CN101330837A - 治疗和/或预防剖腹产分娩的婴儿感染的方法 - Google Patents

治疗和/或预防剖腹产分娩的婴儿感染的方法 Download PDF

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Publication number
CN101330837A
CN101330837A CNA2006800473329A CN200680047332A CN101330837A CN 101330837 A CN101330837 A CN 101330837A CN A2006800473329 A CNA2006800473329 A CN A2006800473329A CN 200680047332 A CN200680047332 A CN 200680047332A CN 101330837 A CN101330837 A CN 101330837A
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composition
baby
mentioned
cesarean section
compound sugar
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琼希姆·施密特
伯恩德·斯塔尔
詹·诺尔
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Nutricia NV
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Nutricia NV
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Abstract

本发明提供了一种包含糖醛酸低聚糖的且用于制造对剖腹产分娩的婴儿进行肠道给予的一种组合物的应用。

Description

治疗和/或预防剖腹产分娩的婴儿感染的方法
技术领域
本发明涉及喂养剖腹产分娩的婴儿的方法。
背景技术
人乳包含了非消化低聚糖，这些低聚糖能特异地促进产乳酸细菌的生长，比如属于双歧杆菌种和乳酸菌种的一些细菌，并且能预防其他致病菌的生长和/或其对肠壁的粘附。因此，当婴儿得到了人乳的哺乳，这个婴儿的肠道菌群发展成含有丰富乳酸菌的有益菌群。肠道有益菌群的存在能够促进肠屏障的成熟和/或完整，促进粘液的形成和抑制病原体的生长，并且增强免疫系统。
国际专利申请WO2005039597揭示了一种可以增强免疫系统的方法，这种方法可以治疗和预防哺乳动物尤其是婴儿免疫系统相关的疾病，上述方法包括酸性低聚糖和中性低聚糖的给予。
在出生前婴儿的肠道通常是无菌的。在阴道分娩的过程中，婴儿的肠道接种了阴道的和/或母亲排泄物的细菌，导致婴儿的胃肠道被来源于其周围环境的细菌的侵袭。
公司生产了益生菌产品Life这种产品是专为婴儿设计的并且适合剖腹产分娩的婴儿。Life
Figure A20068004733200043
是用婴儿双歧杆菌制成的。因为这种Life
Figure A20068004733200044
产品仅仅包含唯一的一种双歧杆菌菌种，这样对于婴儿的益处就会非常有限。
发明内容
本发明发现剖腹产分娩的婴儿体内有一种肠道菌类，这类肠道菌类不同于阴道分娩的婴儿的肠道菌类。尤其是剖腹产分娩的婴儿双歧杆菌定殖的速度延迟，并且肠道双歧杆菌菌种多样化比阴道分娩的婴儿也要少，尤其是缺少短双歧杆菌，长双歧杆菌，婴儿双歧杆菌，分叉双歧杆菌(例1)。进一步发现剖腹产分娩的婴儿的肠道菌群中的双歧杆菌含量比阴道分娩的婴儿低。而且发现在分娩6周后，剖腹产分娩的婴儿的肠道菌群具有高含量的(不好的)埃希氏大肠杆菌。
克服了这些不足就可以提高健康和预防和/或治疗各种疾病。
健康和完全形成的胃肠道细菌丛有着重要的生理功效。一个重要的方面就是它能降低胃肠道感染的发生。因为剖腹产分娩的婴儿缺乏有益的菌群，对于这些婴儿来说，预防感染显得尤为重要。这些婴儿通常在医院的环境生产，由于医源性细菌的存在使剖腹产有病原感染的风险。而且有益肠道菌群的弱势发展导致了病原细菌的迅速定殖，就好像婴儿的肠道被母亲的细菌接种了一样的情形。
本发明特别的目的在于减少剖腹产分娩的婴儿的胃肠道感染的数量和严重度，通过(i)降低致病细菌对肠道上皮细胞和肠道粘液的粘附性；(ii)抑制致病细菌的生长；(iii)刺激有益细菌尤其是乳酸菌的生长；并且/或iv)调节免疫系统。
本发明的发明人发现糖醛酸低聚糖，尤其是源自果胶的低聚糖能够预防和治疗胃肠道感染。上述的糖醛酸低聚糖非常适合于肠道给予(尤其是口服)，它使得包括在授乳期的婴儿奶粉配方变的简单易行。上述的糖醛酸低聚糖减少了感染的发生，也降低了由于糖醛酸低聚糖的抗粘附作用引起感染的严重度(见例2)。
除了上述的糖醛酸低聚糖，剖腹产分娩的婴儿感染的发生和严重度甚至可以进一步通过提供一种或更多种益生菌低聚糖而减少。这些低聚糖能够促进有益胃肠道菌群的发展。低聚半乳糖和/或低聚果糖尤其适合作为促进长双歧杆菌，短双歧杆菌和/或婴儿双歧杆菌的生长(例3)。
