CN102762216A - 包含益生菌的用于1-10岁儿童的全营养液 - Google Patents
包含益生菌的用于1-10岁儿童的全营养液 Download PDFInfo
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Abstract
本发明涉及儿童营养领域。具体地,本发明涉及预期用于胃肠道功能受损的儿童的营养组合物。本发明的一个实施方案涉及包含益生微生物的、待施用于胃肠道功能受损的儿童的营养组合物。该益生微生物可以是非复制的,例如生物学活性的热处理的益生微生物。
Description
发明领域
本发明涉及儿童营养领域。具体地,本发明涉及旨在用于胃肠道功能受损的儿童的营养组合物。本发明的一个实施方案涉及施用于胃肠道功能受损的儿童的营养组合物,所述营养组合物包含益生微生物。该益生微生物可以是非复制的,例如生物学活性的、热处理的益生微生物。
背景技术
儿童有特殊的营养需要。这些需要随着儿童的年龄和发育状态而极大不同。儿童期通常理解为在出生和青春期阶段之间的时间段。
儿童的机体在儿童发育时所经历的显著改变需要营养物的持续供应以支持该过程。平衡的膳食最佳地向儿童提供他们所需的全部。
然而,某些儿童患有胃肠(GI)道功能受损。因此,此类儿童不总是能够向他们的机体供应足够量的营养。
这些儿童可能患有例如食欲减退、容量不耐受(volume intolerance)、便秘或腹泻,这不允许充足的食物摄取,或不允许从摄取的食物适当地吸收到所需的营养物。
已开发了专门的营养组合物用于此类情况,从而使得甚至在此类不利的情况下,儿童的特殊需求仍可以得到满足。
一般地,在食物摄取不充分的情况下,食物组合物中的常量营养物被加工,以使得其更易于吸收。
然而,希望还支持消化道的功能,从而使得消化系统更有效地工作。
儿童常与许多其他儿童密切接触,并且因此需要强的免疫系统。然而,取决于发育状态,他们的免疫系统可能仍是未成熟的。由GI道功能受损引起的营养不良可以进一步削弱免疫系统。
如果组合物具有抗炎作用,这也是期望的。
因此,期望的是,不仅给儿童提供营养支持还提供对免疫系统的支持,在儿童生病或从疾病中恢复的情况下提供允许降低炎症程度的天然组合物、和/或提供允许消化道更好地发挥功能的手段。
故,本领域需要能够根据儿童的特殊需要给儿童提供专门营养同时减少炎症、加强免疫系统和/或改善消化的营养组合物。优选的是,这通过使用如下天然成分来达到,所述天然成分可以安全施用而无副作用,且可以容易地通过使用工业化加工而掺入营养组合物内。
本发明人解决了这一需求。因此,本发明的目的是对现有技术的改善,提供满足上文所述需要的儿童用营养组合物。
本发明人很惊讶,他们可以通过独立权利要求的主题达到这个目的。从属权利要求进一步发展本发明的想法。
发明内容
由此,本发明人提出:提供包含益生菌的特定口服营养组合物,以施用于具有受损的GI道功能的儿童。
为了本发明的目的,儿童应理解为1-13岁的人。
已经发现,益生菌能够在液体营养组合物的框架中提供其健康益处。
因为施用于特定患者的液体营养组合物通常具有比包含益生菌的酸乳饮品长的货架期,所以益生菌通常不加入此类营养组合物中,因为不确定益生菌的生活力是否可以在延长的货架期中得到保证。
本发明人现在能够证实,甚至非复制性益生菌也可以提供益生菌的健康益处,且甚至可以具有提高的益处。
因此,本发明的一个实施方案是施用于儿童的组合物,其向患者提供全营养,且包含益生微生物。
该儿童可患有例如受损的胃肠道功能。
组合物提供全营养,患者可以从该组合物获得所有需要的营养而无需额外的食物来源。
本发明的组合物可以作为口服施用的营养组合物或作为经由管饲施用的营养组合物而提供。
本发明的营养组合物提供平衡的肽谱,以支持氮吸收和生长。肽可以是完全或部分基于乳清的,以利于胃排空。
作为完全基于乳清的蛋白质来源,可以使用酶促水解的乳清蛋白质。
可替代地,奶蛋白质浓缩物和乳清蛋白质浓缩物的混合物可以以约1∶1的比率使用。
本发明的营养组合物可以施用于1-10岁的儿童。
本发明的一个实施方案是这样的组合物,其具有在0.9-1.1kcal/ml范围中的卡路里密度、在250-270mOsm/kg水范围中的重量摩尔渗透压浓度,且包含占组合物约11-13%卡路里的蛋白质来源、占组合物约43-56%卡路里的碳水化合物来源、和占组合物约32-45%卡路里的脂质来源。
可以选择高MCT∶LCT比率,以降低脂肪吸收不良的可能性。
因此,MCT(中链甘油三酯)∶LCT(长链甘油三酯)比率对于正常患者可以在20∶80至24∶76范围中。对于患有脂肪吸收不良的患者,可以优选采用约58∶42至62∶38的MCT∶LCT比率。
本发明的组合物可以含有纤维以帮助促进健康肠道微生物群(gutmicrobiota)。可以使用豌豆纤维、低聚果糖和菊粉的混合物。纤维可以以5.5-7.5g/L的量存在。
本发明的组合物可以具有在175∶1至190∶1范围中的NPC∶N比率。非蛋白质千卡路里与氮的比率(NPC∶N)通过计算每天供应的氮克数(1gN=6.25g蛋白质)并用总的非蛋白质千卡路里除以氮克数进行计算。
