消化的糖A和水溶性、不可消化的糖B的组合物。糖A和糖B具有不同的糖苷键、不同的聚合度和/或不同的单糖组成。优选地，糖A是GAL-oligo。
根据本发明的优选实施方式，糖A中选自葡萄糖、果糖和半乳糖的至少一个单糖单位的百分比要比糖B中相同单糖单位的百分比高至少40％，优选至少50％、更优选至少75％，甚至更优选至少90％。单糖单位多样性的增加能够刺激更为广泛的肠道(有益)细菌群，从而使菌群得以改善。所述糖中单糖单位的百分比可简单地通过用存在于所述糖中的各单糖单位(例如，葡萄糖)的数量除以存在于所述糖中的单糖单位的总数计算。
优选地，水溶性、不可消化的糖A和B具有介于2和200之间的聚合度(DP)。优选地，至少80wt％，更优选至少95wt％，最优选至少98wt％累积重量的水溶性、不可消化的糖A和B具有低于100，更优选低于60，最优选低于40的聚合度(DP)。较低的DP可有益地降低粘度并增加不可消化的糖的可发酵性。优选地，至少50wt％，更优选至少75wt％累积重量的水溶性、不可消化的糖A和B具有2-8的DP。通过使用具有高重量百分比的具有低DP的糖，将提高可发酵性和对乳酸细菌和双歧杆菌的生长的刺激效应。
根据本发明的优选实施方式，水溶性、不可消化的糖A的DP比水溶性、不可消化的糖B的DP要低至少5个，优选至少10个，甚至更优选至少15个单糖单位。包括聚合度增加的糖能降低渗透负载，并导致沿结肠的发酵延长，从而同样在结肠的更末端部分改善对有益细菌的刺激。优选地，水溶性、不可消化的糖A具有2-10(更优选2-8)的DP。优选地，水溶性、不可消化的糖B具有11-100的DP。具有不同DP的水溶性、不可消化的糖A和B可具有相同或略有不同的单糖组成，优选为不同的单糖组成。
在本发明的优选实施方式中，水溶性、不可消化的糖A的至少一种糖苷键占存在于糖A中的总糖苷键的百分比，比在水溶性、不可消化的糖B中相同糖苷键的百分比高至少40％，优选至少50％，甚至更优选至少75％。本发明中所用术语“糖苷键”指通过脱水在两个环状单糖单位的环之间形成的C-O-C键。糖苷键多样性的增加刺激更广范围的有益细菌。糖苷键之间的区别在于其在单糖单位的不同编号位置共价结合碳原子，和/或其形成α或β键。出现在水溶性、不可消化的糖中的不同糖苷键的实例有β(1，3)、α(1，4)、β(2，1)、α(1，2)和β(1，4)键。优选地，水溶性、不可消化的糖A中的糖苷键包含至少40％(更优选至少75％)的β(1，4)糖苷键。水溶性、不可消化的糖B中的糖苷键优选包含至少40％(更优选至少75％)的β(2，1)糖苷键。
在一个优选实施方式中，本发明的组合物含有Gal-oligo与选自由果聚糖(例如，菊粉)组成的组的水溶性、不可消化的糖的组合，更优选具有介于2和10之间的平均DP的GAL-oligo与选自果聚糖和果寡糖的水溶性、不可消化的糖的组合，最优选反式半乳糖寡糖和菊粉的组合。
优选地，糖A和糖B的重量比为3/97至97/3，更优选5/95至95/5。以充分相对比例存在的糖A和B将对菌群具有更佳的效果。最优选地，糖A与B的重量比为2/3至95/5。更优选略微过量的糖A(优选GAL-oligo和/或寡糖)，因为这将对菌群具有更佳的效果。
长链多不饱和脂肪酸(LC-PUFA)
优选地，本发明的组合物额外包含长链多不饱和脂肪酸和/或长链多不饱和脂肪酰基链(LC-PUFA)。在本发明中，术语LC-PUFA涉及20或更多个碳原子长以及至少两个不饱和键的脂肪酸或脂肪酰基链。优选地，所述组合物包含选自二十碳五烯酸和/或酰基链(EPA)、二十二碳六烯酸和/或酰基链(DHA)和花生四烯酸和/或酰基链(AA)的LC-PUFA。在一个实施方式中，所述组合物包含DHA。在另一个实施方式中，所述组合物包含AA。更优选地，所述组合物包含DHA和AA。LC-PUFA有益地增强待出生婴儿的免疫系统。因此，与单独施用水溶性、不可消化的糖相比，给孕妇施用包含水溶性、不可消化的寡糖和LC-PUFA的组合物对婴儿免疫系统具有改善的效果。