除了减少感染的发生外，剖腹产分娩的婴儿的其他重要的疾病可以被本方法预防。像过敏和湿疹这种疾病可以通过促进有益肠道菌群的生长来预防。
另一个方面，本发明能够通过掺入上述的活性组分到一种营养组合物中而恰当的进行实践。这种组合物可以给予婴儿并且不会引起剖腹产分娩的婴儿过重的负担。
发明的详细描述
本发明提供了一种包含糖醛酸低聚糖的且用于制造对剖腹产分娩的婴儿进行肠道给予的一种组合物的应用。另一个方面，本发明提供了一种包含糖醛酸低聚糖且用于制造i)治疗和/或预防剖腹产分娩婴儿的疾病和/或ii)促进剖腹产分娩婴儿健康的一种组合物的应用。另一个方面，本发明提供了一种对于剖腹产分娩婴儿给予糖醛酸低聚糖的方法，尤其是对于预防和/或治疗剖腹产分娩婴儿的感染和/或过敏的一种较好的方法。
另一个方面，本发明提供了一种促进剖腹产分娩婴儿的肠道有益菌群的发展和/或减少其肠道病原体的发生的方法，这种方法包括以下步骤：
a)混合I)在营养上的或配药学上可接受的液体；并且II)一种干燥的组合物，其中这种干燥的组合物II包含糖醛酸低聚糖，尤其是选自低聚古罗糖醛酸，低聚艾杜糖醛酸，核糖酸低聚糖，低聚甘露糖醛酸，低聚半乳糖醛酸，低聚葡萄糖醛酸，并且
b)向这些婴儿给予从步骤a)中得到的组合物。
更进一步地方面，本发明提供了能够促进剖腹产分娩婴儿的肠道有益菌群的发展和/或减少其肠道病原体的一种方法，包括给予婴儿一种含有糖醛酸低聚糖、尤其是选自低聚古罗糖醛酸，低聚艾杜糖醛酸，核糖酸低聚糖，甘露糖醛酸，低聚半乳糖醛酸，低聚葡萄糖醛酸的组合物。
剖腹生产术
本发明涉及向剖腹产分娩的婴儿肠道给予一种包含糖醛酸低聚糖的组合物。剖腹产(c-section)是一种外科生产程序，其中婴儿是通过切开母亲的腹壁和子宫壁而分娩出来的。通常剖腹产是当相对于阴道分娩对母亲或婴儿更安全时被施行。作为一种选择，产妇可以选定剖腹产而不进行阴道分娩。
糖醛酸低聚糖
上述组合物包含糖醛酸低聚糖。本发明中使用的术语糖醛酸低聚糖涉及一种低聚糖，该低聚糖中至少25％的单糖单元是糖醛酸，至少50％单糖单元是糖醛酸则更好，尤其是一种选自低聚古罗糖醛酸，低聚艾杜糖醛酸，核糖酸低聚糖，甘露糖醛酸，低聚半乳糖醛酸，低聚葡萄糖醛酸的糖醛酸。首选的糖醛酸低聚糖应包含至少占糖醛酸低聚糖中全部糖醛酸单元50％的半乳糖醛酸。
本发明中使用的糖醛酸低聚糖较好的是来源于果胶，果胶酸盐，藻酸盐，软骨素，透明质酸，肝磷脂，乙酰型肝素，细菌糖类，和/或唾液酸多糖，更好是来源于果胶和/或藻酸盐，甚至更好的来源是果胶，最好是来源于多聚半乳糖醛酸。上述的糖醛酸低聚糖最好是果胶降解产物和/或藻酸盐降解产物。最好的果胶降解产物是一种果胶水解产物(经过水解制成)和/或是果胶溶解产物(经过β-降解)。果胶降解产物较好的是由水果胶质或者蔬菜胶质制备而成的，更好的是由苹果，柑橘类和/或甜菜中提取的苹果胶质，柑橘类胶质和/或甜菜胶质。这种果胶降解产物最好是经过果胶裂解酶，也就是经过β-降解和/或经过不同的温度和压力处理而制成的。这种果胶降解产物较好的是经裂解酶和/或不同温度、压力的裂解酶得到的，更好的是经果胶溶解产物制得，即经β-降解的果胶溶解产物。这种果胶降解产物较好的是胶质溶菌液。
上述的组合物较好的是包含具有2-250个聚合度(DP)的糖醛酸低聚糖，更好的是具有2-100个聚合度，甚至更好是有2-50个聚合度，最好地是具有2-20个聚合度。上述组合物较好的是包含占该组合物中糖醛酸的总重量的25-100wt.％，更好地是50-100wt.％的具有2-250个聚合度，更好的是2-100个聚合度，甚至更好是2-50个聚合度，最好地是2-20个聚合度糖醛酸低聚糖。
上述的糖醛酸低聚糖最好是通过果胶裂解酶，内切多聚半乳糖醛酸酶和/或果胶酶对果胶进行消化得到的。最好果胶裂解酶和/或半乳糖醛酸低聚糖是从细菌产物中制备的。
一个首选的例子是至少在糖醛酸低聚糖中有一个末端己糖醛酸单元有一个双键，这个双键最好位于末端的己糖醛酸单元C4和C5之间。这个双键能有效的抵抗致病细菌粘附到肠道上皮细胞。最好有一个末端的己糖醛酸单元含有一个双键。例如这个末端的己糖醛酸单元双键能够通过果胶裂解酶水解而得到。
进一步的例子为糖醛酸低聚糖混合物的应用，它们有着不同的聚合度和/或包含不饱和的及饱和的末端的己糖醛酸单元。较好的是至少5％的糖醛酸低聚糖中的末端的己糖醛酸单元是一个不饱和的己糖醛酸单元，更好是至少10％，甚至更好是25％。每一个单独的糖醛酸低聚糖最好含有唯一的一个不饱和的末端己糖醛酸单元，最好不超过50％的末端己糖醛酸单元是不饱和的己糖醛酸单元(也就是含有一个双键)。糖醛酸低聚糖混合物最好包含占末端己糖醛酸单元总量2％-50％的不饱和末端己糖醛酸单元，最好在10％-40％之间。
糖醛酸低聚糖可以被衍生化。糖醛酸低聚糖可以被甲氧基化和/或酰胺化。一个首选的例子是糖醛酸低聚糖甲氧基化度超过20％，更好是超过30％，甚至更好是超过70％。在这里，“甲氧基化度”(也可以为DE或“酯化度”)是要平均在糖醛酸低聚糖中的游离的羧酸基被酯化(例如被甲氧基化)的程度。在另外一个首选的例子中，糖醛酸低聚糖的甲基化度超过20％，较好的甲基化度是30％甚至超过70％。
