CN101951794B - 鞘髓磷脂和非消化性碳水化合物改善肠道微生物群的用途 - Google Patents
鞘髓磷脂和非消化性碳水化合物改善肠道微生物群的用途 Download PDFInfo
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- CN101951794B CN101951794B CN200880125301.XA CN200880125301A CN101951794B CN 101951794 B CN101951794 B CN 101951794B CN 200880125301 A CN200880125301 A CN 200880125301A CN 101951794 B CN101951794 B CN 101951794B
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Abstract
本发明提供一种用于提供和/或保持最佳肠道微生物群的包含鞘磷脂或其降解产物和至少一种非消化性碳水化合物的组合物。所述组合物特别适于作为婴儿营养品。
Description
技术领域
本发明的领域为恢复或维持良好平衡的肠道微生物群的营养组合物。所述组合物特别适于婴幼儿。
背景技术
出生时婴儿没有肠道微生物群。出生后,大肠快速生长,其中的微生物群也迅速形成和增加。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)的菌种和其他产乳酸的细菌组成。配方奶粉喂养的婴儿的微生物群更加多样,通常含有属于拟杆菌属(Bacteroides)、梭状芽孢杆菌属(Clostridium)和肠杆菌科(Enterobacteriaceae)的更多菌种。这种微生物群组成上的差异被认为会引起对于免疫***、胃肠屏障功能和抗病原菌功能的许多有益作用,使得胃肠感染在发病率和发病时间上的下降,过敏性疾病例如食物***反应、过敏性皮炎、***反应诱导的哮喘的减少以及母乳喂养的婴儿中便秘的减轻。
WO2006/091103公开了用于抵抗数种疾病的包含益生菌和两种非消化性糖类的组合物。WO00/08948公开了改善肠道微生物群的非消化性寡糖和多糖的混合物。
WO2006/041316公开了鞘髓磷脂(sphingomyelin)降解产物用于降低艰难梭状芽胞杆菌(Clostridium difficile)的量的用途。
WO2007/073194公开了包含磷脂、鞘脂和胆固醇、任选地包含非消化性碳水化合物的组合物用于防止肥胖症和/或糖尿病中的用途。
发明内容
本发明基于包含鞘磷脂和/或其降解产物——特别是神经酰胺、鞘氨醇碱(sphingoid base)、磷酸鞘氨醇(sphingoid phosphate)和/或溶血鞘磷脂(lysosphingophospholipid)——以及非消化性寡糖的组合物对所述肠道微生物群的组成和/或活性的预料不到的有益效果。这种结合物令人惊讶地显示了对所述肠道微生物群的组成的加强的有益效果。具体地,观察到厚壁菌(Firmicutes)/拟杆菌(Bacteroidetes)的比例下降,艰难梭状芽胞杆菌/总细菌的比例下降,和/或益生菌指数升高。
发明人认识到婴儿期形成的微生物群的组成影响婴儿期后的微生物群的组成。在婴儿期形成的微生物群的不同被认为导致了在至少7岁大的儿童中的肠道微生物群组成的不同。因此在婴儿期形成良好平衡的微生物群对婴儿期之后直至儿童期、***和/或成年期都具有健康的结果。
因此,在从出生至婴儿期和/或不足36个月的幼儿期给予包含鞘磷脂和/或其降解产物以及非消化性碳水化合物的组合物时,会在给予此组合物的时期之后的时期内(即不足36个月的时期,例如儿童期、***和/或成年期)有利地影响与肠道微生物群不平衡有关的疾病的预防。
因此,良好平衡的微生物群,特别是厚壁菌/拟杆菌或者梭状芽孢杆菌/拟杆菌比例低的微生物群,被认为影响脂肪细胞中的脂肪储存和/或对肥胖症具有预防和/或治疗作用。因此,本发明组合物特别适合治疗和/或预防肥胖症。由于脂肪细胞,特别是内脏脂肪细胞在婴儿期形成和增殖,因此本发明组合物特别适合给予年龄不足36个月的人类受试者,以预防当该人类受试者年龄超过36个月时发生肥胖。