EPA/DHA的重量比优选为1或更低，更优选低于0.5。LC-PUFA可以游离脂肪酸、以甘油三酯的形式、以磷脂的形式、或以一或多种上述形式的混合物提供。本发明的组合物优选地包含以磷脂形式存在的AA和DHA中的至少一种。优选地，DHA与AA的重量比介于0.1和20之间，更优选介于0.5和5之间。
优选地，所述组合物包含每日剂量50至3000mg(更优选100至1500mg，最优选200至500mg)的LC-PUFA。
其他成分
在一个优选的实施方式中，所述组合物额外地包含益生菌。在本发明中，益生菌是指这样的微生物，其在施用后能够对于宿主产生有益效果。益生菌对孕妇的肠道菌群、阴道菌群和/或免疫系统以及她们待出生的婴儿具有有益效果，因此水溶性、不可消化的糖和益生菌的组合将对二者的肠道菌群和/或免疫系统具有上佳的效果。优选地，所述益生菌选自乳杆菌属和双歧杆菌属。更优选地，所述益生菌选自嗜酸乳杆菌(Lacobacillus acidophilus)类群、鼠李糖乳杆菌(L.rhamnosus)、干酪乳杆菌(L.casei)、类干酪乳杆菌(L.Paracasei)、植物乳杆菌(L.plantarum)、路氏乳杆菌(L.reuteri)、发酵乳杆菌(L.fermentum)、婴儿双岐杆菌(Bifidobacterium infantis)、动物双歧杆菌乳制品亚种(B.animalis subsp.lactis)、短双歧杆菌(B.breve)、长双歧杆菌(B.longum)和双歧双歧杆菌(B.bifidum)。甚至更优选地，所述益生菌是类干酪乳杆菌和/或短双歧杆菌，因为施用水溶性、不可消化的糖能够在相同程度上对大多数种类的乳杆菌和双歧杆菌类群进行刺激，但对短双歧杆菌和类干酪乳杆菌的刺激程度较低。由于双歧杆菌在婴儿肠道菌群中比乳杆菌更具有统治地位，所以短双歧杆菌是最优选的。优选地，益生菌在每日剂量中含每种不同的益生菌1x106菌落形成单位(cfu)至1x1013cfu，更优选1x107至1x1011，最优选1x108至1x1010。
所述组合物额外地包含对孕妇有益的维生素和矿物质。通常，包含维生素和矿物质的添加剂会被孕妇出于自身或胎儿的利益而摄取。在本发明中的组合物中包括这些维生素和矿物质方便地降低了孕妇待摄取的组合物的量。优选地，所述组合物包含选自叶酸、维生素B1、维生素B2、维生素B6、维生素A、维生素D、铁、锌和碘的至少一种成分，更优选至少三种成分，最优选至少六种成分。优选地，这些成分在每日剂量中含推荐的每日供给量(RDA)的25-100％，更优选介于45-100％。优选地，维生素A以β-胡萝卜素进行补充。
组合物
可以棒(bar)、胶囊、片剂、液体或粉末的形式给孕妇施用包含所述水溶性、不可消化的糖的组合物。
优选地，所述组合物是基于乳的液体，其包含脂肪、蛋白质和可消化的碳水化合物。优选地，所述基于乳的液体的脂肪含量低于2g/l以保持待消耗的卡路里数量较低。优选地，这一基于乳的液体可被包装成体积为50至1000mL(更优选60至500mL，最优选75至125mL)的容器或菱角包(tetrapack)中。优选地，所述组合物是水活度低于0.8(优选低于0.65)的棒，即可咀嚼的固体。优选地，所述组合物为粉末，其被包装在包含1至10g(更优选1.5至7g，最优选2至5g)的粉末的小药囊中。
剂量
在本发明的方法中，优选地将本发明的糖以介于0.5g/天和50g/天(优选介于3g/天和25g/天，最优选介于6g/天和12g/天)的量施用给孕妇。优选地，按每日一份施用这一每日剂量。优选地，将这一每日剂量分成2或3或4份，每天分别使用2、3或4次。
优选地，可在预产期(due delivery)之前给孕妇施用所述组合物至少2周，更优选至少6周，最优选至少12周。
应用
当下文中涉及特定的治疗方法时，所述方法包括给孕妇施用有效量的上面所描述的组合物或施用有效量的至少水溶性、不可消化的糖，这还涉及至少一种水溶性、不可消化的糖用于制备用于所述目的组合物的用途。两种本发明的用词方式同样被诸如本发明的组合物可用于某种目的或本发明的组合物的施用可用于某种目的这样的措辞所涵盖。