上述组合物最好是每100g上述的组合物干重含有0.01-10g酯化度为2-250的糖醛酸低聚糖，更好是含有0.05-6g，甚至更好是含有0.2-2g。上述的组合物最好是每100g上述组合物干重含有0.01-10g酯化度为2-250(更好是酯化度为2-100)的半乳糖醛酸低聚糖，更好是在0.05-6g，甚至更好是0.2-2g。
糖醛酸低聚糖在人体上消化道内最好是不易被消化的并且是水溶性的(根据L.L.Prosky et al，J.Assoc.Anal.Chem 71：1017-1023，1988所揭露的方法)。糖醛酸低聚糖最好是可被肠道菌群发酵的。本发明中的糖醛酸低聚糖有效地减少了致病微生物对肠道上皮细胞的粘附，因此减少了剖腹产分娩婴儿结肠中医源性致病细菌的定殖。此外，本发明中的糖醛酸低聚糖是被发酵的，能很好地促进肠道有益菌群的形成和/或调整免疫系统，导致肠道有机酸产物和降低肠道pH值，这样能够抑制医源性致病细菌的生长。
不同于糖醛酸低聚糖的非消化低聚糖
除了糖醛酸低聚糖以外，上述组合物最好包含非消化低聚糖(下文被称为“非消化中性低聚糖”)，能够很好地促进肠道乳酸菌的生长，尤其是双歧杆菌和乳酸杆菌。
在本发明中所使用的术语“非消化低聚糖”是指低聚糖/碳水化合物，它们在肠道中不能被消化或者仅仅在人上消化道(小肠和胃)中的酸或消化酶的作用下在肠中被部分消化，而是被人肠道菌群进行发酵。上述的非消化低聚糖包含聚合度为2-250的低聚糖，较好是聚合度为2-100，甚至更好是聚合度为2-60，最好聚合度为2-10。例如蔗糖，乳糖，麦芽糖和糊精被认为是可消化的。不同于糖醛酸，非消化低聚糖是非消化中性低聚糖。在本发明中使用的术语“中性低聚糖”是指低聚糖，其中超过75％的糖类单位是选自葡萄糖，果糖，岩藻糖，半乳糖，甘露糖，核糖，树胶醛糖，鼠李糖和木糖的，较好是超过85％，最好是超过95％，甚至最好是超过99％。首选的非消化中性低聚糖是低聚半乳糖和低聚果糖。
上述非消化低聚糖是益生菌低聚糖。术语“益生菌低聚糖”是指不能被消化的低聚糖，其进入结肠后可有选择地促进结肠中的一种或少数几种有益细菌的生长和/或活动，从而对宿主产生有益的作用。
最好上述非消化低聚糖是可溶的。在这里使用的术语“可溶”意思是根据L.Prosky et al.，J.Assoc.Off.Anal.Chem.71，1017-1023(1988)描述的方法，当涉及多糖，纤维或低聚糖时是可溶的。
最好上述组合物包括至少一种低聚糖选自低聚半乳糖，非消化糊精，低聚木糖，低聚阿拉伯糖，低聚葡萄糖(包括龙胆低聚糖和环式糊精)，甲壳低聚糖，低聚岩藻糖，低聚甘露糖，低聚异麦芽糖，葡甘露低聚糖，半乳甘露低聚糖，阿拉伯半乳糖低聚糖，低聚果糖，更好低聚半乳糖和低聚果糖，尤其是低聚半乳糖。
这里提到的术语“低聚果糖”是指一种碳水化合物，它含有一个至少有3个β-连接的果糖单位的链，聚合度为2-250，较好是聚合度为7-100，更好是聚合度在20-60。尤其是菊糖的使用。菊糖的商标是“Raftilin
Figure A20068004733200111
”。上述低聚果糖的平均聚合度是较好至少为7，更好是至少为10，最好低于100。菊糖最好有一个β(2→1)键连接的果糖单元。在本发明中的低聚果糖包括例如菊糖，果糖多聚糖，多聚果糖，果聚糖或者果糖的混合物。上述的组合物最好包含聚合度为2-100的低聚果糖。
非消化多聚糊精是指能够抵抗消化的(麦芽)糊精或多聚糊精，它们具有10-50的聚合度，较好是10-20的聚合度。非消化的多聚糊精含有α(1→4)，α(1→6)糖苷键且具有1→2和1→3连接。非消化多聚糊精的商标是来自Matsutami产业的“Fibersol
Figure A20068004733200112
”或Danisco公司的
本发明的发明者发现低聚半乳糖能够有效地应用于本发明的组合物中，因为这些低聚糖能特别促进双歧杆菌的生长。因此，本发明的组合物中首选包含低聚半乳糖。在这里提到的术语“低聚半乳糖”是指非消化的低聚糖，其中至少30％的糖单元是半乳糖单元，较好至少50％，更好是至少60％。本发明的组合物最好包含聚合度为2-100的低聚半乳糖，更好的是包含聚合度是2-10。最好低聚半乳糖中的这些糖单元是以β连接的方式连接的，因为人乳中低聚糖-核心结构就是这样的。
本发明组合物中最好包含一种选自反式低聚半乳糖，乳糖-N-四糖(LNT)和乳糖-N-新四糖(neo-LNT)的低聚半乳糖。特别优选的例子是本发明的方法包含反式低聚半乳糖([半乳糖]n-葡萄糖；其中n是在1至60之间的整数，也就是2，3，4，5，6，....59，60；最好是2，3，4，5，6，7，8，9和/或10)的给予。例如反式低聚半乳糖(TOS)是以商标名VivinalTM(Borculo Domo Ingredients公司，荷兰)在销售。最好这些低聚半乳糖中的糖单元是以β连接的方式连接的。