此外,由于所述有益效果,鞘磷脂和/或其降解产物与非消化性碳水化合物的结合物对于用于治疗和/或预防与肠道微生物群的组成有关的疾病例如胃肠感染、腹泻、胃肠炎症和/或便秘特别有利。
由于良好平衡的肠道微生物群也改善免疫***和/或提高肠的成熟和/或胃肠屏障功能,因此本发明的结合物也可用于治疗和/或预防过敏性疾病例如***反应,更具体地为食物***反应、过敏性皮炎、***反应诱导的哮喘以及全身感染和呼吸道感染。
具体实施方式
本发明涉及一种使人类受试者的肠道微生物群向在健康的瘦受试者和/或母乳喂养的婴儿中存在的微生物群正常化的方法,所述方法包含给予所述人类受试者包含以下成分的组合物:
A:鞘磷脂,优选鞘髓磷脂,和/或至少一种选自神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和游离鞘氨醇碱的鞘磷脂降解产物,以及
B:至少一种非消化性碳水化合物,其选自低聚果糖(fructo-oligosaccharide)、半乳寡糖(galacto-oligosaccharide)、低聚葡萄糖(gluco-oligosaccharide)、低聚***糖(arabino-oligosaccharide)、低聚甘露糖(mannan-oligosaccharide)、低聚木糖(xylo-oligosaccharide)、低聚岩藻糖(fuco-oligosaccharide)、***半乳寡糖(arabinoglacto-oligosaccharide)、葡甘露寡糖(glucomanno-oligosaccharide)、半乳甘露寡糖(galactomanno-oligosaccharide)、含唾液酸的寡糖和糖醛酸寡糖。
换言之,本发明涉及包含以下成分的营养组合物用于制备使人类受试者的肠道微生物群向在健康的瘦受试者和/或母乳喂养的婴儿中存在的微生物群的组合物正常化的用途:
A:鞘磷脂,优选鞘髓磷脂,和/或至少一种选自神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和游离鞘氨醇碱的鞘磷脂降解产物,以及
B:至少一种非消化性碳水化合物,其选自低聚果糖、半乳寡糖、低聚葡萄糖、低聚***糖、低聚甘露糖、低聚木糖、低聚岩藻糖、***半乳寡糖、葡甘露寡糖、半乳甘露寡糖、包含唾液酸的寡糖和糖醛酸寡糖。
本发明也可被描述为用于使人类受试者的肠道微生物群向在健康的瘦受试者和/或母乳喂养的婴儿中存在的微生物群正常化的包含以下成分的营养组合物:
A:鞘磷脂,优选鞘髓磷脂,和/或至少一种选自神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和游离鞘氨醇碱的鞘磷脂降解产物,以及
B:至少一种非消化性碳水化合物,其选自低聚果糖、半乳寡糖、低聚葡萄糖、低聚***糖、低聚甘露糖、低聚木糖、低聚岩藻糖、***半乳寡糖、葡甘露寡糖、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
本发明组合物包含非消化性碳水化合物。非消化性碳水化合物改善所述微生物群。非消化性碳水化合物刺激双歧杆菌和拟杆菌的生长和/或活性。如实施例1中所示,已发现给予非消化性碳水化合物有利地降低厚壁菌/拟杆菌即梭状芽孢杆菌/拟杆菌的比例。
优选地,本发明的组合物包含DP为2-250、更优选为2-60的非消化性碳水化合物。所述非消化性碳水化合物为至少一种、优选地至少两种选自低聚果糖(包括菊粉)、半乳寡糖(包括反式半乳寡糖或β半乳寡糖)、低聚葡萄糖(包括龙胆寡糖(gentio-oligosaccharide)、黑曲霉寡糖(nigero-oligosaccharide)、环糊精寡糖(cyclodextrin-oligosaccharide)和聚右旋糖)、低聚***糖、低聚甘露糖、低聚木糖、低聚岩藻糖、***半乳寡糖(包括***树胶)、葡甘露寡糖、半乳甘露寡糖(包括部分水解的瓜尔胶)、包含唾液酸的寡糖和糖醛酸寡糖(包括半乳糖醛酸寡糖和果胶降解产物)的物质。优选地,本发明的组合物包含低聚果糖、半乳寡糖和/或半乳糖醛酸寡糖,更优选地包含半乳寡糖,最优选地包含β半乳寡糖。