本发明提供了用于改善婴儿肠道菌群和/或免疫系统的方法，所述方法包括向怀有所述婴儿的孕妇施用本发明的组合物(即，包含水溶性、不可消化的糖的组合物)。
在一个实施方式中，婴儿的免疫系统得到加强。在本发明中加强免疫系统涉及免疫系统的改善、刺激和/或增强。优选地，所述改善、刺激和/或增强是相对于对照组而言的，其在本发明的上下文中指相对于未摄取水溶性、不可消化的糖的孕妇。本发明人观察到施用水溶性、不可消化的糖可将新生儿免疫系统引向Th1应答和/或改善Th1/Th2平衡。发现在分娩前未出生儿童的免疫系统是通过增强受体CD14和TLR2所激发的。
在一个实施方式中，给孕妇施用水溶性、不可消化的糖被用于预防婴儿中特应性疾病的发生。在一个实施方式中，给孕妇施用所述组合物以在婴儿中预防变态反应(即，食物变态反应)、湿疹(即，特应性皮炎)、哮喘、鼻炎、枯草热、鼻结膜炎和/或喘鸣(最优选变态反应和/或特应性皮炎)的发病和/或降低其严重性。湿疹(即，特应性皮炎)的特征为干燥和/或发红和/或瘙痒的皮肤。
在一个实施方式中，给孕妇施用水溶性、不可消化的糖被用于改善婴儿的肠道菌群。施用本发明的组合物可被包括在用于在出生后增强结肠和/或粪便中的双歧杆菌和/或乳杆菌占存在于婴儿菌群和/或粪便中的总细菌的百分比的实施方式中。富含双歧杆菌和/或乳杆菌的菌群可加强婴儿的免疫系统并增进胃肠健康。与其母亲在妊娠期未摄取包含水溶性、不可消化的糖的本发明的组合物的婴儿的胃肠健康相比，改善的胃肠健康涉及胃肠感染的发生率降低、肠道感染的持续时间更短、胃肠炎症的发生率和严重性降低、腹泻的发生率和/或严重性降低、便秘的减少、或痉挛的减少。在本发明的上下文中，“加强”或“加强的”以及“改善”和“改善的”是相对于其母亲在妊娠期未摄取包含水溶性、不可消化的糖的本发明的组合物的婴儿而言的或是相对于未摄取包含水溶性、不可消化的糖的本发明的组合物的孕妇而言的。加强的免疫系统将对特应性疾病和/或呼吸道感染具有预防作用。在一个实施方式中，给孕妇施用本发明的组合物被用于在出生后的婴儿中预防选自变态反应(即，食物变态反应)、湿疹(即，特应性皮炎)、哮喘、鼻炎、枯草热、鼻结膜炎、喘鸣、肠道感染、阴道感染、呼吸道感染、腹泻、便秘、痉挛和肠道炎症的疾病和/或降低其严重性。在一个实施方式中，给孕妇施用本发明的组合物被用于预防出生后婴儿的选自肠道感染、呼吸道感染、腹泻、便秘、痉挛和/或肠道炎症的疾病。
本发明还包括具有指明在使用所述组合物之后孕妇能够给予其婴儿出生后的最佳开始，例如，关于肠道定植、肠道菌群、菌群组合和/或免疫系统(例如免疫防御或加强的或改善的或增强的或被刺激的免疫性)的文字的、包含本发明的组合物的包装。
在一个实施方式中，施用本发明的组合物用于改善孕妇的免疫系统。
在一个实施方式中，施用包含水溶性、不可消化的糖(优选包含两种不同的水溶性、不可消化的糖)的本发明的组合物被用于加强孕妇的免疫系统、肠道菌群和/或阴道菌群。在一个优选的实施方式中，施用优选包含两种不同的水溶性、不可消化的糖的本发明的组合物被用于增强孕妇肠道和/或阴道中乳杆菌和/或双歧杆菌占总细菌的百分比。由于在妊娠期间阴道菌群紊乱经常发生，因此这是至关重要的，且病原体的过度生长和阴道微生物微环境的破坏可通过乳杆菌的稳定定植而得以预防。
实施例
实施例1 临床实验
对总共33位妊娠的健康志愿者进行具有平行组设计的CA预期性、双盲、随机化、安慰剂对照研究。她们从妊娠第25周开始接受实验添加剂或安慰剂直至分娩。所述实验添加剂是基于不可消化的寡糖，并包含3g GOS(来自Vivinal GOS，Borculo Domo，荷兰)+菊粉(RaftilinHP，Orafti，比利时)(9:1的wt/wt比)以及3g可消化的麦芽糊精。这一添加剂每天摄取3次。对照组添加剂由6g可消化的麦芽糊精组成。