本发明的组合物最好每100g干重包括0.5-75g非消化低聚糖，较好是0.5-50g。本发明的组合物中较好是每100g干重包含0.1-95g低聚半乳糖，最好是包含0.1-50g。
本发明的方法最好是包含0.05-25g非消化低聚糖/餐的给予，最好是在0.1-5g。本发明的方法最好包含0.05-25g低聚半乳糖/餐的给予，最好在0.1-5g低聚半乳糖。
本发明的发明者也发现一种长链非消化低聚糖和短链非消化低聚糖的混合物能够互相促进有益肠道菌群的生长，尤其是双歧杆菌并且能减少剖腹产分娩的婴儿体内的大肠杆菌的存在。
本发明的组合物因此最好包含至少两种具有不同平均聚合度的非消化的中性低聚糖。最好重量比为：
a.(聚合度为2-5的非消化中性低聚糖)：(聚合度为6，7，8和/或9的非消化中性低聚糖)＞1；并且/或
b.(聚合度为10-60的非消化的中性低聚糖)：(聚合度为6，7，8和/或9的非消化中性低聚糖)＞1；
较好的是两种重量比都大于2，甚至更好为大于5。
为了进一步的改进，上述非消化低聚糖最好有相当高含量的短链非消化低聚糖，因为这些低聚糖可以强烈的促进双歧杆菌的生长。因此，最好至少10wt.％的非消化低聚糖的聚合度为2-5(也就是2，3，4，和/或5)并且至少5wt.％聚合度为10-60。至少50wt.％的非消化低聚糖具有2-9的聚合度(也就是2，3，4，5，6，7，8，和/或9)是比较好的，至少75wt.％则更好。
为了促进生物多样性和促进肠道微生物的多样性的生长，本发明的组合物最好包含两种具有不同结构的非消化低聚糖。本发明的组合物最好包含至少两种不同的非消化低聚糖，其中非消化低聚糖90％以下具有一种同源的糖单元，较好是50％以下，甚至更好是25％以下，甚至最好是5％以下。在本发明中提到的术语“同源”是同样的糖单元在不同的非消化低聚糖中的百分比的累积。例如，低聚糖1(OL1)具有fruc-fruc-glu-gal的结构，因此其包含50％的fruc，25％gal和25％glu。低聚糖2(OL2)具有fruc-fruc-glu的结构，因此其包含66％fruc，33％glu。不同的非消化低聚糖因此具有75％同源性(50％fruc+25％glu)。
本发明的组合物包含低聚半乳糖和低聚果糖，较好的是包含具有聚合度为2-7的反式低聚半乳糖和聚合度为10-100的低聚果糖。
乳酸菌
本发明组合物最好包含乳酸菌，不管是死的乳酸菌还是活的乳酸菌。例如死的乳酸菌经过加热和/或超声波降解法对细菌进行灭活处理来制备。活的乳酸菌可以有利的组合在一起促进迅速的定殖于婴儿的肠道。乳酸菌可以更好的提供活的微生物单一或混合的培养物。每克本发明组合物干重应包含102-1013个乳酸菌的集落形成单元(cfu)，较好是102-1012，更好是105-1010，最好是104-5x109cfu.。
本发明组合物最好包含乳酸菌种或者双歧杆菌种的细菌。本发明组合物至少包含一种选自长双歧杆菌，短双歧杆菌，婴儿双歧杆菌，链状双歧杆菌，假小链双歧杆菌，青春双歧杆菌，动物双歧杆菌，高卢双歧杆菌，乳双歧杆菌和分叉双歧杆菌的双歧杆菌，较好是短双歧杆菌，婴儿双歧杆菌，分叉双歧杆菌，链状双歧杆菌，长双歧杆菌，最好是长双歧杆菌和短双歧杆菌，尤其是短双歧杆菌。最好上述组合物至少包含两种不同的双歧杆菌菌种，亚种或者菌株。最好上述组分至少包含一种，更好的是至少包含两种，甚至更好的是包含三种，甚至最好的是包含四种不同的双歧杆菌菌种。最好上述组分至少包含一种，更好的是至少包含两种，甚至更好的是包含三种，甚至最好的是包含四种不同的双歧杆菌菌株。最好上述组分至少包含长双歧杆菌和短双歧杆菌。通常的上面提到的组合的目的在于增加剖腹产分娩的婴儿肠道中的微生物的种类和/或数量。这有利的影响婴儿并提供大量的健康益处。
本发明的组合物最好包含一种乳酸菌，乳酸菌选自于干酪乳杆菌，罗伊氏乳酸杆菌，副干酪乳杆菌，鼠李糖乳杆菌，嗜酸乳杆菌，约氏乳杆菌，乳酸乳球菌，唾液乳酸杆菌，卷曲乳杆菌，格氏乳酸杆菌，玉米乳杆菌，发酵乳杆菌和植物乳杆菌；较好的是干酪乳杆菌，副干酪乳杆菌，鼠李糖乳杆菌，约氏乳杆菌，嗜酸乳杆菌，发酵乳杆菌；最好是副干酪乳杆菌。
甚至更好地，本发明的组合物包含短双歧杆菌和/或副干酪乳杆菌，因为相比母乳喂养的婴儿在配方喂养的婴儿的肠道中这些细菌的生长要受损。进一步增加的生物多样性对剖腹产分娩的婴儿的健康会带来促进的作用。
长链多聚不饱和脂肪酸
本发明的组合物最好包含长链多聚不饱和脂肪酸(LC-PUFA)。LC-PUFA是具有22-24个碳原子，最好是20-22个碳原子的，且有两个或更多双键的长链脂肪酸或酰基链。本发明的组合物最好包含二十碳五烯酸(EPA，n-3)，二十二碳六烯酸(DHA，n-3)和/或花生四烯酸(ARA，n-6)，因为这些LC-PUFA能够高效地减少肠道紧密连接的渗透性。降低了的紧密联结的渗透性减少了感染的发生并且/或者减少了过敏原的通道。因此在本发明的组合物中的EPA，DHA和/或ARA的结合能够增强肠屏障的完整性，这对于剖腹产分娩的婴儿来说是非常重要的，因为这些婴儿只有不太完善的肠道菌群，因此他们只有成熟较缓慢的肠屏障。这些LC-PUFA的结合会进一步的互相促进降低感染和过敏的发生和严重度。