优选地,所述组合物包含半乳寡糖。优选地,半乳寡糖选自β半乳寡糖、乳-N-四糖(LNT)、乳-N-新四糖(neo-LNT)、岩藻糖基乳糖、岩藻糖化LNT和岩藻糖化neo-LNT。在一个特别优选的实施方案中,本发明的组合物包含β半乳寡糖。本发明所用的β半乳寡糖是指由大于50%、优选大于65%的半乳糖单元(以单体亚基计)所构成的寡糖,其聚合度(DP)为2-20,其中至少50%、更优选地至少75%、甚至更优选地至少90%的半乳糖单元通过β糖苷键、优选β-1,4-糖苷键连接在一起。平均DP优选地为3-6。葡萄糖单元可位于半乳糖单元链的还原端。β半乳寡糖有时也被称作反式半乳寡糖(TOS)。β半乳寡糖的一个合适来源为GOS(可从Borculo Domo Ingredients,Zwolle,Netherlands购得)。其他合适来源为Oligomate(Yakult)、Cupoligo(Nissin)和Bi2muno(Classado)。
优选地,所述组合物包含低聚果糖。本发明所用的低聚果糖是指由大于50%、优选大于65%的果糖单元(以单体亚基计)所构成的碳水化合物,其中至少50%、更优选地至少75%、甚至更优选地至少90%的果糖单元通过β糖苷键优选、β-2,1-糖苷键连接在一起。葡萄糖单元可位于半乳糖单元链的还原端。优选地,所述低聚果糖的DP或平均DP为2-250,更优选地为2-100,甚至更优选地为10-60。低聚果糖包括左聚糖(levan)、水解左聚糖、菊粉、水解菊粉和合成低聚果糖。优选地,所述组合物包含平均聚合度(DP)为3-6的短链低聚果糖,更优选水解菊粉或合成低聚果糖。优选地,所述组合物包含平均DP大于20的长链果聚糖(fructan),例如RaftilinHP。优选地,所述组合物同时包含短链和长链果聚糖。适用于所述组合物的低聚果糖也容易购得,如HP(Orafti)。
本发明组合物优选地包含糖醛酸寡糖,更优选地包含半乳糖醛酸寡糖。本发明所用的术语半乳糖醛酸寡糖是指其中至少50%的单糖单元为半乳糖醛酸的寡糖。本发明中所用的半乳糖醛酸寡糖优选地通过果胶、果胶酸和/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、柑桔和/或甜菜果胶,甚至更优选由至少一种裂解酶降解的苹果、柑桔和/或甜菜果胶的水解和/或β消除而制备。在一个优选实施方案中,所述半乳糖醛酸寡糖的至少一个末端半乳糖醛酸单元具有双键。该双键有效地保护肠上皮细胞免于被病原细菌所附着。优选地,末端半乳糖醛酸单元之一包含C4-C5双键。所述半乳糖醛酸寡糖可被衍化。所述半乳糖醛酸寡糖可被甲氧基化和/或酰胺化。在一个实施方案中,所述半乳糖醛酸寡糖的特征在于甲氧基化的程度大于20%,优选地大于50%,更优选地大于70%。
在一个优选实施方案中,所述组合物包含菊粉和低聚果糖的混合物。在一个优选实施方案中,所述组合物包含半乳寡糖和低聚果糖的混合物,所述低聚果糖选自短链低聚果糖和菊粉,更优选菊粉。至少两种不同的非消化性碳水化合物的混合物比单一非消化性碳水化合物更大程度地对肠道微生物群的有益细菌进行有利刺激。优选地,两种不同的非消化性碳水化合物——优选半乳寡糖和低聚果糖——的混合物之间的重量比在20和0.05之间,更优选地在20和1之间。半乳寡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的半乳寡糖和/或DP为2-60的低聚果糖。已发现这些结合物协同地增加双歧杆菌和乳酸杆菌。优选地,所述组合物包含β半乳寡糖、低聚果糖和果胶降解产物。与半乳寡糖和果聚糖相比,这三种非消化性寡糖的存在更进一步地刺激双歧杆菌,同时减少了拟杆菌和梭状芽胞杆菌。反式半乳寡糖:低聚果糖:果胶降解产物的重量比优选地为(20-2):1:(1-20),更优选地为(12-7):1:(1-3)。
优选地,每100ml所述组合物包含80mg到2g、更优选150mg到1.50g、甚至更优选300mg到1g的非消化性寡糖。基于干重计,所述组合物优选地包含0.25-5.5重量%、更优选地包含0.5-4重量%、甚至更优选地包含1.5-3重量%的非消化性寡糖。更少量的非消化性寡糖对微生物群中的有益细菌的刺激不太有效,而过高量会造成腹胀和腹部不适的副作用。
鞘磷脂及其降解产物