一般地,具有在80∶1范围中的NPC∶N比率的营养增补物用于最严重应激的患者,在100∶1范围中的NPC∶N比率用于严重应激的患者,并且在150∶1范围中的NPC∶N比率用于未应激的患者。
对于儿童,通常不需要太高的蛋白质含量。然而,在严重应激的儿童的情况下,NPC∶N比率可以相应地调整。
本发明的组合物可以具有在4.5∶1-5.5∶1范围中的n6∶n3脂肪酸比率的脂质来源。
一般地,本发明的组合物包含约83-87%游离水。游离水是满足最低限度液体需求所必需的。一般地,GI功能受损的儿童饮水不够。
本发明的组合物可以用于下述的营养管理:肠切除术、囊性纤维化、脑瘫、肿瘤、胰腺炎、HIV/AIDS、吸收不良、短肠综合征、发育迟滞、营养不良、IBD(炎性肠病)、脂肪吸收不良、便秘、Crohn氏病、腹泻、胃肠道受损、谷蛋白不耐受、消化和吸收受损、乳糖不耐受、限制的肠功能、儿科胃肠道病症、专门儿科营养需要、和/或生长迟滞(failure to thrive)。
本发明的组合物可以部分包含或仅包含非复制的益生微生物。
本发明人惊讶地发现,例如就免疫加强效应而言和/或就抗炎效应而言,非复制益生微生物甚至可以比复制性益生微生物更有效。
这是令人惊讶的,因为益生菌常被定义为“当以足够量施用时,对宿主赋予健康益处的活微生物”(FAO/WHO指南)。绝大多数的出版文献涉及活益生菌。此外,有几项研究调查了由非复制性细菌递送的健康益处,并且其中大多数指出,益生菌的灭活(例如通过热处理)会导致据称的益生菌的健康益处的丧失(Rachmilewitz,D.等人,2004,Gastroenterology126:520-528;Castagliuolo等人,2005,FEMS Immunol.Med.Microbiol.43:197-204;Gill,H.S.和K.J.Rutherfurd,2001,Br.J.Nutr.86:285-289;Kaila,M.等人,1995,Arch.Dis.Child 72:51-53.)。某些研究显示被杀死的益生菌可以保留某些健康作用(Rachmilewitz,D.等人,2004,Gastroenterology 126:520-528;Gill,H.S.和K.J.Rutherfurd,2001,Br.J.Nutr.86:285-289),但明显地,活益生菌迄今为止在本领域中被公认为更有效。
根据本发明的组合物可以包含任何有效量的益生微生物,例如相应于约106-1012cfu/g干重的量。
益生微生物可以是非复制性益生微生物。
“非复制”益生微生物包括已经热处理的益生细菌。这包括灭活的、死的、无生活力的和/或作为碎片例如DNA、代谢物、细胞质化合物和/或细胞壁物质存在的微生物。
“非复制”意指通过经典铺平板方法无法检测到活细胞和/或菌落形成单位。经典铺平板方法在微生物学教科书中有总结:James Monroe Jay,Martin J.Loessner,David A.Golden.2005.Modern food microbiology.第7版,Springer Science,New York,N.Y.第790页。一般地,活细胞的不存在可以如下显示:在用不同浓度的细菌制剂(‘非复制’样品)接种和在合适条件下孵育(有氧和/或缺氧大气,至少24小时)后,在琼脂平板上无可见菌落或在液体生长培养基中无增加的浊度。
为了本发明的目的,益生菌定义为“对宿主的健康(health)或康健(well-being)具有有利作用的微生物细胞制剂或微生物细胞组分”。(Salminen S,Ouwehand A.Benno Y.等人“Probiotics:how should they bedefined”Trends Food Sci.Technol.1999:10107-10)。
使用非复制益生微生物的可行性提供了几个优点。在严重免疫受损患者中,活益生菌的使用可能因发展菌血症的潜在危险而在异常的情况下受限制。非复制益生菌可以使用而无任何问题。
此外,非复制益生微生物的提供允许热重构同时保留健康益处。
本发明的组合物包含足以至少部分地产生健康益处的量的益生微生物和/或非复制益生微生物。足以完成这点的量定义为“治疗有效剂量”。对于这个目的有效的量将取决于本领域技术人员已知的许多因素,例如患者的重量和一般健康状态,以及食物基质的影响。
在预防应用中,根据本发明的组合物施用于对病症敏感或有罹患病症危险的消费者,其施用量足以至少部分地降低发展该病症的危险。此量定义为“预防有效剂量”。再次,精确量取决于许多因素例如患者的健康状态和重量,以及食物基质的影响。
本领域技术人员将能够适当地调整治疗有效剂量和/或预防有效剂量。
一般而言,本发明的组合物含有治疗有效剂量和/或预防有效剂量的益生微生物和/或非复制益生微生物。
一般地,治疗有效剂量和/或预防有效剂量在约0,005mg-1000mg益生微生物和/或非复制益生微生物/日剂量的范围内。
