CN112805010A - 用于治疗患有甲基丙二酸血症和丙酸血症的患者的膳食纤维 - Google Patents
用于治疗患有甲基丙二酸血症和丙酸血症的患者的膳食纤维 Download PDFInfo
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Abstract
本发明涉及一种包含膳食纤维的组合物,其用于甲基丙二酸血症(MMA)和/或丙酸血症(PA)的膳食管理,以及/或者用于治疗和/或减轻MMA和/或PA,以及/或者治疗、减轻和/或预防与之相关的症状。
Description
技术领域
本发明涉及甲基丙二酸血症(MMA)和丙酸血症(PA)的膳食管理领域,并涉及用于治疗与之相关的症状的领域。
背景技术
有机酸尿症(OA)患者患有罕见的先天性代谢缺陷。OA中最大的病症是甲基丙二酸血症(MMA)和丙酸血症(PA)。两种病症有共同的生化和临床特征:分别由于丙酰辅酶A羧化酶或甲基丙二酰辅酶A变位酶的缺乏,导致丙酰辅酶A和/或甲基丙二酸(MMA)和其他代谢产物的积累。PA和MMA的最初症状包括进食不良、呕吐、食欲不振、肌张力弱(张力减退)和精力不足(嗜睡)。这些症状有时会发展为更严重的医学问题,包括心脏异常(心肌病)、胰腺炎、癫痫发作(seizures)、昏迷甚至可能死亡。
丙酸是丙酰辅酶A的前体。人体内丙酸的产生源于肠道中膳食纤维的氨基酸代谢、奇数链脂肪酸代谢和厌氧细菌发酵。除乙酸和丁酸外,丙酸是由微生物群在肠道中产生的主要短链脂肪酸(SCFA)之一。来自健康成年人的大部分肠道共生体(commensal)携带三种已知产生丙酸的代谢途径中至少一种的基因。即使决定在任何给定的人类肠道中哪些途径有效的因素尚不清楚,差异途径的活性也可能会对肠道菌群的功能产生影响。换言之,任何主要SCFA(例如丙酸)产生中的任何变化都可能会对微生物群所使用的底物和微生物群作为整体性实体(collective entity)所产生的代谢产物产生影响。不同的丙酸产生(或合成)途径将对整体SCFA产生潜力(不仅是丙酸本身的产生潜力)产生不同的影响。据估计,MMA和PA患者中的总丙酸的至少25%源于肠道细菌,尽管这由于目前MMA和PA患者的微生物群几乎没有被表征而可能被低估。
纤维是正常饮食的组成部分,并被广泛认为是健康营养的重要组成部分。有许多不同类型的纤维,其通常被分类为可溶的或不可溶的,并且可以进一步被分类为可发酵的、不可发酵的或难发酵的。已表明纤维对肠道健康具有许多有益的作用,包括改善大便稠度、使肠道转运时间正常化、产生短链脂肪酸以及恢复平衡的肠道菌群组成。并非所有类型的纤维都具有相同的定性或定量作用。通过消耗各种纤维来源可以最好地获得纤维对健康的全方位益处。可发酵的纤维对于产生短链脂肪酸和恢复平衡的微生物群是重要的。发酵较差的纤维会增加大便体积、稠度和粘度,并可能有助于减少细菌移位。
尽管由于可发酵的纤维增加了大肠中短链脂肪酸的水平,他们被认为是有益的,但对于MMA和PA患者而言,这种增加可能是不利的,因为丙酸的水平可能会因此而增加。
目前所使用的用于MMA和PA患者的现有技术营养产品通常含有未优化用于治疗MMA和PA患者的膳食纤维,因为当存在的纤维被肠道菌群发酵时,仍然产生大量的丙酸。MMA/PA Next和MMA/PAjunior包含消化的纤维混合物以促进消化健康;纤维混合物包括低聚果糖、菊粉、阿拉伯胶、纤维素、大豆多糖和抗性淀粉。产品包含无甲硫氨酸、无苏氨酸和无缬氨酸且低异亮氨酸的氨基酸组合物。两种MMA/PA Anamix产品均面向MMA/PA患者销售。
