CN101687897A - 通过所选的非病原性微生物处理天然多糖及其制备和使用方法 - Google Patents
通过所选的非病原性微生物处理天然多糖及其制备和使用方法 Download PDFInfo
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- CN101687897A CN101687897A CN200880023924A CN200880023924A CN101687897A CN 101687897 A CN101687897 A CN 101687897A CN 200880023924 A CN200880023924 A CN 200880023924A CN 200880023924 A CN200880023924 A CN 200880023924A CN 101687897 A CN101687897 A CN 101687897A
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- polysaccharide
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Abstract
本发明包括制备和使用一种膳食补充剂的组合物和方法,该膳食补充剂由一种或多种天然多糖制造,天然多糖事先和益生细菌在生物反应器系统中孵育,其中细菌处理天然多糖,将得到的处理过的多糖以营养补充剂提供。
Description
发明技术领域
本发明主要涉及益生菌领域,更具体地说,涉及输送经由益生菌处理和加工的膳食补充剂的组合物及方法。
发明背景
所述本发明的背景与益生菌相关,但不限定发明范围。
益生菌对健康可以具有许多积极效果。通常,提供益生菌,使其进入并定殖在部分消化道。益生菌可与先前在消化道定殖的原有微生物竞争。这些原有微生物抑制其它微生物的定殖,在某些情况下,原有微生物可能对有益健康的消化细菌群的增殖有害。目前已有许多种益生菌提供,它们被摄取后可致力于建立一个理想的、积极的肠内菌群。然而,摄取后致力于与原有微生物竞争的益生培养物的效用往往受限于菌到达靶位点、抑制原有微生物、建立稳定菌落并与已存在的微生物竞争营养的能力。不期望的消化菌存在的问题在于它们对抗生素的抗性经常提高,变成稳定存在于肠粘膜中,已经能够适应原有的环境,有效竞争营养物质,而不会被排出消化道。
Schmitt等人的美国专利No.7,172,777提出了一种这样的致力于解决益生菌定殖问题的发明,该发明涉及制备用于益生酸奶食品的粉末。简单地说,Schmitt提出了一种用于制备益生酸奶食品的粉末,该粉末含有具有预先设定比例的活益生乳酸菌的益生培养物,一种产热分解脂肪的再吸收加强剂,特别是胡椒提取物,以加强肠内的再吸收过程,以及一种毛细血管扩张剂,特别是烟酸,从而对肠道毛细血管产生扩张作用。
Watson等人的美国专利No.6,468,525提出了另一发明,该发明涉及用于食品补充剂和用于重建人体肠道有益细菌的材料的益生菌制剂,该制剂包括一种有益益生微生物菌群的混合物,其包含嗜酸乳杆菌,两歧双歧杆菌,唾液乳杆菌,婴儿双歧杆菌和长双歧杆菌,低聚果糖,L-谷氨酰胺,N-乙酰葡糖胺。
Perry的美国专利No.6,203,797提出了涉及一种用作益生菌的膳食补充剂和方法的另一发明,其用于减轻肠易激综合症相关的症状。提出的膳食补充剂为益生菌,用于减轻肠易激综合症的症状,其包括冻干芦荟,低聚果糖,大丽花菊粉汁混合物,以及任选的维生素B6(吡哆醇)锰和L-谷氨酰胺。另一特别用于减轻肠易激综合症症状的替代实施方式在基本配方中包括了菠萝蛋白酶和木瓜蛋白酶。同时,以下有益菌也用于特定的益生功能:保加利亚乳杆菌,嗜酸乳杆菌,植物乳杆菌和两歧双歧杆菌,它们可以添加到基本配方中。
Brown等人的美国专利No.6,060,050提出了用于包含在食品中以增强其营养价值的益生菌组合物。该组合物包含一种或多种如双歧杆菌的益生微生物和将微生物转运到大肠或胃肠道其它区域的载体。该载体是变性或未变性的抗性淀粉,尤其是高度直链淀粉,其作为微生物在大肠或胃肠道其它区域的生长介质或维持介质。
美国专利申请No.20070059296提出了一种具有耐酸肠溶薄膜包衣的益生菌组合物,其包含15-20重量%的奶粉,25-30重量%的玉米淀粉,8-15重量%的变性淀粉(胶囊),10-15重量%的乙基纤维素,5-15重量%的细菌肉汤和10-15重量%的滑石。该益生菌组合物被装入微胶囊中,形成多个包被耐酸肠溶薄膜包衣的微胶囊,用于改善益生菌组合物的肠耐酸性,益生菌存活率,抗菌性能,稳定性,防潮性和防止其在潮湿环境中凝结的流动性,并作为应用于牲畜饲料的添加剂使用。
发明概述
尽管人们多次尝试采用各种各样的输送方法和以不同的剂量输送多种形式的益生菌重建消化菌群,然而对具有生物可利用营养物的微生物膳食补充的需求仍存在。本发明人认识到在消化菌群和/或有益消化菌群重建中缺乏变化,仍然需求这些共生微生物从宿主消耗的食物中产生的营养物。共生的消化道微生物为宿主提供了多个有利作用,包括:发酵未使用的能量底物;激活免疫系统;防止非共生或有害物种的生长;为宿主产生维生素和营养物前体(包括生物素和维生素K),以及产生特定的激素或激素-前体。
本发明主要涉及利用微生物物种将天然多糖生物处理成具有膳食补充剂或食品效用的有用产品的新方法和组合物。本发明包括将天然多糖和所选的益生菌在生物反应器系统中混合,使细菌在体外对多糖进行处理。之后生物反应器的产物被用来制备食品或膳食补充剂。在本发明的另一实施方式中,所选的天然多糖的剂型和所选的非病原性(益生)微生物物种组合起来提供营养补充,同时输送必需的益生菌营养物和共生微生物。通过同时将这些物质给予人体胃肠道,非病原性的微生物物种将多糖处理成其它有益产物,该处理可以在人胃肠道范围内完成。
所选多糖成分经这样的微生物处理过程产生新产物,预期该产物对人体健康具有有益效果,包括:(1)通过与粘膜相关的淋巴网组织(MALT)相互作用改善胃肠道和全身免疫功能;(2)通过(a)改善胃肠道消化和营养吸收效率;(b)减少人体胃肠道中不期望的微生物物种;和(c)引入的益生微生物和多糖产物在人体胃肠道内与多种控制因子(即激素受体)相互作用控制体重和减少肥胖;和/或(3)改善血脂参数,例如降低胆固醇和降低甘油三酯的水平。
本发明的一个方面是一种膳食补充剂,其包括一种由一种或多种天然多糖制造的补充剂,天然多糖事先与益生菌在生物反应器系统中孵育,其中该细菌处理该天然多糖,产生的经处理的多糖以营养补充剂提供。在一实施方式中,所获得的处理的多糖被制成食品或膳食补充剂,例如制成单一剂型。用于本发明的多糖可包括葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。在一实施方式中,多糖和微生物活细胞在单一剂型中分别提供。在另一实施方式中,多糖和微生物活细胞在生物反应器中孵育。多糖和微生物活细胞也可以以缓释形式提供。多糖的例子包括杂多糖,同多糖或者杂多糖和同多糖。在膳食补充剂的一个例子中,多糖和微生物细胞是分开的,分开的多糖被装载到选自粉末、胶囊、胶囊锭(gelcap)、片剂、泡腾片、液体或口胶(gummy)的剂型中。