在进行第一次添加剂施用前，在妊娠第25周采集粪便样本。在最后一次分娩前的标准化常规医院检查之后采集第二次粪便样本。在分娩时，从胎盘脐静脉采集一份脐带血样本。在分娩后的第5天、20天和6个月采集新生儿的粪便样本。
通过FISH和实时PCR分析母体和新生儿粪便样本的微生物菌群。可使用FACS分析和用有丝分裂原和变应原进行体外刺激检测对脐带血(CB)进行表型表征。
可使用本领域公知的方法测定以下参数：
a)先天免疫应答
NKT细胞、单克隆T细胞受体的频率(即，Va24JaQ TCR的同源N-区域、Toll样受体表达细胞的定量(TLR2、TLR4)；粒细胞计数。NK细胞活性。
b)适应性免疫应答
采用四色细胞计量术进行淋巴细胞亚群分析。在非刺激细胞中与TH1/TH2相关的mRNA细胞因子和趋化因子受体模式(TNF-α、INF-g、IL-4、IL-8、IL-10、IL-12、IL-13、TGFβ、CD25、CD45RA、CD45RO、CTLA-4、CCR3、CCR4、CCR5、CXCR3)的表征通过实时RT PCR和之后使用ConA/PHA和LPS离体进行全血刺激进行测定。对在CD4+和CD8+T细胞亚群中产生TH1/TH2-细胞因子的比例分析进行了确定。
从28位分娩者获得胎盘脐带(cortical)血样本，并用伴刀豆球蛋白A(Con A)/(PHA)、脂多糖(LPS)、葡萄球菌肠毒素B(SEB)、β-乳球蛋白(BLG)、来自Dermatophagoides pteronyssinus的主要屋尘螨变应原(Der p1)、卵清蛋白(Ova)刺激24小时。
用适当稀释的抗人CD4、CD8、CD45RA、CD45RO、CD25、CD69、CCR4、CCR5、CD14、CCR1、CCR2、CCR6、CCR7、CCR8、CCR9、CXCR3、CXCR4、CXCR5、CRTH2的FITC-、PE-、PC5-或APC-标记的单克隆抗体和适当的同种型对照对CB T淋巴细胞(50μl全血样本)进行染色。染色后，污染的红细胞被裂解。对CD4+T辅助细胞(Th)群中趋化因子受体(CKR+)和表达CKR+CD45RA+的淋巴细胞的百分比，以及CD4+CD45RA+群中表达CKR+的细胞的百分比进行分析。在CD8+T细胞毒性(Tc)和CD8+CD45RA+淋巴细胞群中进行相同的分析程序。对CXCR4，确定其平均荧光强度(MFI)。测定T调节细胞上CD4+CD25高表达。
全CB刺激分析
在RPMI-1640中将肝素化的CB稀释1-5倍。在24-孔培养板中用伴刀豆球蛋白A(ConA50μg/mL)、β-乳球蛋白(100μg/mL BLG)、卵清蛋白(100μg/mL OVA)、脂多糖(0.1μg/mL LPS)、葡萄球菌肠毒素B(0.1μg/mL SEB)、Dermatophagoides pteronyssinus(10μg/mL Der p1)或单独用培养基刺激1mL经稀释CB等分试样。将细胞于37℃、在5％CO2气氛中温育24小时或48小时，并将上清液储存于-80℃用于细胞因子分析。
多重分析
用人多重化、基于颗粒的流式细胞分析对培养物上清液中的细胞因子进行定量。无须进一步稀释即可对上清液中的TNF-α、INF-γ、IL-1β、IL-2、IL-4、IL-10、GM-CSF、G-CSF浓度进行直接测定。为测定IL-6、IL-8、MCP-1和MIP-1β，将上清液按1：10进行稀释于RPMI中。相对于阴性对照，对细胞因子表达的差异进行测定并将浓度标准化为从全血计数获得的淋巴细胞(对于IL-2)和总白细胞(对于所有其他细胞因子)的数目(pg/mL/10E3个细胞)。
尽管在补充开始之前，在母体微生物菌群组合中存在大的个体内变异，总细菌负载以及每毫升双歧杆菌和乳杆菌的细胞中值数在两组之间没有差异。但是，在使用包含GOS和菊粉的添加剂进行补充后，在孕妇粪便菌群中观察到总双歧杆菌和乳杆菌所占百分比增加。参见表1。在母亲粪便样本中，在补充前和补充后，在两组中最常见的种类是链状双歧杆菌(B.catenulatum)、婴儿双岐杆菌和嗜酸乳杆菌。