本发明组合物包含鞘磷脂和/或其一种降解产物。本发明中的术语鞘磷脂涉及一类鞘酯,其由通过酰胺键与一个脂肪酸键合、并通过氧与一个包含磷酸酯(磷酸酯、磷酸胆碱、磷酸丝氨酸、磷酸乙醇胺、磷酸甘油或磷酸肌醇)的极性首基键合的鞘氨醇碱组成。在本发明的另一实施方案中,所述组合物中包含鞘磷脂的降解产物,尤其是神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和/或游离鞘氨醇碱。本发明中的鞘氨醇碱优选地为链长为14个原子或更长、具有(2S,3R)-赤式立体化学的2-氨基-1,3-二羟基烷烃或烯烃。鞘氨醇碱可包含三个而不是两个羟基。其脂肪链可为单不饱和的、多不饱和的(顺式或反式构象)或饱和的。所述脂肪链可带有支链。鞘氨醇碱包括神经鞘氨醇(sphingosine)、二氢神经鞘氨醇(sphinganine)、植物鞘氨醇(phytosphingosine)和二氢植物鞘氨醇(dihydrophytosphingosine)。优选地,所述组合物包含鞘髓磷脂。鞘髓磷脂是神经酰胺-磷酸胆碱。神经酰胺由通过酰胺键与脂肪酸连接的鞘氨醇碱构成。
口服鞘磷脂和/或其降解产物尤其是溶血鞘磷脂、神经酰胺、磷酸鞘氨醇和/或鞘氨醇碱,可减少肠道微生物群中的有害细菌例如厚壁菌特别是梭状芽胞杆菌。本发明组合物同时具有有益细菌的刺激物和有害细菌的抑制剂,因此能更有效地改善微生物群的组成和/或保持微生物群的良好平衡。
优选地,每100ml所述组合物包含10-200mg、更优选20-150mg、甚至更优选60-100mg的鞘髓磷脂。基于脂肪计,所述组合物优选地包含0.25-5.5重量%、更优选地包含0.5-4重量%,甚至更优选地包含1.5-3重量%的鞘髓磷脂。基于干重,所述组合物优选地包含0.07-1.5重量%、更优选地包含0.15-1.1重量%、甚至更优选地包含0.5-0.8重量%的鞘髓磷脂。更低的量不太有效,而更高的量会减少有益的必需物质和长链脂肪酸的含量。鞘磷脂的适合来源为乳脂,更合适的来源为酪乳脂或奶油乳清脂、蛋黄和/或大豆卵磷脂。
优选地,非消化性寡糖和鞘髓磷脂之间的重量比在0.4和200之间,更优选在1和75之间,甚至更优选在3和15之间。所述组合物中的这一比例会确保对微生物群中有益细菌的刺激作用和对微生物群中有害细菌的减少作用之间的平衡。
其他脂类
本文中LA是指亚油酸(18:2n6);ALA是指α-亚麻酸(18:3n3);LC-PUFA是指脂肪酰基链中含有至少20个碳原子并具有2个或更多不饱和键的酰基链和/或长链多不饱和脂肪酸;DHA是指二十二碳六烯酸(22:6,n3);EPA是指二十碳五烯酸(20:5n3);ARA是指花生四烯酸(20:4n6);DPA是指二十二碳五烯酸(22:5n3)。
LA优选地以足以促进健康生长和发育的量存在,然而又要以尽可能低的量存在以预防以后肥胖症的发生。因此,所述组合物优选地包含小于总脂肪酸的15重量%的LA,优选地包含5-14.5重量%的LA,更优选地包含6-12重量%的LA。优选地,ALA以足以促进健康生长和发育的量存在。因此本发明组合物优选地包含占总脂肪酸至少1.0重量%的ALA。所述组合物优选地包含占总脂肪酸至少1.6重量%的ALA,更优选地包含占总脂肪酸至少2.0重量%的ALA。所述组合物优选地包含少于总脂肪酸10重量%的ALA,更优选地包含少于总脂肪酸5.0重量%的ALA。LA/ALA的重量比应达到良好平衡以预防肥胖症尤其是向心性肥胖(central obesity),同时确保正常的生长和发育。因此,本发明组合物的LA/ALA的重量比优选地为2-15,更优选地为2-7,更优选地为3-6,甚至更优选地为4-5.5,甚至更优选地为4-5。
优选地,本发明组合物包含LC-PUFA,因为LC-PUFA抑制以后的肥胖,更优选地抑制向心性肥胖。更优选地,本发明组合物包含n-3LC-PUFA,甚至更优选地包含EPA、DPA和/或DHA,甚至更优选地包含DHA。已发现这些n-3LC-PUFA减轻肥胖。由于低浓度DHA、DPA和/或EPA已经有效,并且由于正常生长和发育的重要性,本发明组合物中n-3LC-PUFA的含量优选地不超过总脂肪酸含量的15重量%,更优选地不超过10重量%,甚至更优选地不超过5重量%。本发明组合物优选地包含占总脂肪酸含量至少0.2重量%、更优选地至少0.5重量%、更优选地至少0.75重量%的n-3LC-PUFA。优选地,本发明组合物中n-6LC-PUFA/n-3LC-PUFA的重量比很低以预防以后的肥胖。本发明组合物中n-6LC-PUFA/n-3LC-PUFA的重量比优选地低于1.5,更优选地低于1.0,甚至更优选地低于0.6。LC-PUFA的另一优点是它们促进有益细菌的附着,从而进一步改善微生物群和/或保持良好平衡的微生物群。