在另一方面,本发明是一种益生食品或膳食补充剂制剂,其包含一种或多种天然多糖,以及选自乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种的微生物活细胞。多糖可以为葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。在一实施方式中,多糖和微生物活细胞以单一剂型分开提供。在另一实施方式中,多糖和微生物活细胞在生物反应器中孵育。而另一实施方式中,多糖和微生物活细胞以缓释形式提供。
在另一方面,本发明是一种膳食补充剂,该膳食补充剂包含由非病原性的益生微生物物种在生物反应器中对所选天然多糖进行处理得到的提取物。而在另一方面,本发明包括制备膳食补充剂的方法,其通过在刺激细菌对天然多糖进行处理的条件下,在生物反应器系统中混合一种或多种天然多糖和益生细菌,来制备经处理的多糖;以及在至少部分天然多糖已经被细菌处理后制备膳食补充剂。在一实施方式中,细菌处理多糖,产生的经处理的多糖被制成单一剂量营养补充剂。在一实施方式中,该方法进一步包括从天然多糖和细菌中分离经处理的多糖;和制备包含经处理的多糖的剂型的步骤。在另一实施方式中,该方法进一步包括制备包含经处理的天然多糖,天然多糖和细菌的剂型的步骤。在另一实施方式中,该方法进一步包括将经处理的多糖装载到选自粉末、胶囊、胶囊锭、片剂、泡腾片、液体或口胶的剂型中。另一实施方式中,经处理的多糖从细菌中分离出来,和经处理的多糖被装载到选自粉末、胶囊、胶囊锭、片剂、泡腾片、液体或口胶的剂型中。
在另一方面,本发明是一种膳食补充剂或食品,其包括和益生细菌在生物反应器或发酵罐系统中孵育的经处理的芦荟内叶胶,其中该细菌将芦荟内叶胶处理成生物可利用的产品。在一实施方式中,该益生细菌包括选自乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种的细菌或其组合。
附图简述
为了更加完整的理解本发明的特征和优势,现在结合附图来对发明进行详细描述,其中:
附图1为标准分子量为5000,10000和800000的聚麦芽三糖的HPLC保留时间图,其中y轴为分子量,x轴为以分钟计的保留时间。
附图2为显示和4种受试人体结肠细菌孵育72小时后的落叶松阿拉伯半乳聚糖(LAG)终产物的示意图。
附图3为显示和4种受试人体结肠细菌孵育72小时后的芦荟胶多糖(AVP)终产物的示意图。
附图4为显示和4种受试人体结肠细菌孵育72小时后的混合糖类补充剂(MSS)的终产物的示意图。
发明详述
尽管本发明多个实施方式的制备和使用将在下文详细讨论,应当理解本发明提供多种可实施的发明概念,它们可以体现于广泛的特定上下文中。此处讨论的特定实施方式只是对制备和使用本发明的特定方法进行说明,而非对本发明的范围加以限制。
为了帮助理解本发明,下文对多个术语进行了定义。此处定义的术语的含义可普遍被本发明相关领域的普通技术人员所理解。如“一个”、“一种”(“a”,“an”)和“该”(the)的术语并不意味仅指一个单独的实体,而是包括可用来说明的特定实例的一般种类。此处使用的术语是用来描述本发明的特定实施方式,除了在权利要求中提出之外,它们的使用并非对本发明进行限制。
此处使用的术语“营养有效量”是用来定义可在哺乳动物中提供有益营养效果或反应的量。例如,因为不同哺乳动物对膳食补充剂的营养反应不同,应当理解所选益生细菌和天然多糖的营养有效量会相应的改变。本发明包括两者,一是从益生细菌中分离出的经益生菌处理的天然多糖(至少部分从益生细菌中分离的),其与失活的益生菌混合,二是天然多糖和益生细菌。
本领域技术人员将认识到某些个体将从一种或多种经过益生细菌处理的天然多糖的组合制剂中获益(例如,拥有正常消化菌群的个体,无需额外益生菌补充的个体,甚至正在消除益生细菌的个体)。同样,已知缺乏带有所选益生细菌的天然多糖会影响生理功能和细胞功能。
本发明公开的带有所选益生细菌的天然多糖的营养有效量可用来保持和/或提高食物中这些关键营养物的水平,所述食物如寻求维持或提高其饮食中这些营养补充剂的人的食物。因此,尽管一哺乳动物可能需要以一定量存在的带有所选益生细菌的天然多糖的特定方案,另一哺乳动物可能需要以不同量存在的维生素和矿物质的相同特定方案。
如本发明使用的术语“糖”、“多糖”、“天然多糖”、“糖营养”或“糖质营养素”是指碳水化合物、多糖、寡糖、二糖或单糖,不管是支链的或直链的,衍生的或非衍生的,不管是可从天然来源中获得的复合的或简单的,它们对多种通讯和信号分子的生化合成是必需的,这些通讯和信号分子可以游离在细胞间质流体,活跃于细胞与细胞通讯中(即细胞因子,生长因子等),或者组成包含细胞膜高特异性分子活性位点的分子构型(即受体位点,离子转运通道,抗原识别等等)。
本发明的天然多糖可以在自然中发现,如单,寡和/或多糖。因此,本发明的组合物可以含有单体的,低聚物的和/或聚合体形式的糖。就天然多糖的已知天然来源及其应用的列表而言,请参考美国专利申请No.2003072770,相关糖类及糖类来源通过引用结合于本发明中。
在一些实施方式中,本发明的活性剂可以制备成以修饰或延迟释放的形式输送。例如,当活性剂对酸敏感,该活性剂可以采用肠溶包衣输送以使其在释放前到达肠道。如本发明所用的术语“修饰的释放”,“缓释”和“控释”描述一种或多种释放情形,即使营养有效量的营养物在延长的时间段中有效输送,该时间段本发明限定为采用本发明的制剂时为约60分钟和约2、4、6、8或更多个小时。修饰的释放也可以功能性限定为在约60分钟和约2、4、6或甚至8小时后释放超过80-90%的营养物。释放也可以通过使天然维生素或天然矿物质为使用者所利用进行评估,不管吸收与否,因为有些活性物可能永远也不被动物吸收。如本发明公开的,基于包衣材料和/或包衣的厚度的选择,本领域技术人员可以容易地设计多种修饰的释放剂型,以实现在小肠和大肠,只在小肠,或只在大肠中释放。
可用于长链多糖的修饰例包括,例如,改变长链多糖中糖的类型或组成,化学修饰(有机地或化学地)糖的侧链(例如乙酰化),水解长链多糖,改变长链多糖的大小,聚合更长的长链多糖,选择更短和更长的长链多糖的组合,通过如电穿孔、FPLC、HPLC、分子量排阻、分子量排阻层析、沉淀等方法分离长链多糖。可以制备和输送缓释制剂,以使其在下段肠道某些一般可预定的位置实现释放,这些位置要比如果未经释放修饰改造所实现释放的位置要远。
如本发明所用的,采用的术语“碳水化合物”可与术语“糖(saccharide)”、“多糖”、“寡糖”和“糖(sugar)”互换,这些术语的定义对糖化学领域的技术人员是公知的。尽管本发明的组合物意指包括至少两种或更多种基本糖,但是应当注意该糖可以是单、寡和/或多糖的形式,例如,可以认为含有黄蓍胶和瓜尔豆胶的组合物含有半乳糖醛酸,唾液酸,甘露糖和半乳糖。因此,通过控制特定膳食补充剂中特定胶的量,可以控制在膳食补充剂中相应糖的量。
如本发明所用的,术语“分离的”是指进行了分级以去除多种其它成分且基本保留了其表现的生物活性的有机分子或类似分子的组。而使用术语“基本纯化的”时,该名称指一种组合物,其中组合物的营养物的活性形式占组合物中总分子的约10%,20%,30%,40%,50%,60%,70%,80%,90%,95%或更多。在某些情况下,营养物的活性形式无法在不影响其活性的情况下成功从其正常细胞环境中分离。实际上,本发明利用了益生微生物在生物反应器中对多糖进行天然处理,以输送最高质量和数量的活性营养化合物。然而,在某些情况下,在处理或“分离”水平,化合物效用和总成本和对环境的影响之间达成了平衡。技术人员将认识到,在成为环境负责的管理者的同时,使化合物的效用最大化是可能的。就植物而言,例如本地生植物,必须维持与本地培植和群落的平衡,从而把对包含分离出的用于本发明的营养化合物的植物生产的影响最小化。