就数值量而言,“短时间高温”处理的非复制微生物可以以对应于104-1012等价cfu/g干组合物的量存在于组合物中。明显地,非复制微生物不形成菌落,因此,这个术语应理解为得自104-1012cfu/g复制细菌的非复制微生物量。这包括灭活的、无生活力的或死的、或作为碎片例如DNA或细胞壁或细胞质化合物存在的微生物。换言之,组合物含有的微生物的数量以该数量的微生物的菌落形成能力(cfu)来表达,就如同所有微生物是活的一样,而不管它们事实上是否是非复制性的,例如灭活的或死的、成碎片的、或是这些状态的任何或所有的混合物。
优选地,非复制微生物以等价于104-109cfu/g干组合物的量,更加优选以等价于105-109cfu/g干组合物的量存在。
益生菌可以通过本领域已知的任何方法而成为非复制的。
目前可用于使益生菌菌株成为非复制性的技术通常有热处理、γ-辐射、UV光或化学试剂(福尔马林、多聚甲醛)的使用。
优选使用在食品工业的工业化环境下相对易于应用的技术来使益生菌成为非复制性的。
目前上市的含有益生菌的大多数产品是在其生产过程中被热处理过的。因此,有利的是,能够连同所生产的产品一起或至少以相似方式热处理益生菌,同时益生菌保留或改善其对于消费者的有利特性或甚至获得新的有利特性。
然而,益生微生物通过热处理的灭活在文献中一般与益生活性的至少部分丧失相关。
本发明人目前已惊讶地发现,致使益生微生物非复制(例如通过热处理),并不导致益生菌健康益处的丧失,而是——相反地——可以增强已有的健康益处且甚至生成新的健康益处。
因此,本发明的一个实施方案是组合物,其中非复制益生微生物已通过热处理而成为非复制性的。
此热处理可以在至少71.5℃执行至少1秒。
可以使用长期热处理或短期热处理。
在工业规模中,目前通常的短期热处理例如UHT样热处理是优选的。这类热处理减少细菌载量,并且减少加工时间,从而减少对营养物的破坏。
本发明人首次证实,高温短时间热处理的益生微生物,无论其初始性质如何,均显示出抗炎免疫谱/性质。特别地,通过该热处理,可以发展新的抗炎谱/性质,或增强已有的抗炎谱/性质。
因此,目前可以通过使用对应于一般工业上适用的热处理的特定热处理参数,生成具有抗炎免疫谱的非复制益生微生物,即使活的对应微生物不是抗炎菌株。
因此,例如,热处理可以是在约71.5-150℃高温处理约1-120秒。高温处理可以是高温/短时间(HTST)处理或超高温(UHT)处理。
可以对益生微生物实施在约71.5-150℃约1-120秒的短期高温处理。
更优选可以对微生物实施在约90-140℃,例如90-120℃,约1-30秒的短期高温处理。
这种高温处理致使微生物至少部分地非复制。
高温处理可以在正常大气压下执行,但也可以在高压下执行。一般压力范围是1-50巴,优选1-10巴,更加优选2-5巴。明显地,优选的是,当应用热时,在液体或固体的培养基中对益生菌进行热处理。待应用的理想压力因此将取决于提供微生物时微生物所在的组合物的性质和使用的温度。
高温处理可以在约71.5-150℃、优选约90-120℃、更加优选约120-140℃的温度范围中执行。
高温处理可以执行约1-120秒、优选约1-30秒、更加优选约5-15秒的短时间。
该给定的时帧是指对益生微生物施加该给定温度的时间。注意,取决于提供微生物的组合物的性质和量且取决于使用的加热器的构造,热应用时间可以不同。
然而,一般地,本发明的组合物和/或微生物通过高温短时间(HTST)处理、巴氏瞬间灭菌(flash pasteurization)、或超高温(UHT)处理来进行处理。
UHT处理是通过将组合物在超过135℃(275℉)的温度(这是杀死奶中的细菌孢子所需的温度)加热约1-10秒的短时间,涉及至少部分地灭菌组合物的超高温加工或超热处理(两者均缩写为UHT)。例如,使用超过135℃的温度以这种方式加工奶,允许在该必要的保持时间(至2-5秒)中细菌载量的减少,从而使得连续流操作成为可能。
存在2种主要类型的UHT系统:直接和间接系统。在直接系统中,通过蒸汽注射或蒸汽输注,处理产品;而在间接系统中,使用板式换热器、管式换热器或刮面式换热器来热处理产品。UHT系统的组合可以在产品制备过程中的任何步骤或多个步骤应用。
HTST处理定义如下(高温/短时间):设计以达到奶中活微生物数目的5-log减少,即,杀死99,9999%的活微生物,的巴氏灭菌方法。这被认为足以破坏几乎所有酵母、霉菌和常见腐败细菌,并且还确保对常见致病性耐热生物产生足够破坏。在HTST过程中,将奶加热至71.7℃(161℉)15-20秒。
巴氏瞬间灭菌法是易腐饮料如果汁和蔬菜汁、啤酒和乳制品的热巴氏灭菌方法。它在填充到容器内之前完成,以便杀死腐败微生物,使得产品更安全且延长其货架期。液体以受控的连续流进行移动,同时被施加于71.5℃(160℉)-74℃(165℉)的温度约15-30秒。
为了本发明的目的,术语“短时间高温处理”应包括例如高温短时间(HTST)处理、UHT处理和巴氏瞬间灭菌。
因为此热处理提供了具有改善的抗炎谱的非复制益生菌,所以本发明的组合物可以用于炎性病症的预防或治疗中。
可以通过本发明的组合物治疗或预防的炎性病症并无特别的限制。例如,它们可以选自:急性炎症例如败血症;烧伤;和慢性炎症例如炎性肠病,例如Crohn氏病、溃疡性结肠炎、隐窝炎(pouchitis);坏死性小肠结肠炎;皮肤炎症例如UV或化学品诱导的皮肤炎症、湿疹、反应性皮肤(reactive skin);肠激惹综合征;眼炎症;变态反应、哮喘;及其组合。