优选地,本发明组合物包含胆固醇和胆固醇酯。所述组合物中鞘磷脂和胆固醇和/或胆固醇酯的同时存在延缓鞘磷脂在小肠中的消化,从而增加到达大肠的鞘磷脂的量,并因此增加鞘磷脂和/或其降解产物抵抗肠道微生物群中有害细菌的活性。本发明组合物优选地包含占总脂肪至少0.005重量%、更优选地至少0.01重量%、更优选地至少0.05重量%、甚至更优选地至少0.1重量%的胆固醇和/或胆固醇酯。胆固醇和/或胆固醇酯的量优选地不超过总脂类的10重量%,更优选地不超过5重量%,甚至更优选地不超过总脂类的1重量%。最优选地,胆固醇的量为总脂类的0.5-0.7重量%。
营养组合物
本发明组合物优选口服。鞘磷脂被消化酶降解对于提高其抵抗肠道微生物群中有害细菌的作用是必须的。本发明组合物优选为营养配方组合物,更优选为婴儿配方组合物。包含非消化性碳水化合物和鞘磷脂和/或其降解产物的本发明组合物不是人乳。
本发明组合物可有益地用作一种婴儿完全营养品。本发明组合物优选地包含脂类、蛋白质和可消化碳水化合物,优选地以液体形式给予。本发明包括干食品(如粉末),其附有将所述干食品混合物与合适的液体(例如水)混合的指导说明。
本发明有利地提供一种其中脂类提供5-50%总卡路里的组合物。本发明有利地提供一种其中蛋白质提供5-50%总卡路里的组合物。本发明有利地提供一种其中可消化碳水化合物提供15-90%总卡路里的组合物。本发明有利地提供一种其中脂类提供5-50%总卡路里,蛋白质提供5-50%总卡路里,可消化碳水化合物提供15-90%总卡路里的组合物。优选地,本发明组合物中脂类提供35-50%总卡路里,蛋白质提供7.5-12.5%总卡路里,可消化碳水化合物提供40-55%总卡路里。为计算蛋白质提供的总卡路里的百分比,需要考虑由蛋白质、肽和氨基酸提供的总能量。总卡路里涉及由脂类、可消化碳水化合物和蛋白质提供的卡路里之和。
营养物制剂中所用的蛋白优选地选自非人动物蛋白(优选乳蛋白)、植物蛋白(优选大豆蛋白和/或稻蛋白)、游离氨基酸以及它们的混合物。本发明组合物优选地含有酪蛋白、乳清、水解的酪蛋白和/或水解的乳清蛋白。所述蛋白优选地包含完整的蛋白,更优选地包含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轻婴儿的***反应,因此所述蛋白优选地选自水解的乳蛋白。
本发明组合物优选地含有选自蔗糖、乳糖、葡萄糖、果糖、玉米糖浆固体、淀粉和麦芽糊精的可消化碳水化合物,更优选地含有乳糖。
本发明组合物优选地包含核苷酸和/或核苷,更优选地包含核苷酸。所述组合物优选地包含5'-胞苷酸、5'-尿苷酸、5'-腺苷酸、5'-鸟苷酸和/或5'-肌苷酸,更优选地包含5'-胞苷酸、5'-尿苷酸、5'-腺苷酸、5'-鸟苷酸和5'-肌苷酸。所述组合物每100g干重优选地包含5-100mg、更优选地5-50mg、更优选地10-50mg核苷酸和/或核苷。核苷酸和/或核苷的存在有利地降低拟杆菌、卟啉单胞菌(porphyromonas)和/或普氏菌(Prevotella)群与双歧杆菌的比例。
所述核苷酸和/或核苷被认为与本发明组合物的其他成分协同作用。
大便不正常例如大便硬、大便量不足、腹泻是婴儿的一个严重问题。已发现大便问题可通过以摩尔渗透压浓度为50-500mOsm/kg、更优选100-400mOsm/kg的液体形式给予本发明组合物而减轻。大便不正常的减轻增强了健康肠道微生物群的建群和发展。
由于上述原因,液体食品不具有过高的卡路里密度,但又能提供足够的卡路里来供给受试者也是重要的。因此,所述液体食品的卡路里密度优选为0.1-2.5kcal/ml,更优选为0.5-1.5kcal/ml,最优选为0.6-0.8kcal/ml。
应用
包含鞘磷脂和/或其降解产物(优选鞘髓磷脂)以及非消化性碳水化合物的本发明组合物特别适合用于年龄不足36个月的人类受试者以使肠道微生物群的组成正常化。本发明组合物特别合适用于年龄不足36个月的人类受试者以使所述人类受试者年龄超过36个月时的肠道微生物群的组成正常化。