本发明采用的制备天然多糖和益生细菌有用剂型的技术和组合物在以下一份或多份参考文献中有描述:Ansel,Introduction to PharmaceuticalDosage Forms 2nd Edition(1976);Remington′s Pharmaceutical Sciences,17thed.(Mack Publishing Company,Easton,Pa.,1985);Advances in PharmaceuticalSciences(David Ganderton,Trevor Jones,Eds.,1992);Advances inPharmaceutical Sciences Vol 7.(David Ganderton,Trevor Jones,James McGinity,Eds.,1995);Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms(Drugs and the Pharmaceutical Sciences,Series 36(James McGinity,Ed.,1989);Pharmaceutical Particulate Carriers:Therapeutic Applications:Drugs and thePharmaceutical Sciences,Vol 61(Alain Rolland,Ed.,1993);Drug Delivery to theGastrointestinal Tract(Ellis Horwood Books in the Biological Sciences.Series inPharmaceutical Technology;J.G.Hardy,S.S.Davis,Clive G.Wilson,Eds.);Modern Pharmaceutics Drugs and the Pharmaceutical Sciences,Vol 40(Gilbert S.Banker,Christopher T.Rhodes,Eds.)等,相关的部分以引用方式结合于本发明。
例如,本发明的组合物可以包含在片剂中。片剂可以含有如适合的粘合剂,滑润剂,崩解剂,着色剂,调味剂,引流剂,粘胶剂,咀嚼剂和/或溶解剂。例如,口服可以以片剂、胶囊锭、囊片或胶囊的单位剂型进行,活性药物组分与无毒、药学可接受的惰性载体相结合,该惰性载体例如乳糖,明胶,琼脂,淀粉,蔗糖,葡萄糖,甲基纤维素,硬脂酸镁,磷酸二钙,硫酸钙,甘露醇,山梨糖醇及其混合物等等。本发明采用的合适的粘合剂包括:淀粉,明胶,天然糖(如葡萄糖或β-乳糖),玉米甜味剂,天然和合成胶(如阿拉伯树胶,黄蓍胶或藻酸钠),羟甲基纤维素,聚乙二醇,蜡等等。本发明采用的润滑剂可以包括:油酸钠,硬脂酸钠,硬脂酸镁,安息香酸钠,醋酸钠,氯化钠,磷酸二钙及其混合物等等。崩解剂可以包括:淀粉,甲基纤维素,琼脂,膨润土,黄原胶及其混合物等等。
本发明的膳食补充剂包含的多、寡、二或单糖可从多种天然或合成的来源获得,例如灌木,树,植物,酵母,真菌,霉菌,胶,树脂,淀粉和纤维素衍生物和天然粘蛋白来源。本发明所用的某些多糖的天然来源的非限制性例子包括:(a)含有阿拉伯树胶,刺梧桐树胶,黄蓍胶或茄替胶的灌木或树木渗出液;(b)包含琼脂,褐藻胶或角叉菜胶的海生胶;(c)含有瓜尔豆胶,槐豆,或欧车前的种子胶;(d)含果胶或乙酰聚甘露糖的植物提取物;(e)淀粉和纤维素衍生物,例如羧甲基纤维素,乙基纤维素,羟丙基甲基纤维素,甲基纤维素,氧化纤维素;和含葡聚糖和黄原胶的微生物胶。然而,应当理解本发明的组合物并不打算受相应糖类获得的来源所限。
如本发明所用的,术语“植物来源的”,“植物粉末”,“植物提取物”和“草药提取物”可用于互换地指代在植物组织中产生的且可被本发明的益生微生物处理的多、寡、二或单糖的天然来源。形成本发明一部分的天然来源的多、寡、二或单糖的天然来源通常由其天然状态分离出植物的至少一部分,例如通过去除水(如提取汁液和/或果肉),化学提取、机械提取、热提取一种或多种组分,按大小或者以另外的方式采用极性、非极性、矿物质、石油或其他溶剂分离组分,所述组分具有某种程度有益健康或治疗活性。从植物中分离活性剂取决于活性剂的性质,如水溶的,不溶的,可混溶的等,分解敏感性(如因热,pH,氧,光等变性)。植物提取物也包括脱水植物材料,其中大量液体被去除来浓缩植物或草药中的生物可利用固体。绝大多数草药药剂可能是有毒的,尤其在浓缩的情况下,但在它们作为“治疗疾病和促进健康的民间药物”以茶剂和膏状物的其更传统的方式使用时一般是安全的。
益生菌是活的非病原性的和不产生毒素的微生物物种,包括乳杆菌,双歧杆菌和酵母,这些物种可以是胃肠(GI)道微生物菌群的天然成分,也可以通过一定的食物或膳食补充剂经补充引入到胃肠道的微生物菌群中。益生菌被摄取后可以通过改善肠道微生物菌群的平衡对宿主生物体产生有利影响。近期一些研究表明某些活的微生物可能具有免疫调节和抗癌作用以及其他健康益处。一些胃肠道微生物菌群也通过处理,例如发酵,完成对某些食物成分的消化。肠道微生物菌群对免疫系统的成熟,正常肠形态的发育和为维持长期的、免疫平衡的炎症反应非常重要。微生物菌群加强肠粘膜的屏障功能,阻止病原体的附着和致过敏物质的进入。目前有很多针对靶向益生菌的积极的科学研究,这些研究采用因具有特定健康促进效用而选择出来的已充分表征的细菌。目前,在《医师案头参考》(Physician’s Desk Reference,PDR)中确定双歧杆菌和乳杆菌,以及乳酸乳球菌,嗜热链球菌,屎肠球菌和布拉酵母的多种菌种为益生菌。
粉末。经益生菌处理的多糖可以以粉末形式提供。粉末形式也可以包括本发明公开的益生细菌或其部分。通常,粉末形式也可以包括一种或多种改善外观,触感和甚至有助于保存粉末的载体,赋形剂,润湿剂,流动剂,调味品,着色剂等等。
胶囊。胶囊可以通过向每个标准两部分硬明胶胶囊中填充1到1000毫克益生菌处理的多糖来制备。胶囊可以填充赋形剂,载体等等,如0.5到150毫克乳糖,0.1到500毫克纤维素和0.1到60毫克硬脂酸镁。胶囊还可以包括本发明公开的益生细菌。
软明胶胶囊。将益生菌处理的多糖的混合物溶解于可消化油中,例如大豆油,棉仔油,或橄榄油等。采用容积泵将益生菌处理的多糖注射到明胶中以形成软明胶胶囊,软明胶胶囊含有如100到500毫克益生菌处理的多糖。软胶胶囊经洗涤并干燥。软胶胶囊也可以包含本发明公开的益生细菌。
片剂。通过传统程序制备片剂,使单位剂量含有100到500毫克益生菌处理的多糖,0.2毫克胶体二氧化硅,5毫克硬脂酸镁,50到275毫克微晶纤维素,11毫克淀粉和98.8毫克乳糖。可应用适当的包衣来提高适口性或延迟吸收。片剂也可以包括本发明公开的益生细菌。