如果长期热处理用于致使益生微生物非复制,那么此热处理可以在约70-150℃的温度范围中执行约3分钟-2小时,优选在约80-140℃的范围中约5分钟-40分钟。
虽然现有技术一般教导,就发挥其益生特性而言,通过长期热处理致使非复制的细菌通常比活细胞效力低,但本发明人能够证实与其活性对应物比较,热处理的益生菌在刺激免疫系统方面更佳。
本发明还涉及包含益生微生物的组合物,所述益生微生物已经通过在至少约70℃热处理至少约3分钟而是非复制性的。
非复制益生菌的免疫增强效应通过体外免疫谱分析而得到证实。所用的体外模型使用来自人外周血单核细胞(PBMCs)的细胞因子谱分析,该模型在本领域中被公认为是用于测试免疫调节化合物的标准模型(Schultz等人,2003,Journal of Dairy Research 70,165-173;Taylor等人,2006,Clinical and Experimental Allergy,36,1227-1235;Kekkonen等人,2008,World Journal of Gastroenterology,14,1192-1203)。
该体外PBMC分析法已被几个作者/研究组用于例如根据益生菌的免疫谱,即其抗炎或促炎特征,来分类益生菌(Kekkonen等人,2008,WorldJournal of Gastroenterology,14,1192-1203)。例如,该分析法已显示允许预测益生菌候选物在肠道结肠炎小鼠模型中的抗炎效应(Foligne,B.等人,2007,World J.Gastroenterol.13:236-243)。此外,该分析法被常规用作临床试验中的读出手段,并且已经被证实导致与临床结果相一致的结果(Schultz等人,2003,Journal of Dairy Research 70,165-173;Taylor等人,2006,Clinical and Experimental Allergy,36,1227-1235)。
变态反应疾病在过去数十年一直在稳步地增加,目前被WHO视为流行病。一般地,变态反应被认为起因于免疫系统的Th1和Th2应答之间的失衡,导致强烈地偏向Th2介质的产生。因此,通过恢复免疫系统的Th1和Th2臂之间的合适平衡,可以减轻、下调或防止变态反应。这提示减少Th2应答或增强(至少瞬时地)Th1应答的必要性。后者将是免疫加强应答的特征,通常伴随例如更高水平的IFNγ、TNF-α和IL-12。(Kekkonen等人,2008,World Journal of Gastroenterology,14,1192-1203;ViljanenM.等人,2005,Allergy,60,494-500)
因此,本发明的组合物允许治疗或预防与受损的(compromised)免疫防御有关的病症。
相应地,可以通过本发明的组合物治疗或预防的与受损的免疫防御有关的病症并无特别的限制。
例如,它们可以选自:感染,特别是细菌、病毒、真菌和/或寄生物感染;吞噬细胞缺陷;低至严重的免疫抑制水平,例如由应激或免疫抑制药物、化疗或放疗诱导的那些;天然的低免疫活性的免疫系统状态,例如新生儿的免疫系统;变态反应;及其组合。
本发明中所述的组合物还允许增强患者对疫苗特别是口服疫苗的应答。
任何量的非复制微生物都是有效的。然而,通常优选至少90%、优选至少95%、更优选至少98%、最优选至少99%、理想地至少99.9%、最理想地所有的益生菌是非复制的。
在本发明的一个实施方案中,所有的微生物是非复制的。
因此,在本发明的组合物中,至少90%、优选至少95%、更优选至少98%、最优选至少99%、理想地至少99.9%、最理想所有的益生菌可以是非复制的。
所有的益生微生物都可以用于本发明的目的。
例如,益生微生物可以选自双歧杆菌属(bifidobacteria)、乳杆菌属(lactobacilli)、丙酸杆菌属(propionibacteria)或其组合,例如长双歧杆菌(Bifidobacterium longum)、乳双歧杆菌(Bifidobacterium lactis)、动物双歧杆菌(Bifidobacterium animalis)、短双歧杆菌(Bifidobacterium breve)、婴儿双歧杆菌(Bifidobacterium infantis)、青春双歧杆菌(Bifidobacteriumadolescentis)、嗜酸乳杆菌(Lactobacillus acidophilus)、干酪乳杆菌(Lactobacillus casei)、副干酪乳杆菌(Lactobacillus paracasei)、唾液乳杆菌(Lactobacillus salivarius)、罗伊氏乳杆菌(Lactobacillus reuteri)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、约氏乳杆菌(Lactobacillus johnsonii)、植物乳杆菌(Lactobacillus plantarum)、发酵乳杆菌(Lactobacillusfermentum)、乳酸乳球菌(Lactococcus lactis)、嗜热链球菌(Streptococcusthermophilus)、乳酸乳球菌(Lactococcus lactis)、双乙酰乳球菌(Lactococcusdiacetylactis)、乳脂乳球菌(Lactococcus cremoris)、保加利亚乳杆菌(Lactobacillus bulgaricus)、瑞士乳杆菌(Lactobacillus helveticus)、德氏乳杆菌(Lactobacillus delbrueckii)、大肠杆菌(Escherichia coli)和/或其混合物。