Knol等人(J.Pediatr.Gastroenteral Nutr.,vol 40(1),2005年1月)证明了包含以9:1比例的GOS/FOS的婴儿配方物能够降低7至8周龄婴儿的粪便中丙酸与短链脂肪酸的比例。该出版物未提及产生的SCFA总量。一般而言,膳食纤维消化的结果无法从婴儿推断至较大年龄的受试者。与婴儿相比,较大年龄的受试者具有完全不同的微生物组(Edwards和Parrett;Brit.J.Nutr.2002,88:Suppl.1,S11-S18)。这种差异通常归因于肠道的自然发育、变化的营养模式以及在某些情况下例如疾病和使用抗生素的事件。青春期期间的激素变化也可能进一步影响微生物组。据信,微生物组的最大变化发生在0至3岁。
Venkatamaran等人(Microbiome(2016),4:33)证明了抗性淀粉(2型)对年轻人大便中的丙酸无显著影响。
本发明的目的是改善针对MMA和PA患者的已知纤维组合物,以通过发酵产物(例如乳酸和丁酸)来优化纤维的总体健康作用,并且同时限制当由肠道菌群发酵时丙酸的产生。
发明内容
发明人发现某些纤维和纤维混合物能够调节丙酸的产生,这在MMA和PA患者的临床特征中发挥重要作用,因此也改善了这些患者的胃肠道并发症。发明人发现,即使当增加短链脂肪酸的总量时,也可以减少丙酸的产生。因此,MMA和PA患者可以从本发明的膳食纤维混合物的益处中受益,同时降低丙酸的水平并因此改善他们的病症。发明人还出乎意料地证明了这些益处也出现在成年人人群中。
实例表明,低聚半乳糖(GOS)或包含GOS的纤维混合物导致微生物组所产生的丙酸低于预期。这些纤维的SCFA总量也增加。此外,发明人出乎意料地发现,当将GOS与抗性淀粉结合时,丙酸的水平可以被进一步降低,而现有技术报道抗性淀粉对丙酸形成无影响。
优选实施方案列表
1.包含低聚半乳糖的组合物,其在年龄至少为3岁的人类受试者中用于:
-治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状;
-MMA和/或PA的膳食管理;以及/或者
-减少肠道菌群引起的丙酸产生。
2.根据实施方案1所述的用于所述用途的组合物,其中所述受试者的年龄至少为12岁,优选至少为18岁。
3.根据前述实施方案中任一项所述的用于所述用途的组合物,其中所述组合物还包含抗性淀粉。
4.根据前述实施方案中任一项所述的用于所述用途的组合物,其中所述组合物还包含阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种。
5.包含低聚半乳糖、抗性淀粉、阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种的组合物,其在患有MMA或PA的患者中用于:
-治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状;
-MMA和/或PA的膳食管理;以及/或者
-减少肠道菌群引起的丙酸产生。
6.根据实施方案1-5中任一项所述的用于所述用途的组合物,其中所述组合物包含至少10重量%,优选至少20重量%,最优选至少30重量%的抗性淀粉,基于膳食纤维总重量计。
7.根据实施方案1-6中任一项所述的用于所述用途的组合物,其中所述组合物包含至少20重量%,优选至少30重量%,最优选至少50重量%的抗性淀粉和低聚半乳糖的组合,基于膳食纤维总重量计。
8.根据实施方案1-7中任一项所述的用于所述用途的组合物,其中所述组合物还包含产乳酸菌,其优选选自双歧杆菌属(Bifidobacteria)和乳杆菌属(Lactobacilli)。
9.根据实施方案1-8中任一项所述的用于所述用途的组合物,其中所述组合物还包含瓜尔胶。
10.根据实施方案1-9中任一项所述的用于所述用途的组合物,其中所述组合物包含小于5重量%的纤维素,基于膳食纤维总重量计,优选所述组合物不包含纤维素。
11.根据实施方案1-10中任一项所述的用于所述用途的组合物,其中所述组合物为以下形式:
(i)营养补充剂,优选其中补充剂还包含氨基酸;或者
(ii)全(complete)营养组合物,其中营养组合物还包含蛋白质部分、可消化碳水化合物、维生素和矿物质,优选所述蛋白质部分以氨基酸的形式。