为提供泡腾片,将适当的量的如柠檬酸钠和碳酸氢钠混合在一起,然后在无水情况下进行碾压,形成薄片之后压碎后成为颗粒。之后,颗粒与益生处理的多糖、药物和/或其盐、传统成丸剂(beading agent)或填充剂和任选的甜味剂、调味剂和润滑剂组合。泡腾片也可以包括本发明公开的益生细菌。
悬浮液。制备用于口服的水悬浮液,使之每5毫升含100毫克精细分开的益生菌处理的多糖,200毫克羧甲基纤维素钠,5毫克苯甲酸钠,1.0克U.S.P.山梨糖醇溶液和0.025毫升香兰素。悬浮液也可以包括本发明公开的益生细菌。
就迷你片剂来说,压缩经益生处理的多糖使其硬度范围在6到12Kp之间。最终的片剂的硬度受制备颗粒时采用的线性碾压力的影响,这又受例如碳酸氢单钠和碳酸氢钠的微粒大小影响。对于较小微粒,可以采用约15到20KN/cm的线性碾压力。
对于可消耗的口胶,本发明可结合Yang等人的美国专利No.5,928,664的教导,相关部分以引用方式结合于本发明中。简单来说,其提出了一种可消耗的口胶输送系统,其中将本发明结合到口胶输送系统,这个系统包括益生菌处理的多糖与甘油化明胶基质的混合物,该甘油化明胶基质的制备方法为加热明胶和甘油的水溶液到一定温度,且加热时间足够去除最初水溶液中的一些水分。本发明提出的益生菌处理的多糖可以由剪切成型基质载体输送。对于提供“胶状稠度”的基于植物的制剂来说,本发明可以采用如Grazela等人的美国专利No.6,586,032中教导的组合物和方法,其相关部分以引用方式结合于本发明。简单地说,采用吉兰糖胶和角叉菜胶的不含明胶的胶状糖膏剂,在不含明胶的胶状糖膏剂中提供坚硬、有弹性的、类似明胶的结构。可消耗的口胶也可包括本发明公开的益生细菌。
同样已知胃肠道微生物菌群的某些菌种,例如多形拟杆菌,产生可帮助物质消化的酶,例如β-联结的植物纤维,该纤维无法通过人体产生的正常消化酶降解。显然多形拟杆菌可以通过产生β-葡萄糖苷水解酶实现这一点。这些酶和其它物质看来可以通过接触特定多糖底物而被诱导产生。值得注意的是,报道表明这些酶中的一些是细胞外分泌的。一些近期研究也披露了多形拟杆菌在诱导宿主分子岩藻糖基化,刺激血管生成和诱导肠道内先天性免疫应答方面的作用。近期表明拟杆菌属的另一菌种脆弱拟杆菌可以产生一种细菌多糖(PSA),这种多糖可以引导小鼠免疫系统发育中的细胞成熟和身体成熟。这一点是非常重要的,因为拟杆菌属在肠道微生物菌群中定殖最早和数量最大。特别地,脆弱拟杆菌是定殖于哺乳动物下胃肠道的普遍存在且重要的革兰氏阴性厌氧微生物。
细菌菌种例如多形拟杆菌释放细胞外β-葡萄糖苷水解酶可以导致β-联结的多糖降解成更小的多糖,寡糖,简单单糖和二糖。实际上,已经证实了多形拟杆菌在采用落叶松阿拉伯半乳聚糖的连续培养物中的生长能力,落叶松阿拉伯半乳聚糖包括短,中和长链多糖。之后这些酶消化产物可提供给其它微生物吸收和利用或者通过肠道为人体所吸收。尽管某些微生物种类,例如肠杆菌和产乳酸细菌,对多糖的细胞内发酵已经得到了广泛的研究,然而很明显,通过细菌,例如多形拟杆菌,在人体胃肠道内进行细胞外酶消化的实际生物学重要性还未得到充分的探索。
肠球菌,一种乳酸菌,其在生态上多功能,能够耐受大范围的温度和pH条件。其定殖于人体小肠和大肠。在本研究中,最能竞争所有三种IPs的两种细菌种类粪肠球菌和屎肠球菌是常见的益生菌。人体益生菌补充研究已经证明两种细菌都能够刺激免疫系统。屎肠球菌也表现出减少血清胆固醇,降低炎症反应中有关细胞受体的表达。
益生元是刺激某些胃肠道微生物生长或活性的食品成分。市场上可以买到的益生元通常是植物来源的不能消化的多糖,其通过某些有益乳酸菌如双歧杆菌和乳酸杆菌经厌氧发酵代谢得以选择性的利用。通常利用的一些益生元包括菊粉,果糖寡聚体(FOS)和洋姜。
实施例1选择益生培养物用于促进在所选多糖底物上的生长
存在于人体胃肠道中的不同细菌菌种和菌株具有利用不同多糖底物的能力。例如,在对来自双歧杆菌属,消化链球菌属,乳杆菌属,瘤胃球菌属,粪球菌属,真细菌属和梭菌属的22种不同种的154个菌株的研究中,调查它们对21种不同复合碳水化合物的发酵能力。在研究中,常见食品多糖淀粉(直链淀粉)和支链淀粉可被绝大多数细菌菌株发酵。至少调查的22个种中7个种的一些菌株能够利用直链淀粉和/或支链淀粉。其它多糖,例如D-半乳糖胺,葡聚糖,刺梧桐树胶,岩藻多糖,藻酸盐,角叉菜胶,硫酸软骨素,透明质酸盐,肝素,卵类粘蛋白和牛下颚粘液,不能被任何测试的菌株发酵。调查中包括的其它多糖,葡糖胺,岩藻糖,木聚糖,落叶松阿拉伯半乳聚糖,瓜尔豆胶,槐树豆胶,阿拉伯树胶,茄替胶,黄蓍胶,果胶,聚半乳糖醛酸盐和昆布多糖选择性地被某些细菌菌株发酵,但不被另外的菌株发酵。这项研究表明从人体胃肠道中选择细菌菌株,通过发酵对所选多糖进行选择性处理是可能的。
培养食物例如经发酵的蔬菜,酸奶,开菲尔(kefir),衣梅尔(ymer),脱脂酸牛奶,laban,采用多种微生物生产食物以供人们食用。
很多种细菌和酵母都可以安全应用于这些食品的生产中。这些微生物安全应用于人类食品的历史很长,是筛查其将纯化的长链多糖化合物处理成较小的生物活性化合物能力的绝佳候选微生物,较小生物活性化合物例如较短多糖,寡糖,二糖和单糖。这一处理过程可设计在体内发生,其方式为通过将一种或多种此类微生物和天然多糖混合,以两种成分同时由人体或其它动物口服的形式进行。在此第一个例子中,微生物处理天然多糖将在通过胃肠道的过程中发生。或者,微生物和多糖可在一机械发酵装置中在受控物理条件下(即营养物,温度,氢离子浓度,氧化还原电位,氧可用度,水分活性,盐浓度等)中混合,孵育直到期望的最终目标产物(即可接受比例的较短多糖,寡糖,二糖和单糖)产生。
开菲尔粒是一种多种细菌和酵母的稳定混合培养物,其中发现的典型微生物包括:
●嗜酸乳杆菌
●短乳杆菌
●干酪乳杆菌
●乳酸乳杆菌
●植物乳杆菌
●副干酪乳杆菌
●纤维二糖乳杆菌
●德氏乳杆菌
●食果糖乳杆菌
●瑞士乳杆菌
●希氏乳杆菌
●开菲尔乳杆菌
●马乳酒样乳杆菌
●高加索奶粒乳杆菌
●类高加索酸奶乳杆菌
●乳酸乳球菌
●唾液链球菌
●嗜热链球菌
●乳链球菌
●耐久肠球菌
●乳脂明串珠菌
●肠膜明串珠菌
●醋酸醋杆菌
●rasens醋杆菌
●开菲尔假丝酵母
●拟热带假丝酵母
●恶臭假丝酵母
●纤细假丝酵母
●乳酸克鲁维斯酵母
●马克斯克鲁维酵母
●保加利亚克鲁维酵母
●脆壁克鲁维酵母
●开菲尔酵母
●酿酒酵母
●乳酸酵母
●卡氏酵母
●单孢酵母
●鲁氏酵母
●开菲尔圆酵母
●德尔布有孢圆酵母
●汉逊德巴利酵母
●鲁氏接合酵母
蔬菜和奶制品的发酵中采用的部分典型细菌包括:
●嗜酸乳杆菌
●保加利亚乳杆菌
●植物乳杆菌
●乳酸乳杆菌
●德氏乳杆菌
●赖氏乳杆菌
●唾液乳杆菌
●caret乳杆菌
●pentoaceticus乳杆菌
●短乳杆菌
●布氏乳杆菌
●纤维二糖乳杆菌
●混淆乳杆菌
●嗜粪乳杆菌
●发酵乳杆菌
●旧金山乳杆菌
●嗜热乳杆菌
●巴伐利亚乳杆菌
●干酪乳杆菌
●棒状乳杆菌
●弯曲乳杆菌
●植物乳杆菌
●清酒乳杆菌
●葡聚糖明串珠菌
●肠膜明串珠菌
●类肠膜明串珠菌
●屎肠球菌
●粪肠球菌
●乳酸片球菌
●有害片球菌
●戊糖片球菌
实施例2 促进益生微生物生长和多糖利用的其它试剂
除多糖外,加入在体内或体外促进有益细菌生长或抑制竞争细菌生长的其它试剂可能是有益的。
这些额外物质的例子可包括:
(1)抑制革兰氏阴性细菌的生长,而对如乳杆菌和双歧杆菌的革兰氏阳性细菌影响较小的选择性抗生素物质。