本发明的组合物可以例如包含益生微生物,所述的益生微生物选自长双歧杆菌NCC 3001、长双歧杆菌NCC 2705、短双歧杆菌NCC 2950、乳双歧杆菌NCC 2818、约氏乳杆菌La1、副干酪乳杆菌NCC 2461、鼠李糖乳杆菌NCC 4007、罗伊氏乳杆菌DSM17983、罗伊氏乳杆菌ATCC55730、嗜热链球菌NCC 2019、嗜热链球菌NCC 2059、干酪乳杆菌NCC 4006、嗜酸乳杆菌NCC 3009、干酪乳杆菌ACA-DC 6002(NCC 1825)、大肠杆菌Nissle、保加利亚乳杆菌NCC 15、乳酸乳球菌NCC 2287或其组合。
所有这些菌株或是在布达佩斯条约(Budapest treaty)下保藏和/或是可商购获得的。
在布达佩斯条约下保藏的菌株如下:
本领域技术人员将理解它们可以自由地组合本文描述的所有本发明特征,而不脱离所公开的本发明的范围。
根据下列实施例和附图,本发明的进一步的优点和特征是显而易见的。
附图简述
图1A和B表示用“短时高温”处理的益生菌的抗炎免疫谱的增强。
图2表示非抗炎的益生菌株在用“短时高温”处理后变成抗炎的,即表现出显著的体外抗炎免疫谱。
图3A和B表示商购可获得的产品中使用的益生菌株在用“短时高温”处理后体外表现出增强的或新的抗炎免疫谱。
图4A和B表示乳品起子菌株(diary starter strains)(即Lc1起子菌株)在高温热处理后体外表现出增强的或新的抗炎免疫谱。
图5表示非抗炎的益生菌株在用HTST处理后体外表现出抗炎免疫谱。
图6:使用活的和热处理(140℃,15秒)形式的益生菌株和乳品起子菌株产生的PBMC数据(IL-12p40、IFN-γ、TNF-α、IL-10)的主成分分析。每个点表示活的或热处理的一种菌株(通过其NCC号或名称标识)。
图7表示活的和热处理(85℃,20分钟)的菌株的IL-12p40/IL-10比例。总的来说,相比本发明的“短时高温”处理,85℃热处理20分钟引起IL-12p40/IL-10比例的增加(图1、2、3、4和5)。
图8表示用热处理细菌刺激的人PBMCs的体外细胞因子分泌的增加。
图9表示在用盐水攻击(challenged)的OVA-致敏小鼠(阴性对照)、用OVA攻击的OVA-致敏小鼠(阳性对照)和用OVA攻击且用热处理或活的短双歧杆菌NCC2950处理的OVA-致敏小鼠中观察到的腹泻强度的百分数。结果以腹泻强度百分数显示(由4个独立试验计算出的平均值±SEM),100%的腹泻强度对应于阳性对照组(变应原致敏和攻击)发生的症状。
实施例
实施例1:
方法学
细菌制剂:
活的益生菌对宿主免疫系统的健康益处通常被认为是菌株特异性的。体外诱导高水平IL-10和/或诱导低水平促炎细胞因子的益生菌(PBMC分析法)已经显示是有效的体内抗炎菌株(Foligné,B.等人,2007,WorldJ.Gastroenterol.13:236-243)。
使用数种益生菌株来研究热处理的益生菌的抗炎特性。这些菌株是长双歧杆菌NCC 3001、长双歧杆菌NCC 2705、短双歧杆菌NCC 2950、乳双歧杆菌NCC 2818、副干酪乳杆菌NCC 2461、鼠李糖乳杆菌NCC 4007、干酪乳杆菌NCC 4006、嗜酸乳杆菌NCC 3009、干酪乳杆菌ACA-DC 6002(NCC 1825)和大肠杆菌Nissle。还测试了数种起子培养菌株,包括一些商业用于生产NestléLc1发酵产品的菌株:嗜热链球菌NCC 2019、嗜热链球菌NCC 2059、保加利亚乳杆菌NCC 15和乳酸乳球菌NCC 2287。
细菌细胞是在5-15L生物反应器中在针对每种菌株优化的条件下培养的。所有的一般细菌生长培养基均是可用的。这类培养基是本领域技术人员已知的。当pH调至5.5时,连续加入30%碱溶液(NaOH或Ca(OH)2)。当足够时,通过用CO2气体处理顶部空间来维持缺氧条件。大肠杆菌是在标准的需氧条件下培养的。
通过离心(5,000×g,4℃)收集细菌细胞,并且重悬于足够体积的磷酸盐缓冲盐水(PBS)中,以便达到终浓度约109-1010cfu/mL。部分制剂用15%甘油冻存于-80℃。另一部分细胞通过以下进行热处理:
-超高温:140℃,15秒;通过间接蒸汽注射。
-高温短时(HTST):74℃、90℃和120℃,15秒,通过间接蒸汽注射。
-水浴中的长时低温(85℃,20分钟)。