由于低浓度的ARA，DHA和/或EPA已经能够有效地减低紧密联结的渗透性，在本发明的组合物当中的具有20-22个碳原子的LC-PUFA的含量较好不要超过总脂肪含量的15wt.％，更好是不要超过总脂肪含量的10wt.％，最好不要超过总脂肪含量的5wt.％。本发明组合物应包含至少占总脂肪含量0.1wt.％，较好是至少0.25wt.％，更好是至少0.6wt.％，甚至更好是至少0.75wt.％的具有20-22个碳原子的LC-PUFA。由于相同的原因，EPA的含量最好不要超过总脂肪含量的5wt.％，更好的是不要超过1wt.％，但是至少要占总脂肪含量的0.03wt.％，更好的是至少0.05wt.％。DHA的含量较好不要超过总脂肪含量的5wt.％，更好不要超过1wt.％，但是至少是总脂肪含量的0.1wt.％。既然ARA被发现对降低紧密联结的渗透性特别有效，本发明组合物包含相当高的含量，较好至少为总脂肪量的0.1wt.％，甚至更好是至少0.25wt.％，最好是至少0.35wt.％。ARA的含量较好不要超过5wt.％，更好是不要超过总脂肪量的1wt.％。当上述的肠道组合物成分包含ARA时，加入EPA和DHA有利于平衡ARA的作用，例如：减少ARA代谢产物潜在的促炎症反应的作用。过量的ARA的代谢产物能够引起炎症反应。因此，上述组合物最好包含ARA，EPA和DHA，上述组合物中ARA/DHA的重量比是0.25以上，较好是0.5以上，甚至更好是1以上。这个比率较好是低于25，更好是低于15。ARA/EPA的重量比率较好是在1-100之间，更好是5-20之间。
上述组合物较好是包含占总脂肪量5-75wt％的多聚不饱和脂肪酸，较好是10-50％。
LC-PUFA的含量，尤其是具有20-22个碳原子的LC-PUFA，较好是不要超过总脂肪含量的3％，这样才能尽可能地模拟接近人乳。LC-PUFA可以提供游离的脂肪酸，甘油三酸酯，甘油二酯，甘油一酸酯，磷脂，或者是以上其中一种或更多的混合物。上述组成较好应包含至少ARA和DHA在磷脂形式的任何一种。
核苷酸
本发明的组合物最好包含核苷酸和/或核苷，尤其是包含核苷酸。它应包含5′-胞苷酸、5′-尿苷酸、5′-腺苷酸、5′-鸟苷酸和/或5′-次黄苷酸，尤其是包含5′-胞苷酸、5′-尿苷酸、5′-腺苷酸、5′-鸟苷酸和5′-次黄苷酸。
本发明的组合物每100g组合物干重较好包含5-100mg，更好是包含5-50mg，最好是包含10-50mg的核苷酸和/或核苷。核苷酸和/或核苷能够有利地增强婴儿的肠的生长和成熟，对于剖腹产分娩的婴儿来说是至关重要的。核苷酸和/或核苷能进一步的促进免疫系统，因此能够增强对肠道内病原体诸如大肠杆菌的高负荷的抵抗。核苷酸和/或核苷被认为是起到能够增强本发明组合物其他成分的作用。
配方奶粉
本发明组合物较好地是肠道给予，最好是口服。
本发明组合物是很好的营养配方，尤其是婴儿的配方。本发明组合物能够被有效地作为婴儿的完全营养物。本发明组合物应包含一种脂质成分，蛋白成分和碳水化合物成分并且能够较好的以液体的形式给予。本发明包括干燥性食品(例如粉末)，并随附关于用适量的液体(例如：水)来混合上述的干燥性食品的说明。
本发明方便的提供了一种组合物，其中脂质成分提供总热量的5-50％，蛋白成分提供总热量的5-50％，碳水化合物成分提供总热量的15-90％。最好在上述组合物中脂质成分提供总热量的35-50％，蛋白质成分提供总热量的7.5-12.5％，碳水化合物成分提供总热量的40-55％。为了计算蛋白质成份所提供热量占总热量的百分比，由蛋白质、肽类和氨基酸提供的总能量需要被考虑在内。
本发明组合物最好包含选自动物油脂(不包括人体油脂)和蔬菜油脂的至少一种油脂。较好地，本发明组合物包含蔬菜油脂，及鱼油、动物油、藻类油、真菌油和细菌油中的至少一种。本发明的组合物包含除人乳以外的非消化低聚糖。
在上述的营养备料中的蛋白质成份较好是选自非人类的动物蛋白(最好是奶蛋白)，蔬菜蛋白(最好是大豆蛋白和/或大米蛋白)，它们的水解产物，游离的氨基酸和它们的混合物。牛奶中含有氮源，尤其是牛乳蛋白质诸如酪蛋白和乳清蛋白是首选的氮源。较好是蛋白质含有完整蛋白成分，更好是含有完整牛乳清蛋白和/或完整酪蛋白。因为本发明组合物非常适合被用于减少婴儿的过敏反应，其中的蛋白质最好是从含有水解牛乳蛋白中选择的。最好本发明的组合物含有水解酪蛋白和/或水解乳清蛋白，蔬菜蛋白和/或氨基酸。这些蛋白的使用可以进一步减少婴儿的过敏反应。这些水解蛋白的使用可以有利地促进食物中的蛋白质成份通过剖腹产分娩的婴儿的未成熟的肠道的吸收。
本发明组成物中的可消化的碳水化合物最好是选自蔗糖，乳糖，葡萄糖，果糖，淀粉糖浆干粉，淀粉和麦芽，还有他们的混合物，最好是乳糖。
不规则的大便(例如：过硬的大便，不足的大便体积，腹泻)是剖腹产分娩的婴儿中重要的问题。这些可能是由于粪便中大量的大肠杆菌的引起的。研究发现大便的问题可以通过在液体的食物中给予渗透压为50-500mOsm/kg，更好是在100-400mOsm/kg之间的上述的糖醛酸低聚糖来减少。减少了无规则的大便就会增强肠道有益菌群的定殖和发展。