(2)抑制革兰氏阳性细菌的生长,而对如拟杆菌属的革兰氏阴性细菌影响较小的选择性抗生素物质。
(3)刺激益生细菌生长的物质,例如次烟煤腐殖质,这些物质已应用于动物饲料中,以刺激有益细菌的生长。
(4)改变生长系统pH条件以促进有益的、益生微生物的生长的物质,例如无机或有机酸和碱。
(5)改变生长系统氧化-还原条件的物质,例如具有化学还原电位的氢离子和/或其它化学物质,以促进有益厌氧微生物,例如拟杆菌、乳杆菌和双歧杆菌的生长。
实施例3用于选择和制备具备或不具备益生菌的益生菌处理的多糖的组合物和方法
多形拟杆菌
益生食品或膳食补充剂制剂,其含有天然多糖和多形拟杆菌活细胞。
益生食品或膳食补充剂制剂,其含有天然多糖和多形拟杆菌活细胞和刺激革兰氏阴性厌氧菌生长的所选生长促进剂。
采用多形拟杆菌生产细菌修饰的多糖、寡糖、二糖和单糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
采用多形拟杆菌生产细菌修饰的具有免疫活性的多糖和寡糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
脆弱拟杆菌
益生食品或膳食补充剂制剂,其含有天然多糖和脆弱拟杆菌活细胞。
益生食品或膳食补充剂制剂,其含有天然多糖和脆弱拟杆菌活细胞和刺激革兰氏阴性厌氧菌生长的所选生长促进剂。
采用脆弱拟杆菌生产细菌修饰的多糖、寡糖、二糖和单糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
采用脆弱拟杆菌生产细菌修饰的具有免疫活性的多糖和寡糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
长双歧杆菌
益生食品或膳食补充剂制剂,其含有天然多糖和长双歧杆菌活细胞。
益生食品或膳食补充剂制剂,其含有天然多糖和长双歧杆菌活细胞和刺激厌氧菌生长的所选生长促进剂。
采用长双歧杆菌生产细菌修饰的多糖、寡糖、二糖和单糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
采用长双歧杆菌生产细菌的修饰的具有免疫活性的多糖和寡糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
屎肠球菌
益生食品或膳食补充剂制剂,其包括天然多糖和屎肠球菌活细胞。
益生食品或膳食补充剂制剂,其包括天然多糖和屎肠球菌活细胞和刺激革兰氏阴性厌氧菌生长的所选生长促进剂。
采用屎肠球菌生产细菌修饰的多糖、寡糖、二糖和单糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
采用屎肠球菌生产细菌修饰的具有免疫活性的多糖和寡糖的方法,从而实现天然存在的多糖在封闭的生物反应器系统中的酶降解。
多种益生细菌
选择具有利用多糖能力的特定的、非病原性的处理食品的微生物来生产多糖、寡糖、二糖和单糖,微生物选自:乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属。多糖选自:葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶及其组合。
一种或多种多糖和非病原性的微生物活细胞的组合来生产益生膳食补充剂或食品,多糖选自:葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶。微生物种类选自:乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属
利用非病原性的微生物生产部分降解的多糖、寡糖、二糖和单糖的方法实现天然存在的多糖在封闭生物反应器中的酶降解。微生物种类选自:乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属。多糖选自:葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶
利用非病原性的微生物生产具有免疫活性的部分降解的多糖和寡糖的方法实现天然存在的多糖在封闭生物反应器中的酶降解。微生物种类选自:乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属。多糖选自:葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶。
一些已在人类历史中广泛熟悉的药用植物的益处可部分归功于它们的免疫调节多糖(IP)成分。例如,紫锥菊、人参和姜黄的免疫调节活性可部分归功于它们的阿拉伯半乳聚糖成分。芦荟内叶胶中的多糖,特别是乙酰甘露聚糖,也是有效的免疫调节物质。以下为本发明一个实施方式的例子。
在体外,免疫调节多糖(IPs)能够活化巨噬细胞,刺激T细胞和B细胞的增殖,抑制补体活性,调节细胞因子释放和刺激肠道免疫系统。具有更高分子量(MW)的多糖的免疫调节作用更为有效。口服摄入后,IPs可用于癌症患者延长生存期,改善生活质量的辅助治疗。当被摄入时,复合植物多糖(CPPs)通常大部分保持完整地进入肠道,之后在肠道中可被肠道复合微生物菌群降解到不同程度。因而这些物质可以影响细菌菌群的组成和密度,产生单糖、短链脂肪酸、CPP片段和代谢物,以及气体。之后,这些CPP降解产物能够影响胃肠道免疫系统,并被吸收或排泄。下述体外证据阐明了人体结肠细菌对配制来支持免疫系统的混合糖类膳食补充剂(MSS)的利用及其两种CPP组分:阿拉伯半乳聚糖(LAG)和高分子量芦荟内叶胶多糖(AVP)。这一证据选择了最能竞争CPPs的作为能源和作为生产更多细菌的材料的结肠细菌。
以下制剂为本发明所用的有代表性的多糖。
称出的CPPs(落叶松阿拉伯半乳聚糖)样品;高分子量的芦荟内叶胶多糖;混合糖类膳食补充剂(AdvancedAmbrotoseTM,其包括LAG,AVP,阔叶榆绿木树干胶,西黄芪树干胶,葡糖胺HC1和裙带菜提取物),以上成分在轨道振荡器上充分混合于去离子水中,轨道振荡器速度为200rpm,混合4小时。得到悬浮液为7.63-7.9g/L。之后每100ml悬浮液以体积约10L去离子水在4℃下,6000-8000MWCO管中透析20小时。在这20个小时内,更换两次去离子水。透析得到的样品在冻干之前首先在0℃下冷冻1小时。
粪便样本由4个健康人提供。选择受试者时要求年龄低于45岁,全部膳食包括少于25%的快餐,在过去12个月中没有使用抗生素,在过去5年中没有胃肠道问题,没有不规律的肠运动,没有因便秘、胃或肠绞痛或腹泻使用OTC药物,在过去6个月中未食物中毒且不担心生病。粪便样本确认不含下述病原体:艰难梭状芽胞杆菌,沙门氏菌属,志贺氏菌属,弯曲杆菌属,弧菌,耶尔森氏菌属和大肠杆菌O157。将10克粪便样本与750ml脑心浸液混合,在混合器中混合4个30秒脉冲,然后37℃下孵育6个小时。1ml等分试样在使用前储存于80摄氏度的20%甘油中。实验当天,将试样在温水中迅速解冻,之后加到2ml厌氧E培养基中(0.2%w/v柠檬酸,1%w/vK2HPO4,0.35%w/v NaNH4HPO4·4H2O和0.002%w/v MgSO4·7H2O),在加到含CPPs的E培养基上之前孵育48个小时。CPPs在去离子水中搅拌悬浮2小时,然后加入到厌氧E培养基中,使其最终组成达到1%w/v。在厌氧条件下,将20μl粪便悬浮液加到2ml含CPP的E培养基悬浮液中,在厌氧条件下(CO2充气包)37℃下孵育3天。引入由加入到没有CPP的E培养基中的粪便悬浮液组成的一个对照例组,用来评估CPPs在E培养基中的作用,另一在E培养基中含有CPPs的对照例组在培养条件下孵育9天。孵育3天后(即第3天),将20μl培养物加入到含2ml新鲜CPP的E培养基中。第6天再次重复此操作。在9天末,离心收集细菌,并在干冰-乙醇浆中速冻。保留上清,通过HPLC折射检测评估其化学组成。两个对照例组除了不接种粪便外,以同样方式处理。第九天收集细菌并进行16s rDNA鉴定。