12.根据实施方案1-11中任一项所述的用于所述用途的组合物,其中所述组合物还包含基本上由游离氨基酸和二肽组成的蛋白质部分,优选其中所述蛋白质部分基本上不含缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸。
13.根据实施方案1-12中任一项所述的用于所述用途的组合物,其中所述组合物包含DHA。
14.根据实施方案1-13中任一项所述的用于所述用途的组合物,其中所述组合物包含维生素D和/或钙,优选维生素D。
16.组合物,其包含低聚半乳糖、抗性淀粉、阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种。
17.根据实施方案16的组合物,其中GOS的量为组合物中膳食纤维的至少5重量%,并且抗性淀粉为组合物中膳食纤维的至少10重量%,优选至少20重量%,最优选至少30重量%。
18.根据实施方案16或17的组合物,其中所述组合物包含小于5重量%的纤维素,基于膳食纤维总重量计,优选其中所述组合物不包含纤维素。
具体实施方式
本发明涉及一种包含膳食纤维的组合物,其适合于患有甲基丙二酸血症(MMA)和/或丙酸血症(PA)的患者的膳食管理,以及用于治疗和/或减轻甲基丙二酸血症(MMA)或丙酸血症(PA)以及/或者治疗、减轻和/或预防与之相关的症状,以及用于减少肠道菌群引起的丙酸产生,同时保持/增加其他短链脂肪酸的产生。在这方面要使用的组合物称为本发明的组合物,并且在下文中详细定义。
组合物
本发明的组合物包含至少一种膳食纤维并且可包含如下文所定义的其他组分。在优选的实施方案中,组合物还包含蛋白质源,该蛋白质源由专门设计的游离氨基酸的共混物或二肽组成。该氨基酸组合物是具体选择的氨基酸的混合物,可支持MMA/PA患者的生长,并同时支持所选膳食纤维在减少丙酸产生中的作用。
本发明的组合物也可称为营养组合物。组合物可以采用提供膳食纤维的补充剂形式,除常规饮食外,该膳食纤维还可以施用至患者。如果本发明的组合物为补充剂形式,则其包含膳食纤维,并且优选包含氨基酸的共混物。补充剂也可称为膳食补充剂或营养补充剂,并且可以采用本领域已知的任何形式,包括片剂、胶囊剂、(可重构的)粉剂、液体等。组合物也可以采用全营养组合物的形式,其可以代替一餐或多餐施用至患者。如果本发明的组合物为全营养组合物形式,则其包含膳食纤维、蛋白质物质、可消化碳水化合物、维生素和矿物质。优选全营养组合物采用液体形式或旨在用液体重构的粉剂形式。在一个实施方案中,组合物为补充剂。在一个实施方案中,组合物为全营养组合物。在一个实施方案中,组合物为液体形式。本发明的组合物旨在用于患有MMA和/或PA的患者,并且由于这些患者习惯于特殊饮食来应对他们的疾病,因此本发明的组合物的施用易于以他们的日常进食方式进行。
下文对组合物进行进一步定义。在本文中,术语“约”表示+/-10%的范围。
受试者
当提到患者或受试者时,它涉及人类患者或受试者。
在本发明的上下文中,婴儿是0至1岁的受试者,幼儿是1至3岁的受试者,儿童是3至12岁的受试者,青少年是12至18岁的受试者,成年人是大于18岁的受试者。优选患者大于1岁,更优选3岁,甚至更优选12岁,甚至更优选14岁,最优选18岁。优选患者是婴儿、幼儿、儿童、青少年或成年人。
在生命的第一年末,婴儿具有各自独特的微生物特性,其趋向于成年人的典型微生物群,使得在2-5岁的年龄,就组成和多样性而言,其微生物群完全类似于成年人的微生物群。因此,生命的前3年是进行膳食干预以改善生长和发育的最关键时期。这是建立肠道菌群(对健康和神经发育至关重要的资产)的时期,在此期间,肠道菌群的改变有可能会深刻影响宿主的健康和发育。参考Rodriguez等人“The composition of the gutmicrobiota throughout life,with an emphasis on early life”Microb.Ecol.HealthDis.(2015);26。这些发现与儿童、青少年或成年人特别相关;甚至更优选患者为青少年或成年人,最优选患者为成年人。