在分娩后第5天，来自实验组母亲所生婴儿的粪便中含有7.4％的乳杆菌(n＝17，s.e.3.0)；而在分娩后第5天，来自对照组母亲所生婴儿的粪便仅含有2.4％的乳杆菌(n＝16，s.e.0.9)。
婴儿的组内比较表明从第20天至第182天，安慰剂组中乳杆菌的数量明显增加[p＝0.038；pW]。这一结果可通过FISH分析[p＝0.018；pW]进行确认。从第20天至第182天，安慰剂组中对嗜酸乳杆菌表现为阳性的新生儿的百分比有所增加[p＝0.016]。这一区别可通过qPCR分析进行确认(p＝0.012)。
在实验组中，对脐带血的FACS分析揭示在CD14+单核细胞上TLR2+的平均荧光强度水平明显降低(p<0.05)。改变的CD14+和TLR2+表达水平表明，分娩前新生儿免疫系统在分娩后指向了更快速的Th1应答。
表1使用GOS和菊粉的混合物(实验组)或麦芽糊精(对照组)的孕妇粪便中的双歧杆菌和乳杆菌的百分比
| 实验组双歧杆菌的平均数(s.e.)％a | 实验组乳杆菌的平均数(s.e.)％a | 对照组双歧杆菌的平均数(s.e.)％a | 对照组乳杆菌的平均数(s.e.)％a | |
| T＝1b | 13.0(1.7)c | 8.6(2.0) | 18.5(4.1) | 5.4(1.9) |
| T＝2bT＝2 | 24.1(2.6)cd | 9.9(1.7) | 14.7(3.5)d | 7.8(1.9) |
a采用FISH对双歧杆菌进行定量，通过实时PCR对乳杆菌进行定量。
bt＝1：在妊娠第25周，进行补充之前；t＝2：在分娩前进行最后一次医院检查时。
c统计学显著差异，p<0.05，在t＝1和t＝2之间。
d统计学显著差异，p<0.05，在实验组和对照组之间。
为检测母体益生菌补充是否影响胎儿的免疫性，进行广泛的表型淋巴细胞亚群分析。CB CD4+T辅助(Th)细胞和CD8+T细胞毒性(Tc)细胞主要表达初始(CD45RA+)表型(>84％)，而表达CD45RO+少于13％。CD4+/CD8+的比例以及CD4+CD45RA+、CD8+CD45RA+、CD4+CD45RO+和CD4+CD45RO+的百分比在出生前组和安慰剂组之间不存在明显的差异。与CCR7+(87.3％)细胞的高频率不同，所有其它的CKR都以非常低的频率在CD4+和CD8+细胞上表达。CXCR4的MFI在CD4+和CD8+亚群上均高，而CXCR3仅在CD8+细胞上以高的频率进行表达。对CD4+、CD8+、CD4+CD45RA+和CD8+CD45RA+CB T细胞亚群中的CKR+淋巴细胞的频率，以及在不同CD4+和CD8+亚群中Th1/Th2比例(CXCR3/CCR4和CCR5/CCR4)的分析，在两组之间未表现出明显的差异。两组中，早期活化标记物CD69以及晚期活化标记物CD25以类似的水平在不同的CD4+亚群上表达(数据未显示)。未观察到表达CD25高的CD4+T细胞亚群的频率存在差异(中值：1.5Vs1.4；p＝0.683)。
对由有丝分裂原和变应原刺激了24小时的全CB培养物产生的衍生自白细胞的细胞因子谱进行的比较分析揭示了细胞因子表达的典型模式。当分析通过不同刺激(除G-CSF外(对Der p1、BLG和OVA而言p<0.03))诱导的细胞因子浓度时，在两个补充组之间未观察到明显的区别。
这些结果表明，采用水溶性、不可消化的糖进行补充能够导致孕妇的肠道微生物菌群中双歧杆菌和乳杆菌的百分比增加。这导致出生期间婴儿肠道的乳杆菌和/或双歧杆菌接种情况以及出生后定植情况的改善。尤其，出生后短时期内乳杆菌的存在很重要，因为乳杆菌具有使结肠酸化的高的能力，由此使得随后的肠道环境更加适于双歧杆菌而较不适合肠病原体。此外，这些结果表明这样的补充能够改善未出生婴儿以及出生期间和出生后婴儿的免疫系统。
实施例2
包装于100mL容器中的100mL基于液体乳的组合物包含：
-8.1g反式半乳糖寡糖，(来自Vivinal GOS)