采用16s rDNA测序进行细菌鉴定。在第九天,将样本在细菌生长培养板上划线以分离细菌。采用的培养基为:1)DifcoTM乳杆菌MRS琼脂,2)含NNLP(萘啶酸,新霉素,氯化锂,硫酸巴龙霉素)的双歧杆菌MRS,3)含4%NaCl的MRS,4)含2%胆汁盐的MRS,5)pH 5.2的MRS。从4份粪便培养物的传代物中总共选择了57个分离菌株。使用BactReady试剂盒(GenScript;Piscataway,NJ)根据厂商说明从分离菌株中提取DNA。采用TaKaRa SpeedSTAR HS DNA聚合酶试剂和16S rDNA扩增通用引物对纯化DNA进行PCR扩增。通用引物序列:正向F8-5′-AGAGTTTGATCCTGGCTCAG-3′(SEQ ID NO:1)和反向R1492-5′-GGTTACCTTGTTACGACTT-3′(SEQ ID NO:2)。PCR扩增条件为94℃15分钟;94℃40秒,60℃30秒,72℃2分钟,进行35个循环,然后4℃保温。取2μl产物在2%琼脂糖E-凝胶上跑胶确认纯度。采用Alpha Biolabs对扩增产物进行测序。所得序列进行BLAST搜索,并报告最佳匹配。采用试剂盒按照厂商说明对每一个分离菌株进行生化检测革兰氏染色。经分离的菌落在含有5%绵羊血琼脂的DifcoTM、胰酶大豆琼脂板上生长确定其溶血情况。采用氧化酶试剂根据厂商的说明确定氧化酶的产生。根据分离菌株在过氧化氢中产生气泡的能力确定过氧化氢酶的产生。采用API Strep或API20E试纸条根据厂商说明对鉴定结果进行确认。
细菌上清液的化学分析。室温下解冻上清液,加入去离子水,使用0.2μm聚丙烯Mini UniPrepTM过滤器过滤,之后进行HPLC分析。基于分子大小分离,采用BioSep-SEC-S-4000柱HPLC进行评估。将5000;10000和800000聚麦芽三糖分子量标准品加入去离子水中(约1mg/ml),HPLC分析以确定CPP透析已经将较小的糖(<6000分子量)去除,以便能够进行CPPs分子量和上清液的估算(附图1)。附图1为标准分子量为5000,10000和800000的聚麦芽三糖的HPLC保留时间图,其中y轴为分子量,x轴为以分钟计的保留时间。
结果。细菌。测序分析得到了肠球菌属52株分离菌株,大肠杆菌4株分离菌株和克雷伯氏肺炎杆菌1株分离菌株。序列分析在所有分离菌株属水平上和40株分离菌株种水平上都有置信度(>93%)。采用市场上可买到的API测试条和常规微生物检测方法进行生化分析,获得了细菌种别和表性特征的进一步鉴定和确认。序列鉴定、革兰氏染色、氧化酶和过氧化氢酶结果用于确定适合的API测试条,肠球菌采用API 20Strep,肠分离菌株采用API20E。采用API数据库对得到的试纸条信息进行评估,产生的鉴定结果得以确认(表1)。
下面的表1表示从粪便样品中培养得到的,在特定CPP培养基中生长的肠球菌种分离菌株的生化特征。每一个验证的结果由阳性百分比值表示。
表1 肠球菌种分离菌株的生化特征
肠球菌为屎肠球菌(46),粪肠球菌(2),耐久肠球菌(1)和鸟肠球菌(2)。根据以前发表的资料,所有分离得到的肠球菌种都为革兰氏阳性,过氧化氢酶阴性,氧化酶阴性和七叶苷水解阳性。52株分离菌株中只有5株在含血琼脂上为β溶血。100%的屎肠球菌和耐久肠球菌以及50%的粪肠球菌为β-半乳糖苷酶阳性,该酶对阿拉伯半乳聚糖水解是必需的。100%的屎肠球菌和50%的粪肠球菌能够发酵阿拉伯糖,这是阿拉伯半乳聚糖中一种主要的单糖。耐久肠球菌不能发酵阿拉伯糖。
大肠杆菌分离菌株(4)只在采用LAG的培养物中发现。从AVP培养物中发现了单独一株克雷伯氏肺炎杆菌分离菌株。下面的表2显示从大肠杆菌和克雷伯氏肺炎杆菌中得到的代谢分析结果。这些肠道细菌为过氧化氢酶阳性和氧化酶阴性的革兰氏阴性杆菌。只有一株大肠杆菌分离菌株被确认为β溶血。
下面的表2列出了从粪便样品中分离得到的肠道细菌,在CPP培养基上生长的生化特征。每一数值由阳性百分比表示。
表2 肠道细菌的生化特征
上清液。相对于在和细菌培养物所用条件相同的条件下孵育了9天的对照,所有分子量范围的CPPs都有明显的减少。然而,减少情况有不同,且取决于CPP和粪便样品。所有4位受试者的粪便培养物消耗的800,000到大约12,000分子量范围之间的LAG聚合物完全相等,然而小于12,000分子量的聚合物消耗量不同(附图2)。附图2显示了和4位受试者的人体结肠细菌孵育72小时后的落叶松阿拉伯半乳聚糖(LAG)终产物的示意图。LAG对照(实线)采用没有结肠细菌的操作程序。y轴为mRIU,x轴为以分钟计的保留时间。
约1,000,000和约50000分子量之间的AVP聚合成分几乎被来自所有受试者的粪便细菌完全消耗,尽管存在一些变化,尤其是在1,000,000分子量范围。小于10,000的聚合物以一种高度可变方式被不同粪便培养物消耗(附图3)。附图3显示了和4位受试者的人体结肠细菌孵育72小时后的芦荟胶多糖(AVP)终产物。AVP对照(实线)采用没有结肠细菌的操作程序。y轴为mRIU,x轴为以分钟计的保留时间。
约1,000,000的MSS聚合成分没有被消耗,但是800,000到1,000,000分子量之间的聚合物被用MSS选择出的不同培养物以不同程度消耗。令人感兴趣的是,在三个受试者中,MSS粪便培养物的降解,但非AVP或LAG,导致~1,000分子量的小分子量聚合物的积累,而在对照MSS中并未发现,这表明输出了将母体分子剪切为CPPs小部分的糖苷酶(附图4)。附图4显示了和4位受试者的人体结肠细菌孵育72小时后的混合糖类补充剂(MSS)终产品。
讨论。据认为人体肠道微生物菌群包括500~1000个种,生物量约占1.5kg。人体胃肠道体内多糖的细菌利用无疑是一个高度复杂的过程。聚合物降解是利用来自参与这个过程许多不同细菌的酶的协作活动。在这里,粪便细菌重复传代到只含CPPs作为可用碳源的新鲜培养基中,这一过程选出了最能够比较和利用CPPs的细菌。能够有效利用这些糖的细菌将比其它利用效率较低的菌种分裂产生更多的后代。经过一段时间后,这些菌种将在培养物中占优。这是表明肠球菌种利用LAG的首次证明(表1)。