膳食纤维
本发明的组合物包含膳食纤维,该术语还包含膳食纤维的混合物。在本发明的一个实施方案中,膳食纤维包含低聚半乳糖。在本发明的另一个实施方案中,膳食纤维包含低聚半乳糖和抗性淀粉的混合物。在另一个实施方案中,膳食纤维为低聚半乳糖、抗性淀粉和其他纤维的混合物。发明人出乎意料地发现本发明的膳食纤维或膳食纤维的混合物减少了在肠道中发生的厌氧发酵过程中所形成的丙酸的量。
在本发明的上下文中,“纤维”和“膳食纤维”可互换使用。根据本发明,术语膳食纤维意指植物的可食用部分或类似碳水化合物,其在人体小肠中对消化和吸收耐受,而在大肠中完全发酵、部分发酵或不发酵。这包括多糖、低聚糖、木质素和相关的植物物质。优选地,用于本发明的组合物的膳食纤维选自可发酵的纤维和发酵性差的纤维和不可发酵的纤维。优选地,用于本发明的组合物的膳食纤维的混合物的纤维选自可发酵的纤维以及发酵性差的纤维,或不可发酵的纤维,更优选使用两种类型的混合物。不受理论的约束,发明人认为甲基丙二酸血症(MMA)和丙酸血症(PA)患者的便秘和排便有问题通过使用这些发酵性差的纤维或不可发酵的纤维而得到改善。在一个实施方案中,一种或多种发酵性差的纤维或不可发酵的膳食纤维选自半纤维素、木质素、α纤维素和抗性淀粉及其混合物。在一个实施方案中,一种或多种可发酵的膳食纤维选自低聚果糖、菊粉、麦麸、阿拉伯胶、大豆多糖、燕麦纤维、低聚半乳糖、刺槐豆胶、瓜尔胶、果胶、水解果胶及其混合物。在优选的实施方案中,一种或多种膳食纤维选自低聚果糖、菊粉、抗性淀粉、纤维素、甲基纤维素(优选羟丙基甲基纤维素)、麦麸、阿拉伯胶、大豆多糖、燕麦纤维、低聚半乳糖、刺槐豆胶、瓜尔胶、果胶、水解果胶及其混合物。术语“阿拉伯胶(gum Arabic)”和“阿拉伯胶(arabic gum)”可互换使用。
在一个实施方案中,使用一种纤维,其是低聚半乳糖。或者,使用不同的膳食纤维的混合物,例如使用至少2种、至少3种、至少4种、至少5种、至少6种或甚至至少7种不同的膳食纤维的混合物,优选选自以上列表的优选膳食纤维。优选地,纤维的混合物至少包含低聚半乳糖。虽然没有特别限制在本发明的上下文中所使用的不同的膳食纤维的量,但出于实际原因,可以使用最多10种、最多9种或甚至最多8种不同的膳食纤维。优选的纤维(混合物)如下:
(i)纤维是低聚半乳糖。
(ii)纤维混合物包含两种纤维,其中一种是低聚半乳糖。
(iii)纤维混合物包含两种纤维,其中一种是低聚半乳糖,一种是抗性淀粉。
(iv)纤维混合物包含至少三种、优选至少四种、至少五种或至少六种纤维,其中一种是低聚半乳糖,一种是抗性淀粉。
(v)纤维混合物(ii),还包含低聚果糖和/或菊粉、阿拉伯胶和大豆多糖。
(vi)纤维混合物(iv),还包含低聚果糖和/或菊粉、阿拉伯胶和大豆多糖。
(vii)纤维混合物(ii)、(iii)、(iv)、(v)或(vi),还包含瓜尔胶和/或部分水解的瓜尔胶。
(viii)纤维混合物,其包含至少两种、至少三种、至少四种、至少五种、至少六种或全部七种纤维,所述纤维选自低聚果糖、菊粉、抗性淀粉、阿拉伯胶、刺槐豆胶、低聚半乳糖和大豆多糖。
(ix)纤维混合物(ii)、(iv)、(v)、(vi)、(vii)或(viii),不包含纤维素。
(x)纤维混合物,其包含至少两种、至少三种、至少四种、至少五种、至少六种、至少七种或全部八种纤维,所述纤维选自低聚果糖、菊粉、抗性淀粉、纤维素、阿拉伯胶、刺槐豆胶、低聚半乳糖和大豆多糖。
在本发明的组合物中使用的特别优选的膳食纤维为GOS。GOS有助于在沿结肠的长度方向产生的不同的SCFA之间取得平衡,并有助于改善大便的松散性,同时降低丙酸的形成。优选地,将GOS与抗性淀粉结合。该组合结合了不可发酵的膳食纤维和可发酵的膳食纤维的益处。