使年龄不足36个月的本发明人类受试者的肠道微生物群正常化涉及使其肠道微生物群的组成向年龄不足36个月的健康的母乳喂养人类受试者中存在的肠道微生物群正常化的组成。在年龄不足36个月的人类受试者中使用,用于使所述人类受试者年龄超过36个月时的肠道微生物群的组成正常化,涉及使其肠道微生物群的组成向同龄健康受试者的肠道微生物群正常化的组成,所述同龄健康受试者在其年龄不足36个月的往昔曾经母乳喂养。
包含鞘磷脂和/或其降解产物(优选鞘髓磷脂)以及非消化性碳水化合物的本发明组合物特别适合用于年龄超过36个月的人类受试者,用于使肠道微生物群的组成正常化。使年龄超过36个月的人类受试者的肠道微生物群正常化涉及使其肠道微生物群的组成向正常体重的健康人类受试者的肠道微生物群正常化的组成。包含鞘磷脂和/或其降解产物(优选鞘髓磷脂)以及非消化性碳水化合物的本发明组合物特别适合用于肥胖的人类受试者,用于使肠道微生物群的组成正常化。使肥胖的人类受试者的肠道微生物群正常化涉及使其肠道微生物群的组成向正常体重的健康人类受试者的肠道微生物群正常化的组成。
包含鞘磷脂和/或其降解产物(优选鞘髓磷脂)以及非消化性碳水化合物的本发明组合物特别适合用于正在使用或最近使用过抗生素的人类受试者,用于使肠道微生物群的组成正常化。在本发明的上下文中术语“最近”是指停用抗生素不到2个月,例如不到1个月或不到1周。使正在使用或最近使用过抗生素的人类受试者的肠道微生物群正常化涉及使其肠道微生物群的组成向所述人类受试者使用抗生素之前的时期的肠道微生物群正常化的组成或者向其原本的肠道微生物群正常化的组成。
本发明中的使肠道微生物群正常化具体涉及益生菌指数上升、梭状芽胞杆菌/总细菌的比例下降、艰难梭状芽胞杆菌/总细菌的比例下降、艰难梭状芽胞杆菌/总梭状芽胞杆菌的比例下降、乳酸杆菌/总细菌的比例上升、双歧杆菌/总细菌的比例上升、厚壁菌/拟杆菌的比例下降、梭状芽胞杆菌/拟杆菌的比例下降、肠杆菌/总细菌的比例下降。上升或下降是就所述人类受试者服用本发明组合物之前的比例而言,或者就不服用此组合物的对照组而言。所述益生菌指数(PI)涉及(双歧杆菌/总细菌)+(乳酸杆菌/总细菌)-(拟杆菌/总细菌)-(梭状芽胞杆菌/总细菌)的总数,参见Palframan et al,2003,Lett Appl Microbiol37:281-284。优选地,所述指数还可加上直肠真杆菌(Eubacterium rectale)/总细菌的比例,尤其是对于成人。直肠真杆菌产生对成人肠道屏障有利的丁酸盐。
肠道微生物群具体涉及结肠中的微生物群的组成。肠道微生物群的组成可使用本领域所知的特异性探针和/或引物,通过本领域所知的方法包括FISH、实时PCR和微阵列,在门、纲、科、属和/或种的水平上确定。
本发明组合物对于在医院出生的婴儿特别有利,因为他们有被来自医院环境的有害细菌建群的危险。本发明组合物对于通过剖腹产出生的婴儿更加有利,因为这些婴儿缺少来自母亲的有益细菌的适当接种,同时他们有被来自医院环境的有害细菌建群的危险。
由于将本发明组合物给予年龄不足36个月的人类受试者对微生物群具有如上所述的有益效果,因此本发明组合物优选地用于预防和/或治疗肥胖症和/或脂肪过多(adiposity),更优选地用于预防和/或治疗内脏肥胖,更优选地在所述人类受试者年龄超过36个月时用于预防和/或治疗肥胖和/或脂肪过多,更优选地用于预防和/或治疗内脏肥胖。此外,本发明组合物优选地用于预防在所述人类受试者年龄超过36个月时由内脏肥胖引起的继发性疾病,例如2型糖尿病、空腹高血糖、胰岛素抵抗、内脏肥胖、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。在一个实施方案中,肥胖、脂肪过多和内脏肥胖是指肠道微生物群不平衡引起的所述状况。优选地,微生物群不平衡是指与健康瘦受试者和/或与母乳喂养的婴儿相比,厚壁菌/拟杆菌的比例上升、艰难梭状芽胞杆菌/总细菌的比例上升和/或益生菌指数下降。
由于将本发明组合物给予年龄不足36个月的人类受试者对微生物群具有如上所述的有益效果,因此本发明组合物优选地用于治疗和/或预防胃肠感染、腹泻和/或胃肠炎症,更优选地在所述人类受试者年龄超过36个月时用于治疗和/或预防胃肠感染、腹泻和/或胃肠炎症。
由于将本发明组合物给予年龄不足36个月的人类受试者对微生物群具有如上所述的有益效果,因此本发明组合物优选地用于改善免疫***和/或胃肠屏障功能,更优选地在所述人类受试者年龄超过36个月时用于改善的免疫***和/或胃肠屏障功能。