尽管在受试者降解较低分子量(~10,000)部分(附图2,箭头)的能力存在不同,但是LAG被所有受试者不完全降解。同时已经表明口服芦荟胶能够改善肠功能,这是表明芦荟胶多糖被人体结肠细菌利用的首次证明。就利用AVP高分子量(>1,000,000)组分(附图3,箭头)的能力而言,发现在个体之间存在更大的差异。对溶解度有限的非常大的分子的消耗表明肠球菌菌种可以利用这些大分子。有多种途径可被采用,包括将大的CPP穗内化,然后降解成较小成分。另一途径为有些细菌分泌糖苷酶,引起大分子降解成分子量较小的组分。最后,应用可以包括这些过程的结合。已知粪肠球菌编码21种糖苷水解酶。这是人体结肠细菌利用这种混合糖膳食补充剂(MSS)的首次证明。惊人的例证是用MSS培养屎肠球菌引起上清液中大量产生相对小(~1,000)的聚合物(附图4,箭头)。因为MSS对照>5,000,较小分子量物质的产生应该来自于较大分子的降解。这种情况的发生可能源于由屎肠球菌输出到上清液的酶降解大分子,或者源于细菌本身分泌的小聚合物。相当令人惊奇的是,这一现象在单独的LAG或AVP情况下并未观察到。拟杆菌和双歧杆菌菌种为主要菌种,但在该系统的最低阶段肠球菌菌种的量增加。对MSS其它成分的人体结肠降解进行了研究。其它人研究了对来自裙带菜的纯化纤维(α和β-链接的岩藻多糖硫酸酯)和全部海藻纤维(α和β-链接的藻酸盐)的人体体外发酵。纯化的岩藻多糖硫酸酯没有降解。47%-62%的藻酸盐被完全代谢成短链呋喃酸(fury acids)。其它人得出结论,60%的藻酸盐看起来经“不寻常且未知的”发酵途径降解。
肠球菌在生态上有多种功能,能够耐受范围广泛的温度和pH条件。其定殖于人体小肠和大肠。最能竞争三种CPPs的两种细菌,粪肠球菌和屎肠球菌是常见益生菌。人体益生菌补充研究已经证明两种细菌都能够刺激免疫系统。也已经表明补充屎肠球菌可减少血清胆固醇,降低炎症反应中有关细胞受体的表达。肠道中大于99.9%的可培养细菌种群为专性厌氧菌,估计存在于胃肠道中的细菌有80%无法在任何条件下培养。在我们的9天培养物中存在的细菌菌种代表了相对少量的能够利用这些CPPs的菌种;一些菌种可能容易地在体内利用CPPs,但是无法通过采用如本发明使用的方法得以鉴定。
这一证明首次表明人体胃肠道细菌对来自芦荟胶和混合糖膳食补充剂的免疫调节多糖的利用。相对本研究采用的其它菌种,肠球菌菌种利用CPPs效率更高,使其在重复传代之后在培养物中占优势地位。CPP终产物的分子量分析表明从不同个体获得的细菌生物群系在利用CPP能力上不同。在体内,受试者能够完全降解高分子量AVP组分;较低分子量组分的消耗有差异。用MSS培养结肠细菌,引起相对小的聚合物(~1,000)大量产生,这一现象并未在MSS的两个主要成分LAG或AVP存在的情况下观察到。采用本发明也可以以更接近体内胃肠道的系统对这些或其它CPPs进行研究。
可以预计本说明书讨论的任何实施方式都可以以本发明的任何方法、试剂盒、试剂或组合物得以实现,反过来亦然。此外,本发明的组合物能够用于实现本发明的方法。
应该理解本发明所述具体实施方式是用于说明而非限制本发明。本发明的主要特征可应用于多种实施方式而不会脱离本发明的范围。本领域技术人员仅仅采用常规的实验方法将认可或能够确定本发明所述特定程序的众多等同物。这些等同物被认为存在于本发明的范围内且包括在权利要求中。
本说明书提及的所有出版物和专利申请表示了本发明所属技术领域的技术人员的水平。所有出版物和专利申请以引用的方式结合于本发明中,其程度就如同每一单独出版物或专利申请被特别地和单独地指出以引用方式结合一样。
在权利要求书和/或说明书中,“a”、“an”在和术语“包含”联合使用时,可能意为“一个”,但其也和“一个或多个”,“至少一个”和“一个或一个以上”的意思相一致。术语“或”在权利要求书的用来表示“和/或”,除非明确指出用于指代单独的可供选择项或者相互排除的可供选择项,尽管公开的内容支持指代单独的可供选择项和“和/或”的定义。整篇申请中,术语“约”用来说明一个数值包含用于确定该数值采用的设备和方法的误差的固有变化,或者存在于研究受试者中的变化。
当用于说明书和权利要求书中,词语“包含(comprising)”(和包含的任何形式,如“comprise”和“comprises”),“具有(having)”(和具有的任何形式,如“have”和“has”),“包括(including)”(和包括的任何形式,如“include”和“includes”)或“包含(containing)”(和包含的任何形式,如“contains”和“contain”)是包含性的或开放式的,而不排除其它的、未叙述的要素或方法步骤。
本发明使用的词语“或其组合”是指在该术语之前所列出项的所有排列和组合。例如,“A、B、C或其组合”意为包括A、B、C、AB、AC、BC或ABC中的至少一种,而且如果在特定上下文中顺序重要时,还包括BA、CA、CB、CBA、BCA、ACB、BAC或CAB。继续此例,还明确包括含有一个或多个项或术语的重复,例如BB、AAA、MB、BBC、AAABCCCC、CBBAAA、CABABB等等的组合。技术人员能够理解,有代表性地,在任何组合中的项或术语中数目没有限制,除非在上下文中可明显看出不是这样的。
按照本发明公开的内容,本发明公开的和要求保护的所有组合物和/或方法都能够制备和实施,而不需要过度实验。尽管本发明的组合物和方法已经以优选的实施方式加以描述,然而本发明描述的组合物和/或方法、方法的步骤或步骤顺序可以进行变化,而不会脱离本发明的概念、精神和范围,这一点对于本领域技术人员是显而易见的。如所附权利要求书中所定义的,所有这种对本领域技术人员来说显而易见的类似替代和修饰视为处在本发明的精神、范围和概念之内。
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序列表
<110>曼纳泰克公司
<120>通过所选的非病原性微生物处理天然多糖及其制备和使用方法
<130>FIC09210139P
<150>US 60/917,339
<151>2007-05-11
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<170>PatentIn version 3.4
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<213>人工序列
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<223>化学合成的寡核苷酸
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Claims (35)
1.一种膳食补充剂,其包含:
由一种或多种天然多糖制造的补充剂,天然多糖事先和益生细菌在生物反应器系统中孵育,其中细菌处理多糖,将产生的处理过的多糖以营养补充剂提供。
2.权利要求1所述的补充剂,其中所述来自生物反应器的处理过的多糖被制成食品或膳食补充剂。
3.权利要求1所述的补充剂,其中所述处理过的多糖被制成单一剂型。
4.权利要求1所述的补充剂,其中所述多糖包含葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。
5.权利要求1所述所述的补充剂,其中所述多糖包含来自芦荟的乙酰甘露聚糖。
6.权利要求1所述的补充剂,其中所述多糖和益生细菌以单一剂型分别提供。
7.权利要求1所述的补充剂,其中所述多糖和益生细菌在生物反应器中孵育。
8.权利要求1所述的补充剂,其中所述多糖和益生细菌以缓释形式提供。