优选地,GOS或GOS和抗性淀粉的混合物补充有其他膳食纤维,优选补充有阿拉伯胶、大豆多糖以及低聚果糖和/或菊粉的组合。与GOS或GOS和抗性淀粉的混合物相比,该纤维混合物紧密反映了正常饮食中习惯食用的纤维的范围和类型,并进一步降低了丙酸的形成。在优选的实施方案中,抗性淀粉的量为组合物中膳食纤维的至少10重量%,更优选至少20重量%,最优选至少30%。在优选的实施方案中,当两种GOS作为抗性淀粉存在于包含多于2种纤维的纤维混合物中时,抗性淀粉和低聚半乳糖的量的总和为组合物中膳食纤维的至少20重量%,优选至少30重量%,最优选至少50重量%。
优选地,补充有阿拉伯胶、大豆多糖以及低聚果糖和/或菊粉的组合的GOS、GOS和抗性淀粉的混合物或这些纤维补充有瓜尔胶和/或部分水解的瓜尔胶。瓜尔胶和/或部分水解的瓜尔胶是可发酵的纤维,并且可进一步充当掩味剂,因此可以支持掩盖任何口味,例如可能包含在组合物中的纤维和氨基酸的苦味。
优选地,本发明的组合物包含0.4-50g膳食纤维/100kcal,更优选0.6-30g/100kcal,最优选1-20g/100kcal,基于组合物(包含纤维)的总能量含量计。如果本发明的组合物为全营养组合物,则膳食纤维含量优选为0.4-9g膳食纤维/100kcal的组合物,甚至更优选0.6-7g/100kcal的组合物以及最优选0.8-3g/100kcal的组合物。如果本发明的组合物为补充剂,则膳食纤维含量优选为2-50g膳食纤维/100kcal的组合物,甚至更优选4-30g/100kcal的组合物以及最优选5-20g/100kcal的组合物。本发明的组合物优选包含1.5-5g膳食纤维/10g蛋白质,更优选2-4g膳食纤维/10g蛋白质以及最优选2.5-3.5g膳食纤维/10g蛋白质。优选地,本发明的组合物以日剂量提供2-40g膳食纤维,优选10-30g膳食纤维。实际剂量取决于患者的年龄。对于婴儿和直至12岁的儿童来说,优选的日剂量为2-10g膳食纤维,对于成年人来说,优选的剂量为7-30g膳食纤维。即使患者还正在食用低蛋白食物(例如水果和蔬菜),也建议不要修改上述本发明的纤维组合物的日剂量,以限制肠道菌群所产生的丙酸。
本发明的优选营养组合物包含70-250kcal/100ml的营养组合物,以及1-5g膳食纤维/100kcal的营养组合物,更优选1.5-4.5g膳食纤维/100kcal的营养组合物,甚至更优选2.0-4.0g膳食纤维/100kcal的营养组合物。发现这种组合物特别适合于MMA和PA患者的长期膳食管理。
低聚半乳糖(GOS),也称为半乳低聚糖(oligogalactosyllactose)、低聚半乳糖(oligogalactose)、低聚半乳糖(oligolactose)或反式低聚半乳糖(transgalactooligosaccharides,TOS),属于益生元(prebiotics)。GOS通常包含通过连续的反式半乳糖基化反应产生的半乳糖单元链,其带有末端葡萄糖单元。GOS的聚合度可以非常明显地变化,例如,在2-8个单体单元的范围内变化。在优选的实施方案中,纤维混合物包含低聚半乳糖。GOS可以以高达纤维总重量的100重量%存在于组合物中,例如0.5-100重量%,优选1-100重量%或甚至5-100重量%。或者,存在其他纤维并且GOS优选以0.5-90重量%,优选0.5-70重量%,最优选1-30重量%包含在组合物中,基于纤维的总重量计。