根据上面的叙述，虽然仍需给主体提供充足的热量，但是液体的食物不能含有过量的热量密度也是很重要的。因此，液体食物较好应含有在0.1-2.5kcal/ml的热量密度，甚至更好是含有0.5-1.5kcal/ml，最好是含有0.6-0.8kcal/ml。
浓缩的非消化低聚糖
根据进一步首选的实例，本发明提供了对于向剖腹产分娩的婴儿提供营养的一种方法，其中一种含有糖醛酸低聚糖的组合物被混合到这种营养物中，然后这种营养物被给予剖腹产分娩的婴儿。
因此本发明提供了对于向剖腹产分娩的婴儿提供营养的一种方法，上述方法包括以下步骤：
a)混合含有糖醛酸低聚糖的组合物到一种营养物中，这种营养物将给予剖腹产分娩的婴儿；并且
b)给予剖腹产分娩的婴儿以从步骤a)中得到的混合物。
在本方法中步骤a)中提到的营养物较好应是婴儿配方乳粉或者是人乳，包含步骤a)中使用的非消化低聚糖的组合物是浓缩的非消化低聚糖组合物或者换句话说是含有高含量的非消化低聚糖的组合物。
在上述方法中步骤a)中提到的组合物，较好是应包含占组合物干重的至少5wt％，更好是至少10wt％，最好是至少25wt％的糖醛酸低聚糖。
本发明也同样提供了一种组合物，这种组合物可以被恰当的在本发明的方法中作为提供一种营养物来使用，也就是，一种组合物，它含有高浓度的非消化的中性低聚糖。这种组合物包含占其干重的至少5wt％(更好是至少10wt％)的非消化低聚糖，其中非消化低聚糖最好是选自低聚半乳糖，非消化的糊精，低聚木糖，低聚阿拉伯糖，低聚葡萄糖(包括龙胆低聚糖和环式糊精)，甲壳低聚糖，低聚岩藻糖，低聚甘露糖，低聚异麦芽糖和低聚果糖(包括菊糖)，和占组合物干重至少1wt.％(最好至少10wt.％)的上述糖醛酸低聚糖。这种合物最好含有低聚半乳糖和/或低聚果糖。
这种组合物最好是设计成添加到专门的婴儿营养餐中。在本发明中的糖醛酸低聚糖的累积重量，每餐最好在0.01-10g，更好是在0.2-5g。这种组合物较好是按每餐的量被包装起来，也就是说，按一餐的单位剂量包装起来，较好是以小袋的形式包装。每餐的这种组合物应有0.5-25g的干重，最好在1-10g。
应用
本发明提供了i)治疗和/或预防剖腹产分娩的婴儿疾病和/或ii)促进剖腹产分娩的婴儿的健康。尤其是那些由双歧杆菌菌群含量低而造成的疾病。尤其是感染和过敏这样的疾病。本发明被用于调整剖腹产分娩的婴儿的免疫系统。给予含有上述糖醛酸低聚糖的组合物能降低在剖腹产分娩婴儿还未发育完全的肠道中的病源微生物的粘附性和生长。
因此本发明提供了一种为预防和/或治疗感染和/或感染性疾病，尤其是肠与胃感染的方法，特别是治疗和/或预防那些由于一种或多种包括埃希氏菌属，克雷伯菌属，肠杆菌属，气单胞菌属，不动杆菌，变形杆菌属，假单胞菌(尤其是铜绿假单胞菌)，肠球菌，链球菌(尤其是b族链球菌)，葡萄球菌(尤其是表皮葡萄球菌，金黄色葡萄球菌，溶血葡萄球菌)，芽孢杆菌(尤其是枯草芽孢杆菌)，梭状芽孢杆菌(尤其是艰难梭菌)在内的，尤其是大肠杆菌的微生物而引起的感染。
本发明中的组合物特别是为了治疗或预防剖腹产分娩的婴儿的肠道感染，尿路感染，肠炎和/或腹泻的方法中的应用。尤其是用于调节免疫系统预防过敏。
本发明的组合物较好是给予出生一年内的剖腹产分娩的婴儿，较好是在出生后的三个月，甚至更好是在出生后的两个星期之内，甚至更加好是在出生的后100个小时，更加好是在出生后的72个小时，最好的是在出生后的48小时之内。
本发明也同样提供了一种能够促进婴儿肠道有益菌群发展的方法，包括步骤A：混合I)一种特别的营养学上或者配药学上可以接受的液体；和II)一种干燥的组合物，其中这种干燥的组合物II包含糖醛酸低聚糖；和步骤B)给予剖腹产分娩的婴儿以这种从步骤A)中得到的组合物。
给予本发明中的组合物能够导致改良的肠道菌群和/或由微生物发酵产生的代谢终产物有机酸的形成。有机酸量的增加能导致粘液产物的增加，促进肠道的成熟和/或增强肠屏障的功能。因此另一方面，本发明提供一种治疗和/或预防剖腹产分娩的婴儿过敏(尤其是食物过敏)，特应性湿疹(例如特应性皮炎)，哮喘，过敏性鼻炎，过敏性结膜炎的方法，上述的方法包括给予婴儿包含本发明所述的糖醛酸低聚糖的组合物。
并且，本发明组合物的给予能够增强免疫系统。另一方面，本发明能提供一种治疗和/或预防剖腹产分娩的婴儿的全身感染，耳炎和/或呼吸系统感染的方法。
具体实施例
实施例1：剖腹产分娩的婴儿和阴道分娩的婴儿的肠道微生态分子特征的对比
在本发明的研究中，通过利用特异性引物PCR扩增十种双歧杆菌种，三种瘤胃球菌和一种类杆菌种的方法来研究分娩方式(剖腹产相对于阴道分娩)对于出生后第三天肠道微生物成分的影响。
微生物的DNA提取和分析是根据论文：Favier et al，EnvironMicrobiol 2002；68：219-226 and Satokari et al，Appl Environ Microbiol 2001；67：504-513；Satorkari et al System Appl Microbiol 2003；26：572-584所提供的方法进行的。