9.权利要求1所述的补充剂,其中所述多糖为杂多糖、同多糖,或杂多糖和同多糖。
10.权利要求1所述的补充剂,其中将多糖与微生物细胞分离,分离的多糖装载到选自粉末、胶囊、胶囊锭、片剂、泡腾片、液体或口胶的剂型中。
11.一种益生食品或膳食补充剂制剂,其包含一种或多种天然多糖和乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种的微生物活细胞。
12.权利要求11所述的制剂,其中所述多糖包含葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。
13.权利要求11所述的制剂,其中所述多糖包含来自芦荟的乙酰甘露聚糖。
14.权利要求11所述的制剂,其中所述多糖和微生物活细胞以单一剂型分别提供。
15.权利要求11所述的制剂,其中所述多糖和微生物活细胞在生物反应器中孵育。
16.权利要求11所述的制剂,其中所述多糖和微生物活细胞以缓释形式提供。
17.权利要求11所述的制剂,其中所述多糖为杂多糖、同多糖,或杂多糖和同多糖。
18.一种单一剂型的膳食补充剂,其包含天然多糖和非病原性的益生微生物菌种。
19.权利要求18所述的膳食补充剂,其中所述天然多糖和非病原性的益生微生物菌种同时提供进入人体胃肠道。
20.权利要求18所述的膳食补充剂,其中所述非病原性的益生微生物菌种对天然多糖的处理在人体胃肠道范围内完成。
21.权利要求18所述的膳食补充剂,其中所述微生物细胞包含乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种。
22.权利要求18所述的膳食补充剂,其中所述多糖包含葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。
23.权利要求18所述的膳食补充剂,其中所述多糖包含来自芦荟的乙酰甘露聚糖。
24.一种膳食补充剂,其包含非病原性的益生微生物菌种在生物反应器中对所选天然多糖进行处理所得到的提取物。
25.一种制备膳食补充剂的方法,包含:
在生物反应器系统中将一种或多种天然多糖与益生细菌混合,混合是在刺激细菌处理天然多糖以制备处理过的多糖的条件下进行;和
在至少部分天然多糖已被细菌处理后制备膳食补充剂。
26.权利要求25所述的方法,其中所述细菌处理多糖,产生的处理过的多糖被制成单一剂型的营养补充剂。
27.权利要求25所述的方法,进一步包含以下步骤:
从天然多糖和细菌中分离处理过的多糖;和制备包含处理过的多糖的剂型。
28.权利要求25所述的方法,进一步包含制备包含处理过的多糖、天然多糖和细菌的剂型的步骤。
29.权利要求25所述的方法,进一步包含将处理过的多糖装载到选自粉末、胶囊、胶囊锭、片剂、泡腾片、液体或口胶的剂型中。
30.权利要求25的方法,其中所述细菌包含乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种。
31.权利要求25所述的方法,其中所述天然多糖包含葡甘露聚糖,芦荟葡甘露聚糖,魔芋葡甘露聚糖,半乳甘露聚糖,阿拉伯半乳聚糖,落叶松阿拉伯半乳聚糖,海藻多糖,岩藻多糖,真菌多糖,真菌葡甘露聚糖,黄蓍胶,茄替胶,黄原胶,瓜尔豆胶和阿拉伯树胶中的至少一种。
32.权利要求25所述的方法,其中所述天然多糖包含来自芦荟的乙酰甘露聚糖。
33.权利要求25所述的方法,其中将处理过的多糖与细菌分离,并将处理过的多糖装载到选自粉末、胶囊、胶囊锭、片剂、泡腾片、液体或口胶的剂型中。
34.一种膳食补充剂或食品,其包含:
和益生细菌在生物反应器或发酵罐系统中孵育的处理过的芦荟内叶胶,其中细菌将芦荟内叶胶处理成生物可利用的产品。
35.权利要求34所述的产品,其中所述益生细菌包含选自乳杆菌属,乳球菌属,链球菌属,肠球菌属,嗜柠檬酸明串球菌属,醋酸杆菌属,假丝酵母属,克鲁维酵母属,酵母属,圆酵母属,有孢圆酵母属,德巴利氏酵母属,接合酵母属,拟杆菌属,杆菌属,双歧杆菌属,真细菌属,消化链球菌属,瘤胃球菌属和片球菌属中的至少一种的细菌。
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CN111885922A (zh) * | 2018-03-16 | 2020-11-03 | 味之素株式会社 | 饲料用添加剂及饲料 |
CN111820419A (zh) * | 2020-07-24 | 2020-10-27 | 中国海洋大学 | 靶向调控肠道艾克曼菌和短链脂肪酸产生菌的组合物 |
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CN112501049A (zh) * | 2020-10-28 | 2021-03-16 | 石河子大学 | 产转糖基活性β-半乳糖苷酶的开菲尔乳杆菌及制备的β-半乳糖苷酶生产低聚半乳糖的方法 |
CN112501049B (zh) * | 2020-10-28 | 2022-04-19 | 石河子大学 | 产转糖基活性β-半乳糖苷酶的开菲尔乳杆菌及制备的β-半乳糖苷酶生产低聚半乳糖的方法 |
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KR101493302B1 (ko) | 2015-02-13 |
US20080286252A1 (en) | 2008-11-20 |
EP2155768A4 (en) | 2014-02-19 |
KR20100017731A (ko) | 2010-02-16 |
EP2155768A1 (en) | 2010-02-24 |
AR066900A1 (es) | 2009-09-23 |
US20170173067A1 (en) | 2017-06-22 |
EP2155768B1 (en) | 2017-05-03 |
ZA200908063B (en) | 2010-09-29 |
US9855288B2 (en) | 2018-01-02 |
MX2009012140A (es) | 2009-12-11 |
NZ581043A (en) | 2011-11-25 |
BRPI0811131A2 (pt) | 2014-12-23 |
EP3170410A3 (en) | 2017-06-21 |
JP2010526539A (ja) | 2010-08-05 |
US9415056B2 (en) | 2016-08-16 |
AU2008251346B2 (en) | 2012-11-22 |
WO2008141240A1 (en) | 2008-11-20 |
CA2687083A1 (en) | 2008-11-20 |
AU2008251346A1 (en) | 2008-11-20 |
US10117884B2 (en) | 2018-11-06 |
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EP3170410A2 (en) | 2017-05-24 |
US20150306121A1 (en) | 2015-10-29 |
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