抗性淀粉(RS)是未在胃或小肠中消化和吸收并传递到大肠的任何淀粉或淀粉消化产品。RS已经被分类为四种类型。这些类型的任一种都适用于本发明。RS1是指物理上无法接触或无法消化的抗性淀粉,例如在种子或豆类以及未加工的全谷物中存在的那些。RS2是指由于淀粉构象(如高直链玉米淀粉)而无法与酶接触的抗性淀粉。RS3是指当含淀粉的食物(例如面食)在烹饪和冷却时所形成的抗性淀粉。RS3是由于回生(retrogradation)而产生的,回生是指溶解的淀粉在被加热并溶于水然后冷却后变得难溶的聚集过程。RS4是指经过化学修饰可抵抗消化的淀粉。在优选的实施方案中,纤维混合物包含抗性淀粉。如果存在,优选抗性淀粉以0.5-75重量%,优选3-50重量%,更优选10-40重量%,最优选15-30重量%包含在组合物中,基于纤维的总重量计。
菊粉是果糖聚合物或低聚果糖(FOS)的异质集合。菊粉通常是指从植物材料中获得的材料,并且其自身可商购。它由链终止的葡糖基部分和重复的果糖基部分组成,它们通过β(2,1)键连接。标准菊粉的聚合度(DP)的范围为2至60。在制备过程中除去DP低于10的部分后,剩余的产品称为长链FOS(lcFOS)。DP低于10的部分可称为短链低聚果糖或scFOS。在优选的实施方案中,纤维混合物包含菊粉。如果存在,菊粉优选以0.5-40重量%,更优选5-30重量%,最优选10-25.5重量%包含在组合物中,基于纤维的总重量计。
除菊粉外,优选本发明的纤维混合物中存在低聚果糖。低聚果糖为DP通常低于10的低聚果糖,并且是可商购的产品,例如Orafti Oligofructose。在优选的实施方案中,纤维混合物包含低聚果糖。如果存在,优选低聚果糖以0.5-50重量%,优选5-50重量%,最优选5-28.4重量%包含在组合物中,基于纤维的总重量计。
果胶,也称为果胶多糖,富含半乳糖醛酸。在果胶组中已经鉴定出几种不同的多糖并进行了表征。半乳糖醛酸聚糖是直链的α-(1–4)-连接的D-半乳糖醛酸。在自然界中,大约80%的半乳糖醛酸的羧基被甲醇酯化。在果胶提取过程中,该比例降低至不同程度。酯化与非酯化半乳糖醛酸的比例决定了果胶在食品应用中的行为。这就是果胶被分类为高酯果胶相对于低酯果胶(HM果胶相对于LM果胶)的原因,其中全部半乳糖醛酸的多于或少于一半被酯化。果胶可被水解以降低分子量。对于本申请,水解的果胶是优选的,以防止不期望的粘度增加。在优选的实施方案中,纤维混合物包含果胶。如果存在,优选果胶以0.1-45重量%,优选0.2-27重量%,优选0.5-25重量%包含在组合物中,基于纤维的总重量计。
纤维素是分子式为(C6H10O5)n的有机化合物,由数百个至数千个β(1→4)连接的D-葡萄糖单元的直链组成的多糖。纤维素在人体肠道中不被消化或发酵,因此纤维素是排泄在粪便中的纤维,并且因此有助于粪便的稠度。纤维混合物可包含纤维素。在优选的实施方案中,纤维混合物包含相对于组合物中的膳食纤维小于5重量%的纤维素,优选不包含纤维素。如果存在,纤维素可以以0.5-5重量%,优选1-3重量%存在于组合物中,基于纤维的总重量计。或者,纤维素可以以0.5-50重量%,优选6-19.6重量%存在,基于纤维的总重量计。
阿拉伯胶(Gum Arabic),也称为阿拉伯树胶(acacia gum),是一种由各种种类的金合欢树的硬化树液组成的天然胶。阿拉伯半乳聚糖是由阿拉伯糖和半乳糖单糖组成的生物聚合物。它是许多植物胶(包括阿拉伯胶)的主要成分。在优选的实施方案中,纤维混合物包含阿拉伯胶。如果存在,优选阿拉伯胶以0.1-40重量%,优选1-15重量%包含在组合物中,基于纤维的总重量计。
刺槐豆胶是从角豆树的种子中提取的半乳甘露聚糖植物胶。它可以以水解或未水解的形式使用。在优选的实施方案中,纤维混合物包含刺槐豆胶。如果存在,优选刺槐豆胶以0.1-10重量%,优选0.5-3重量%包含在组合物中,基于纤维的总重量计。
大豆多糖,也称为大豆纤维,通常是指从大豆中分离的非淀粉、高度不溶性多糖。当在本发明中提及大豆多糖时,它们的DP通常大于10,优选大于20,更优选大于50,甚至更优选大于100。大豆纤维的合适来源是Fibrim(Solae)。在优选的实施方案中,纤维混合物包含大豆多糖。如果存在,优选大豆多糖以0.01-10重量%,优选0.05-0.5重量%包含在组合物中,基于纤维的总重量计。