表1中列出了在21个剖腹产分娩婴儿的排泄物样品中发现并在出生第3天获得的双歧杆菌和其他菌种。表2给出了在21个阴道分娩婴儿的排泄物样品中发现并在出生第3天获得的双歧杆菌和其他菌种。剖腹产分娩婴儿和阴道分娩婴儿的排泄物中都没有发现齿双歧杆菌，角双歧杆菌，乳酸双歧杆菌，布氏瘤胃球菌，伶俐瘤胃球菌和卵瘤胃球菌菌种的特殊信号。
可以得出结论认为，剖腹产分娩的婴儿与阴道分娩的婴儿所具有的微生物菌群不同。剖腹产分娩的婴儿体内不仅仅双歧杆菌和其他菌种的数量少很多，而且比剖阴道分娩的婴儿的菌群的菌种种类水平也变化较少。因为双歧杆菌在婴儿的体内菌群中是占主要的种类，这些结果也能被推广为剖腹产分娩的婴儿的体内的肠道菌群数量较少和种类较少，导致肠道更易被病原体侵害。
这些结果显示了本发明的组合物和方法是非常有使用价值的，例如：一种能够喂养剖腹产分娩婴儿，减少肠道内病原体，促进肠道内有益菌群并且相应地预防感染，促进健康的免疫系统和肠道成熟的方法。
表1：剖腹产分娩的婴儿
新生婴儿   短双歧杆菌   婴儿双歧杆菌   分叉双歧杆菌 链双歧杆菌群 青春双歧杆菌 长双歧杆菌 高卢双歧杆菌 脆弱类杆菌
  1   -   -   -   -   -   -   -   -
  2   -   -   -   -   -   ++   -   -
  3   -   -   -   -   -   -   -   -
  4   -   -   -   -   -   -   -   -
  5   -   -   -   -   -   -   -   -
  6   -   -   -   -   -   -   -   -
  7   -   -   -   -   -   -   -   -
  8   -   -   -   -   -   -   -   -
  9   -   -   -   -   -   -   -   -
  10   -   -   -   -   -   -   ++   -
  11   -   -   -   -   -   -   -   -
  12   -   -   -   -   -   -   -   -
  13   -   -   -   -   -   -   -   -
  16   -   -   -   -   -   -   -   -
  17   -   -   -   -   -   -   -   -
  18   -   -   -   -   -   -   -   -
  19   -   -   -   -   -   -   -   -
  20   -   -   -   -   -   -   -   -
  21   -   -   -   -   -   -   -   -
  22   -   -   -   -   -   -   -   -
  23   -   -   -   -   -   -   -   -
(-)＝无扩增信号；(+/-)＝弱扩增信号；(+)＝阳性扩增信号；(++)＝强烈的扩增信号
表2：阴道分娩的婴儿
新生婴儿   短双歧杆菌 婴儿双歧杆菌 分叉双歧杆菌 链双歧杆菌群 青春双歧杆菌 长双歧杆菌 高卢双歧杆菌   脆弱类杆菌
  1a   -   +   -   -   -   ++   -   -
  2a   +/-   -   ++   ++   -   ++   -   -
  3a   -   -   -   +   -   -   -   -
  4a   +/-   -   -   ++   +   +   -   -
  5a   +/-   -   ++   ++   -   ++   ++   -
  6a   -   -   +/-   ++   -   ++   -   -
  7a   -   -   +/-   ++   ++   -   -   -
  8a   ++   ++   -   +   ++   -   -   -
  9a   -   -   -   +   ++   +   -   -
  10a   ++   -   -   +   +   -   -   -
  11a   ++   -   ++   ++   -   ++   -   +
  12a   +   +   +   +   -   ++   -   +
  13a   +/-   -   -   +   -   +   -   -
  16a   -   -   -   ++   -   +   -   -
  17a   +/-   -   +   +   -   +   -   -
  18a   +/-   -   +   +   -   +   -   -
  19a   +   -   -   +   -   +   -   -
  20a   -   -   -   +   -   +   -   -
  21a   -   -   -   +   ++   +   -   -
  22a   -   +   -   ++   -   +   -   -