由于将本发明组合物给予年龄不足36个月的人类受试者对微生物群具有如上所述的有益效果,因此本发明组合物优选地用于治疗和/或预防至少一种选自***反应、哮喘、过敏性皮炎、湿疹、全身性感染、***、耳炎和呼吸道感染的疾病,更优选地在所述人类受试者年龄超过36个月时用于治疗和/或预防至少一种选自***反应、哮喘、过敏性皮炎、湿疹、全身性感染、***、耳炎和呼吸道感染的疾病。
本发明旨在使人类受试者的肠道微生物群正常化,优选地其年龄超过36个月,优选地其年龄超过8岁、更优选地其年龄超过15岁,最优选地其年龄超过18岁。
在本文件及其权利要求中,动词“包含”及其各种变形用于以其非限制性的意义表示包括该词之后的项,但并不排除未具体提到的项。此外,由“一个”或“一种”提及的要素并不排除存在多个该要素的可能性,除非上下文明确规定有且只有一个/一种该要素。因此“一个”或“一种”通常是指“至少一个/一种”。
实施例
实施例1
使用刚从4-5名健康成人收集的粪便进行如WO2004/000340的附录I所述的发酵研究。该试验进行两次。将所述粪便加入McBain和Farlane培养基中按1:5稀释,然后在无氧条件下放入渗析管中并用缓冲液悬浮于瓶中,首先在37℃下孵育16小时以适应,然后在t=0时将其用下表的物质接种。
该试验物质每天添加一次(在t=0、24和48h时)。缓冲液每天更新一次。在t=0和t=72h时采集样品。使用较长的时间段是因为细菌数量的变化与形成的短链酸的变化相比较慢。
表1:向含稀释粪便的渗析管中的添加物
使用Vivinal GOS(Borculo Domo,The Netherlands)作为GOS的来源。使用RaftilineHP(Orafti,Belgium)作为菊粉的来源。
用D-鞘氨醇代替鞘磷脂(例如鞘髓磷脂)加入到渗析管中,因为鞘磷脂在小肠中降解生成D-鞘氨醇。使用牛脑(Fluka Sigma Aldrich Chemie)中的D-鞘氨醇作为D-鞘氨醇的来源。
将鞘氨醇溶解在乙醇中(10mg/ml的储液)。将30μl的10mg/ml的储液加入到渗析管中。
将样品通过如Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345中所述的荧光原位杂交(FISH)进行分析。使用Bac303探针测定拟杆菌-普氏菌群(Manz,W.,et al.,Microbiology,1996.142(Pt5):p.1097-106)。使用Chis150和Clit135探针测定梭状芽胞杆菌(Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345)。使用Erec482探针测定直肠真杆菌和球形梭菌(Clostridium coccoides)群(Franks,A.H.,et al.,Appl.Environ.Microbiol.,1998.64(9):p.3336-3345)。使用Bif164探针测定双歧杆菌(Langendijk,P.,et al.,Appl.Environ.Microbiol.,1995.61(8):p.3069-3075)。使用Lab158探针测定乳酸杆菌和肠球菌(Enterococci)(Harmsen,H.J.M.,et al.,Microbial Ecologyin Health and Disease,1999.Volume11:p.3-12)。使用Ec1531探针测定肠杆菌(Poulsen,L.K.,et al.,Infect Immun,1994.62(11):p.5191-4)。通过DAPI染色测定细菌总数。厚壁菌/拟杆菌的比例设定为由Chis150、Clit135、Erec482和Lab158探针检测到的细菌百分数除以由Bac303探针检测到的细菌百分数。由Erec482检测的细菌群通常为人的肠道中最大的厚壁菌群。
结果:
Bac303、Chis150、Clit135、Ec1351和Lab158探针全都显示信号低于FISH检测限,即每克样品种少于106个细胞或相对丰度小于1/1000个细胞(0.1%)。对于Bac303,样品储存在贫瘠条件下,但在加入GOS和菊粉的样品中观察到了微弱信号。Bif164和Erec482探针的FISH结果示于表2。