热处理后,将样品冻存于-80℃,直至使用。
细菌制剂的体外免疫谱分析:
评估活的和热处理的细菌制剂的免疫谱(即体外诱导人血细胞分泌特定细胞因子的能力)。从血液过滤器分离人外周血单核细胞(PBMCs)。通过细胞密度梯度分离后,收集单核细胞并且用Hank平衡盐溶液洗涤两次。然后将细胞重悬于补充有10%胎牛血清(Bioconcept,巴黎,法国)、1%L-谷氨酰胺(Sigma)、1%青霉素/链霉素(Sigma)和0.1%庆大霉素(Sigma)的Iscove改良的Dulbecco培养基(IMDM,Sigma)中。然后将PBMCs(7×105个细胞/孔)与活的和热处理的细菌(相当于7×106cfu/孔)在48孔板中孵育36小时。活的和热处理的细菌的作用是在来自8位单独供体的PBMCs上测试的,分为两个独立试验。孵育36小时后,将培养板冷冻并且保持在-20℃,直至细胞因子测量。细胞因子谱分析是在活的细菌和它们的热处理的对应物中平行进行的(即在相同批次的PBMCs上在相同试验中)。
按照供应商的说明,通过ELISA(R&D DuoSet Human IL-10,BDOptEIA Human IL12p40,BD OptEIA Human TNFα,BD OptEIA HumanIFN-γ)测定36小时孵育后细胞培养物上清液中细胞因子(IFN-γ、IL-12p40、TNF-α和IL-10)的水平。IFN-γ、IL-12p40和TNF-α是促炎细胞因子,而IL-10是有力的抗炎介质。结果是以4位单独供体的平均值(pg/mL)+/-SEM表示的,并且是各用4位供体进行的两个单独试验的代表。计算每个菌株的IL-12p40/IL-10的比值,作为体内抗炎作用的预测值(Foligné,B.等人,2007,World J.Gastroenterol.13:236-243)。
将通过ELISA(参见上面)测定的每个菌株的细胞因子数值(pg/mL)转移至BioNumerics v5.10软件(Applied Maths,Sint-Martens-Latem,Belgium)中。对该组数据进行了主成分分析(PCA,维技术(dimensioningtechnique))。该分析包括减去特征值的平均值和除以特征值的方差(Subtraction of the averages over the characters and division by thevariances over the characters were included in this analysis)。
结果
超高温(UHT)/高温短时(HTST)-样处理产生的抗炎谱
将在研的益生菌株进行一系列的热处理(超高温(UHT)、高温短时(HTST)、和85℃20分钟),并且在体外将它们的免疫谱与活细胞的免疫谱进行比较。当与人PBMC(图1、2、3、4和5)温育时,活的微生物(益生菌和/或乳品起子培养物)诱导不同水平的细胞因子产生。这些微生物的热处理以温度依赖方式改变了PBMC产生的细胞因子的水平。“短时高温”处理(120℃或140℃,15秒)产生具有抗炎免疫谱的非复制细菌(图1、2、3和4)。事实上,UHT-样处理的菌株(140℃,15秒)诱导了更少的促炎细胞因子(TNF-α、IFN-γ、IL-12p40),而维持或诱导额外的IL-10产生(相比活的对应物)。相比活细胞,任何UHT-样处理的菌株产生的IL-12p40/IL-10比例都更低(图1、2、3和4)。对于以HTST-样处理法处理的细菌,该观察也是对的,所述的HTST-样处理即120℃进行15秒(图1、2、3和4),或74℃和90℃进行15秒(图5)。热处理(UHT-样或HTST-样处理)对益生菌株(图1、2、3和5)和乳品起子培养物(图4)的体外免疫谱具有相似的影响。对活的和热处理(140℃,15秒)的益生菌和乳品起子菌株产生的PBMC数据的主成分分析表明,活菌株均沿着x轴分布,说明菌株在体外展示出非常不同的免疫谱,促炎细胞因子的从低(左侧)到高(右侧)的诱导者。热处理的菌株聚集在图的左侧,这表明热处理的菌株诱导了少得多的促炎细胞因子(图6)。通过比较,85℃热处理20分钟的细菌比活细胞诱导更多的促炎细胞因子和更少的IL-10,从而导致更高的IL-12p40/IL-10比例(图7)。
UHT-样和HTST-样处理增强或产生抗炎谱。
UHT和HTST处理的菌株表现出抗炎谱,不管它们各自最初的免疫谱(活细胞)如何。已知具有体内抗炎并且体外表现出抗炎谱的益生菌株(长双歧杆菌NCC 3001、长双歧杆菌NCC 2705、短双歧杆菌NCC 2950、乳双歧杆菌NCC 2818)在“短时高温”处理后表现出增强的体外抗炎谱。如图1所示,UHT-样处理的双歧杆菌属菌株的IL-12p40/IL-10比例低于活对应细菌的比例,从而表明UHT-样处理的样品的改善的抗炎谱。更引人注目地,在非抗炎性活菌株中也证实了通过UHT-样和HTST-样处理可以产生抗炎谱。活的鼠李糖乳杆菌NCC 4007和副干酪乳杆菌NCC 2461表现出体外高的IL-12p40/IL-10比例(图2和5)。两种活菌株显示出不能防止小鼠中TNBS-诱导的结肠炎。在“短时高温”处理(UHT或HTST)后鼠李糖乳杆菌NCC 4007和副干酪乳杆菌NCC 2461诱导的IL-12p40/IL-10比例急剧下降,达到与双歧杆菌属菌株获得的同样低的水平。这些低的IL-12p40/IL-10比例的原因是:低水平的IL-12p40产生并且组合无变化(鼠李糖乳杆菌NCC 4007)或急剧诱导的IL-10分泌(副干酪乳杆菌NCC 2461)(图2)。