  23a   +   -   ++   ++   -   +   -   -
(-)＝无扩增信号；(+/-)＝弱扩增信号；(+)＝阳性扩增信号；(++)＝强烈的扩增信号
实施例2：糖醛酸低聚糖的抗粘附的作用
果胶低聚糖(在半乳糖醛酸分子中每100mol还原低聚糖中有39mol不饱和的半乳糖醛酸；甲基化度为41％)对大肠杆菌(EIEC 4608-58)的侵袭性的作用已经被做了检测。在一个用培养的人小肠上皮细胞(Caco-2)做的侵袭性检测中，由果胶来源的低聚糖被证实具有抗大肠杆菌侵袭感染的作用。这个结果显示了粘附性和侵袭性的降低：在有果胶低聚糖的存在下，在有果胶低聚糖的存在下，1小时接触后，大肠杆菌侵入小肠上皮细胞是49％(对照组是100％)，这最有可能是由于大肠杆菌对小肠上皮细胞的粘附性降低的原因(相比于对照组是46％)。结果也显示了在有果胶低聚糖的存在下，大肠杆菌相对于对照组在细胞外的生长减少了。
实施例3：非消化低聚糖对于剖腹产分娩婴儿的菌群的双歧基因影响。
在粪渣中双歧细菌的含量被测定。在第一周剖腹产分娩婴儿(数目n＝44)体内的所有双歧杆菌种类对于全部细菌的百分比是4.3％，相对于阴道分娩的婴儿(数目n＝28)是19.8％。剖腹产分娩的婴儿在第6周后，大肠杆菌的百分比是11.8％。
这个结果显示给予剖腹产分娩的婴儿以本发明所述的糖醛酸低聚糖是令人满意的。
实施例4：给予剖腹产分娩的婴儿的组合物
一种婴儿配方组合物每100ml现成的食物配方包含：1.6g蛋白质，3.6g脂肪，6.4g可消化的碳水化合物(主要是乳糖)，含有0.54g反式低聚半乳糖的0.8g非消化碳水化合物，0.06g菊糖，和0.2g果胶低聚糖(柑橘类果胶水解酶制备而成的)。
在这种配方组合物附随的包装和/或支撑物上可指明：这种配方组合物适合用于a)防止和/或治疗剖腹产婴儿感染；b)防止和/或治疗剖腹产婴儿大肠杆菌感染；c)防止和/或治疗剖腹产婴儿过敏和/或遗传性过敏皮炎；和/或d)调整免疫系统。
实施例5：喂养剖腹产分娩的婴儿的方法
小袋包装包括：
-0.2g糖醛酸低聚糖(约占干重的2wt.％)
-2g低聚半乳糖和0.3g低聚果糖(约占干重的20wt.％)
-短双歧杆菌和长双歧杆菌，每种菌株的滴度约5*109cfu；
-填充剂

Claims (14)

1.一种适用于生产肠道给予剖腹产分娩的婴儿的组合物的应用，其特征在于：它包含糖醛酸低聚糖。
2.根据权利要求1的组合物，其特征在于：这种组合物还包括选自低聚半乳糖和/或低聚果糖的非消化低聚糖。
3.根据任何一项上述的权利要求，其特征在于：这种组合物还包含长链的聚不饱和脂肪酸和/或核苷酸。
4.根据任何一项上述的权利要求，其特征在于：这种组合物还包含脂质成份，蛋白质成分和碳水化合物成分，其中上述的脂质成分占总热量的5-50％，上述的蛋白质成分占总热量的5-50％并且上述的碳水化合物成分占总热量的15-90％。
5.根据上述任何一项权利要求，其特征在于：适合于治疗和/或预防感染和/或剖腹产分娩的婴儿的感染疾病。
6.根据上述任何一项权利要求，其特征在于：适用于治疗和/或预防剖腹产分娩的婴儿的食物过敏，特应性湿疹即特应性皮炎，哮喘，过敏性鼻炎和/或过敏性结膜炎。
7.根据上述任何一项权利要求，其特征在于：糖醛酸低聚糖是选自具有聚合度DP为2-250的果胶降解产物和/或具有聚合度DP为2-250的海藻酸盐的降解产物。
8.根据上述任何一项权利要求，其特征在于：组合物包含0.01-10g聚合度为2-250的糖醛酸低聚糖/100g组合物干重。
9.根据上述任何一项权利要求，其特征在于：糖醛酸低聚糖包含占上述的全部末端已酸单元的2-50％的末端不饱和己酸单元。
10.根据上述任何一项权利要求，其特征在于：组合物是用于给予出生后一周内的婴儿，最好是在出生后100个小时之内。
11.促进剖腹产分娩婴儿的肠道有益菌群的发展和/或减少肠道病源体的方法，其特征在于：
混合I)营养上或者配药上可以接受的液体；和II)一种干燥的组合物，其中这种干燥的组合物II选自聚古洛糖醛酸低聚糖，艾杜糖醛酸低聚糖，核糖酸低聚糖，甘露糖醛酸低聚糖，半乳糖醛酸低聚糖，葡萄糖醛酸低聚糖，并且
b.给予婴儿以步骤a.中得到的组合物。
12.促进剖腹产分娩的婴儿的肠道有益菌群的发展的方法，其特征在于：包含给予这些婴儿一种含有选自古洛糖醛酸低聚糖，艾杜糖醛酸低聚糖，核糖酸低聚糖，甘露糖醛酸低聚糖，半乳糖醛酸低聚糖，葡萄糖醛酸低聚糖的糖醛酸低聚糖的组合物。
13.向剖腹产分娩的婴儿提供营养的方法，其特征在于：上述方法包括以下步骤：
a.将含有糖醛酸低聚糖的组合物与一种营养成分混合后给予剖腹产分娩的婴儿；并且
b.给予剖腹产分娩的婴儿以从步骤a.中得到的这种混合物。
14.一种包含占这种组合物干重的至少5wt.％(最好10wt.％)的糖醛酸低聚糖和至少5wt.％(最好10wt.％)的非消化糖醛酸低聚糖的组合物，其特征在于：非消化低聚糖选自低聚半乳糖和低聚果糖。
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