表2:Bifl64和Erec482探针的FISH结果。
这些结果表明当非消化性碳水化合物——更具体地为GOS和/或菊粉——发酵时或者当鞘氨醇(作为鞘磷脂在小肠中消化后的降解产物)存在时双歧杆菌增加,并且在两种组分都存在时协同地进一步增加。
这些结果表明当非消化性碳水化合物——更具体地为GOS和/或菊粉——发酵时或者当鞘氨醇存在时,梭状芽胞杆菌和真细菌——作为肠厚壁菌的最大群——减少。当两种组分都存在时,观察到进一步改善的作用。
这些结果表明当消耗非消化性碳水化合物——更具体地为GOS和/或菊粉——以及鞘氨醇时有如下改善:大肠微生物群中的益生菌指数升高、梭状芽胞杆菌/总细菌比例下降、双歧杆菌/总细菌比例下降、厚壁菌/拟杆菌比例下降、梭状芽胞杆菌/拟杆菌比例下降。
实施例2:
每天给予年龄在9-10个月的婴儿500ml包含1.2gβ-半乳寡糖加长链菊粉的配方奶,持续1个月(A组)。给予对照组没有β-半乳寡糖和长链菊粉的配方奶(B组)。总共138名儿童参加了此研究。在此时期之前和之后通过FISH分析检测粪便菌丛。
在介入时间之后,A组中双歧杆菌/总细菌的比例显著高于B组。此外,A组中梭状芽胞杆菌/总细菌的比例低于B组。开始时A组中厚壁菌/拟杆菌的比例为42,B组为39,而在介入一个月后,B组下降到32而A组下降到16。
实施例3:婴儿营养品
婴儿营养品包含提供48%总卡路里的脂类,提供8%总卡路里的蛋白质和提供44%总卡路里的可消化碳水化合物;
(i)所述脂类包含占总脂类约1.4重量%的鞘髓磷脂和约4重量%的胆固醇;
(ii)所述可消化碳水化合物包含50.9g乳糖/100g粉末,并且每100g粉末还包含5.22g DP为2-6的β-半乳寡糖和0.58g DP为7-60的低聚果糖作为非消化性碳水化合物;
(iii)包含牛乳蛋白的蛋白质,包括酪蛋白。
所述组合物包含符合欧盟标准的维生素、微量元素和矿物质。此婴儿营养品的包装标签说明此营养品旨在改善肠道菌丛,增加肠道双歧杆菌的数量,降低肠道病原菌的数量和/或保持肠道菌丛的良好平衡。
Claims (8)
1.一种营养组合物的用途,用于制备一种使人类受试者的肠道微生物群向在健康的瘦受试者和/或母乳喂养的婴儿中存在的微生物群正常化的婴儿配方组合物,所述营养组合物含有:
A:鞘磷脂和/或至少一种选自神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和游离鞘氨醇碱的鞘磷脂降解产物,以及
B:至少低聚果糖和半乳寡糖,其中所述低聚果糖选自短链低聚果糖和菊粉,
其中使所述肠道微生物群的组成在厚壁菌/拟杆菌比例下降方面正常化。
2.权利要求1的用途,其中所述鞘磷脂为鞘髓磷脂。
3.权利要求1或2的用途,其中所述婴儿配方组合物包含占脂类至少0.25重量%的鞘磷脂和/或至少一种选自神经酰胺、溶血鞘磷脂、磷酸鞘氨醇和游离鞘氨醇碱的鞘磷脂降解产物。
4.权利要求3的用途,其中所述鞘磷脂为鞘髓磷脂。
5.权利要求1或2的用途,其中所述婴儿配方组合物还含有糖醛酸寡糖。
6.权利要求1或2的用途,其中所述婴儿配方组合物包含占所述组合物干重至少0.25重量%的包含低聚果糖和半乳寡糖的非消化性碳水化合物。
7.权利要求1或2的用途,其中所述婴儿配方组合物包含提供35-50%总卡路里的脂类、提供40-55%总卡路里的可消化碳水化合物和提供7.5-12.5%总卡路里的蛋白质。
8.权利要求1或2的用途,其中所述婴儿配方组合物包含的鞘磷脂和/或其降解产物与包含低聚果糖和半乳寡糖的非消化性碳水化合物的重量比为0.4-200。
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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 |
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 |
CN101945589A (zh) | 2011-01-12 |
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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