-0.9g果聚糖(来自RaftilineHP)
-750mg鱼油和月见草油，包含
8.4mgAA
Claims (6)
1.水溶性、不可消化的糖用于制备一种组合物的用途，其中所述水溶性、不可消化的糖包含反式半乳糖寡糖，并且其中将所述组合物施用给怀有婴儿的孕妇用于
i.改善出生后婴儿的肠道菌群发育；
ii.加强出生后婴儿的免疫系统和/或预防出生后婴儿的免疫系统相关疾病。
2.权利要求1的用途，其中将所述组合物施用给怀有婴儿的孕妇用于预防出生后婴儿中选自变态反应、湿疹、哮喘、鼻炎、枯草热、鼻结膜炎、喘鸣、肠道感染、阴道感染、呼吸道感染、腹泻、便秘、痉挛和肠道炎症中的至少一种疾病。
3.水溶性、不可消化的糖用于制备一种组合物的用途，其中所述水溶性、不可消化的糖包含反式半乳糖寡糖，并且其中将所述组合物施用给怀有婴儿的孕妇用于
i.加强出生前婴儿的免疫系统。
4.权利要求1-3中任一项的用途，其中所述糖以0.5g/天至50g/天的剂量，在预产期前给药至少2周。
5.权利要求1-3中任一项的用途，
-用于促进出生后婴儿肠道细菌定植，和/或
-提高出生后婴儿结肠和/或粪便中双歧杆菌和/或乳杆菌占总细菌的百分比。
6.权利要求1-3中任一项的用途，其中所述水溶性、不可消化的糖还包含选自果聚糖和果寡糖的水溶性、不可消化的糖，优选菊粉。
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| MY168792A (en) | 2018-12-04 |
| BRPI0708701A2 (pt) | 2011-06-07 |
| MY191118A (en) | 2022-05-30 |
| AR059817A1 (es) | 2008-04-30 |
| PL1993577T3 (pl) | 2014-07-31 |
| RU2008140167A (ru) | 2010-04-20 |
| CA2883256A1 (en) | 2007-09-20 |
| WO2007105945A2 (en) | 2007-09-20 |
| AU2007225549A1 (en) | 2007-09-20 |
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| DK1993577T3 (da) | 2014-05-12 |
| CN101420966A (zh) | 2009-04-29 |
| US9872869B2 (en) | 2018-01-23 |
| EP1993577B1 (en) | 2014-02-12 |
| US20090305996A1 (en) | 2009-12-10 |
| WO2007105945A3 (en) | 2007-11-08 |
| RU2462252C2 (ru) | 2012-09-27 |
| AU2007225549B2 (en) | 2012-09-27 |
| AU2012265617B2 (en) | 2016-02-25 |
| JP2009529574A (ja) | 2009-08-20 |
| AU2012265617A1 (en) | 2013-01-10 |
| PT1993577E (pt) | 2014-05-27 |
| CA2645472C (en) | 2015-09-15 |
| ES2459621T3 (es) | 2014-05-12 |
| NZ571158A (en) | 2011-08-26 |
| EP2388010A1 (en) | 2011-11-23 |
| EP1993577A2 (en) | 2008-11-26 |
| CN103315205A (zh) | 2013-09-25 |
| CA2645472A1 (en) | 2007-09-20 |
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