结果:
-UHT-样和HTST-样热处理可以增强活微生物的抗炎谱/特性(例如长双歧杆菌NCC 2705、长双歧杆菌NCC 3001、短双歧杆菌NCC 2950、乳双歧杆菌NCC 2818)
-UHT-样和HTST-样热处理可以使非抗炎的活微生物产生抗炎谱/特性(例如,鼠李糖乳杆菌NCC 4007、副干酪乳杆菌NCC 2461、乳品起子嗜热链球菌NCC 2019)
-从可商购获得的产品中分离的菌株(包括益生的大肠杆菌菌株)也证实了抗炎谱/特性(图3A&B)。
UHT/HTST-样处理的影响对于所有测试的益生菌和乳品起子是类似的,例如乳杆菌属、双歧杆菌属和链球菌属。
UHT/HTST-样处理已经应用于数种表现出不同体外免疫谱的乳杆菌、双歧杆菌和链球菌。UHT/HTST-样处理后的所有菌株比它们的活对应菌株都诱导了更少的促炎细胞因子(图1、2、3、4、5和6),这证实了UHT/HTST-样处理对这些所得非复制细菌的免疫特性的影响可以概括至所有益生菌,特别是乳杆菌和双歧杆菌以及特定的大肠杆菌菌株,和所有乳品起子培养物,特别是链球菌、乳球菌和乳杆菌。
实施例2:
方法学
细菌制剂:
五种益生菌株用于研究非复制益生菌的免疫增强特性:3种双歧杆菌(长双歧杆菌NCC3001、乳双歧杆菌NCC2818、短双歧杆菌NCC2950)和2种乳杆菌(副干酪乳杆菌NCC2461,鼠李糖乳杆菌NCC4007)。
细菌细胞生长在MRS上,于37℃分批发酵16-18小时,无pH控制。将细菌细胞旋转沉降(5,000×g,4℃),并且重悬于磷酸盐缓冲液中,之后在盐水中稀释以达到终浓度约10E10cfu/mL。将长双歧杆菌NCC3001、乳双歧杆菌NCC2818、副干酪乳杆菌NCC2461、鼠李糖乳杆菌NCC4007在85℃水浴中热处理20分钟。将短双歧杆菌NCC2950在90℃水浴中热处理30分钟。将热处理的细菌悬浮液等分并且冻存于-80℃直至使用。活细菌在PBS-甘油15%中存于-80℃直至使用。
细菌制剂的体外免疫谱分析
评估活的和热处理的细菌制剂的免疫谱/特性(即,体外诱导人血细胞分泌特定细胞因子的能力)。从血液过滤器分离人外周血单核细胞(PBMCs)。通过细胞密度梯度分离后,收集单核细胞并且用Hank平衡盐溶液洗涤两次。然后将细胞重悬于补充有10%胎牛血清(Bioconcept,巴黎,法国)、1%L-谷氨酰胺(Sigma)、1%青霉素/链霉素(Sigma)和0.1%庆大霉素(Sigma)的Iscove改良的Dulbecco培养基(IMDM,Sigma)中。然后将PBMCs(7×105个细胞/孔)与活的和热处理的细菌(相当于7×106cfu/孔)在48孔板中培养36小时。活的和热处理的细菌的作用是在来自8位单独供体的PBMCs上测试的,分为两个独立试验。培养36小时后,将培养板冷冻并且保持在-20℃,直至细胞因子测量。细胞因子谱分析是在活的细菌和它们的热处理对应细菌中平行进行的(即在相同批次PBMCs上在相同试验中)。
按照供应商的说明,通过ELISA(R&D DuoSet Human IL-10,BDOptEIA Human IL12p40,BD OptEIA Human TNF,BD OptEIA HumanIFN-γ)测定培养36小时后细胞培养上清液中细胞因子(IFN-γ、IL-12p40、TNF-α和IL-10)的水平。IFN-γ、IL-12p40和TNF-α是促炎细胞因子,而IL-10是有力的抗炎介质。结果是以4位单独供体的平均值(pg/mL)+/-SEM表示的,并且是各用4位供体进行的两个单独试验的代表。
活的和热处理的短双歧杆菌NCC2950在防止变应性腹泻中的体内作用
变应性腹泻的小鼠模型用于测试短双歧杆菌NCC2950的Th1促进作用(Brandt E.B等人.JCI 2003;112(11):1666-1667)。致敏(以14天的间隔,于第0和14天,2次腹膜内注射卵白蛋白(OVA)和硫酸铝钾)后,将雄性Balb/c小鼠用OVA口服攻击6次(第27、29、32、34、36、39天),导致短暂的临床症状(腹泻)和免疫参数变化(总IgE、OVA特异性IgE、小鼠肥大细胞蛋白酶1即MMCP-1的血浆浓度)。在OVA致敏前(第-3、-2、-1、0天和第11、12、13和14天)和攻击期内(第23至39天)将活的或90℃热处理30分钟的短双歧杆菌NCC2950通过管饲法施用4天。使用每日细菌剂量约109菌落形成单位(cfu)或等价的cfu/小鼠。
结果
热处理后对“促炎”细胞因子分泌的诱导
体外评估了热处理的细菌菌株刺激人外周血单核细胞(PBMCs)分泌细胞因子的能力。用热处理的细菌刺激PBMCs后基于四种细胞因子的免疫谱与在相同的体外分析试验中由活细菌细胞诱导的免疫谱进行比较。
将热处理的制剂铺板并且评估不存在任何存活的细菌计数。热处理的细菌制剂铺板后不产生菌落。
当与人PBMCs温育时,活的益生菌诱导了不同且菌株依赖性水平的细胞因子产生(图8)。益生菌的热处理,与它们的活对应细菌比较,改变了PBMCs产生的细胞因子的水平。热处理的细菌比它们的活对应细菌诱导了更多的促炎细胞因子(TNF-α、IFN-γ、IL-12p40)。通过比较,热处理的细菌比活细胞诱导了相似或更低量的IL-10。这些数据表明热处理的细菌比它们的活对应细菌更能刺激免疫系统,并且因此更能加强减弱的免疫防御。换言之,体外数据说明了热处理后细菌菌株的增强的免疫加强作用。
为了说明热处理的短双歧杆菌NCC2950对免疫系统的增强作用(相比活细胞),在变应性腹泻的动物模型中测试了活的和热处理的短双歧杆菌NCC2950(菌株A)。
相比阳性对照组,用热处理的短双歧杆菌NCC2950处理后腹泻强度显著且一致地下降(41.1%±4.8),而用活的短双歧杆菌NCC2950处理后腹泻强度仅降低20±28.3%。这些结果证实,热处理的短双歧杆菌NCC2950比其活的对应细菌表现出对变应性腹泻的增强的保护作用。
结果显示,热处理后提高了益生菌增强免疫防御的能力。
实施例3-6:
可以制备例如下列营养组合物:
Claims (15)
1.施用于胃肠道功能受损的儿童的组合物,其向患者提供全营养并包含益生微生物。
2.依照权利要求1的组合物,其具有在0.9-1.1kcal/ml范围中的卡路里密度、在250-270mOsm/kg水范围中的重量摩尔渗透压浓度,且包含占组合物约10-13%卡路里的蛋白质来源、占组合物约43-56%卡路里的碳水化合物来源、占组合物约32-45%卡路里的脂质来源,并具有175∶1至190∶1的NPC∶N比率。
3.依照前述权利要求中任一项的组合物,其包含具有4.5∶1至5.5∶1的n6∶n3脂肪酸比率、和/或20∶80至62∶38的MCT∶LCT比率的脂质来源。
4.依照前述权利要求中任一项的组合物,其包含约83-87%游离水。
5.依照前述权利要求中任一项的组合物,其中所述益生微生物包含非复制益生微生物。
6.依照前述权利要求中任一项的组合物,其包含对应于约106-1012cfu的量的益生微生物。
7.依照前述权利要求5-6中任一项的组合物,其中所述非复制益生微生物是已经通过热处理,优选通过在至少71.5℃高温处理至少1秒,而成为非复制的。
8.依照权利要求7的组合物,其中所述热处理是在约71.5-150℃高温处理约1-120秒,并且优选是高温/短时间(HTST)处理或超高温(UHT)处理。
9.依照权利要求8的组合物用于在炎性病症的预防或治疗中使用。
10.依照权利要求7的组合物,其中所述热处理在约70-150℃的温度范围中执行约3分钟-2小时,优选在约80-140℃的范围中约5分钟-40分钟。
11.依照权利要求10的组合物用于在预防或治疗与受损的免疫防御有关的病症中使用。
12.依照前述权利要求中任一项的组合物,其中至少90%、优选至少95%、更优选至少98%、最优选至少99%、理想地至少99.9%、最理想地所有的益生菌是非复制的。
13.依照前述权利要求中任一项的组合物,其中所述益生微生物选自双歧杆菌、乳杆菌、丙酸杆菌或其组合,例如长双歧杆菌、乳双歧杆菌、动物双歧杆菌、短双歧杆菌、婴儿双歧杆菌、青春双歧杆菌、嗜酸乳杆菌、干酪乳杆菌、副干酪乳杆菌、唾液乳杆菌、罗伊氏乳杆菌、鼠李糖乳杆菌、约氏乳杆菌、植物乳杆菌、发酵乳杆菌、乳酸乳球菌、嗜热链球菌、乳酸乳球菌、双乙酰乳球菌、乳脂乳球菌、保加利亚乳杆菌、瑞士乳杆菌、德氏乳杆菌、大肠杆菌、和/或其混合物。
14.依照前述权利要求中任一项的组合物,其中所述益生微生物选自:长双歧杆菌NCC 3001、长双歧杆菌NCC 2705、短双歧杆菌NCC 2950、乳双歧杆菌NCC 2818、约氏乳杆菌La1、副干酪乳杆菌NCC 2461、鼠李糖乳杆菌NCC 4007、罗伊氏乳杆菌DSM17983、罗伊氏乳杆菌ATCC55730、嗜热链球菌NCC 2019、嗜热链球菌NCC 2059、干酪乳杆菌NCC 4006、嗜酸乳杆菌NCC 3009、干酪乳杆菌ACA-DC 6002(NCC1825)、大肠杆菌Nissle、保加利亚乳杆菌NCC 15、乳酸乳球菌NCC2287、或其组合。
15.依照前述权利要求中任一项的组合物,其含有约0,005mg-1000mg非复制微生物/日剂量。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102949416A (zh) * | 2012-11-23 | 2013-03-06 | 西安泰科迈医药科技有限公司 | 一种用于改善胃肠道功能的药物组合物及其制备方法 |
CN102949416B (zh) * | 2012-11-23 | 2018-12-11 | 西安泰科迈医药科技股份有限公司 | 一种用于改善胃肠道功能的药物组合物及其制备方法 |
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