瓜尔胶是从瓜尔豆的种子中提取的半乳甘露聚糖植物胶。它可以以(部分)水解或未水解的形式使用。在本发明的上下文中,最优选使用部分水解的瓜尔胶。在优选的实施方案中,纤维混合物包含部分水解的瓜尔胶。在替代性的实施方案中,纤维混合物不包含部分水解的瓜尔胶作为唯一的膳食纤维。如果存在,优选瓜尔胶以0.01-10重量%,优选0.05-3重量%包含在组合物中,基于纤维的总重量计。
产乳酸菌
优选组合物还包含产乳酸菌。或者,膳食纤维组合物与包含产乳酸菌的组合物一起施用。发明人认为,使用补充的产乳酸菌可以协同地恢复和平衡MMA和PA患者的肠道菌群微生物群,特别是如果避免了产丙酸菌的存在,从而提供与膳食纤维的协同作用。因此,在一个实施方案中,组合物基本上不含产丙酸菌。优选以108菌落形成单位至1012菌落形成单位的日剂量提供包含在本发明的组合物中的产乳酸菌。优选地,产乳酸菌选自低产丙酸菌。优选地,本发明的组合物包含双歧杆菌和/或乳酸杆菌。包含在本发明的组合物中的优选菌株包括植物乳杆菌(Latobacillus plantarum)(优选WCFS1)和/或青春双歧杆菌(Bifidobacterium adolescentis)(优选DSM 18350)。
蛋白质
优选地,本发明的组合物还包含蛋白质部分。优选地,组合物不含完整蛋白和部分水解的蛋白,并且蛋白质部分基本上由游离氨基酸和二肽组成。因此,下文中定义的蛋白质水平优选仅适用于氨基酸。术语“蛋白质当量”在本领域中是公知的,并且是指游离氨基酸的量,犹如它们是蛋白质的一部分,即氨基酸的重量值被理解为蛋白质当量重量值。通常,氨基酸对蛋白质的贡献表示各个氨基重量的约81%。
氨基酸是维持身体细胞质量和几乎所有主要身体机能所必需的。饮食中的蛋白质作为必需氨基酸的来源,并为合成其他氨基酸和具有生理重要性的含氮化合物提供氮。有机酸尿症是由于人体无法分解蛋白质中的某些前体氨基酸(缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸)引起的。因此,优选这些氨基酸被限制或甚至完全排除在本发明的组合物中。换言之,在优选的实施方案中,蛋白质部分基本上不含缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸中的至少两种、更优选至少三种、最优选至少四种。
下表显示了本发明的优选氨基酸谱的概述,以g/10g蛋白质当量。
上表中氨基酸的优选含量单独适用于每种氨基酸以及适用于整个氨基酸谱。值得注意的是,每种单个氨基酸重量对总蛋白质当量重量的贡献约为80%。
优选地,本发明的组合物包含0-50重量%蛋白质当量,基于组合物的干重计,甚至更优选0-40重量%蛋白质当量并且最优选20-35重量%蛋白质当量,基于组合物的干重计。如果本发明的组合物为营养组合物,它优选可包含10-60重量%,优选20-50重量%,更优选25-35重量%,最优选约28重量%蛋白质当量(优选氨基酸),基于干重计。每能量单位,本发明的组合物优选包含2.5-10g氨基酸/100kcal的组合物,优选4-9.5g氨基酸/100kcal的组合物,最优选5-8.0g氨基酸/100kcal的组合物。优选地,本发明的组合物包含小于1.0重量%的每种氨基酸,更优选小于0.5重量%的每种氨基酸,甚至更优选小于0.1重量%的每种氨基酸以及最优选0.0-0.05重量%的每种氨基酸,基于组合物中氨基酸的总重量计;所述氨基酸选自异亮氨酸、缬氨酸、苏氨酸和甲硫氨酸。在优选的实施方案,本发明的组合物还包含肉毒碱,优选至少0.01重量%肉毒碱,更优选0.05-7.5重量%肉毒碱,更优选0.05-5重量%肉毒碱,基于组合物中氨基酸的总重量计。
提供给患者的最佳蛋白质含量通常取决于由医生或营养师根据各个患者的计算需求所开处方的组合物的量。取决于年龄和临床病症,平均蛋白质需求量可在每天1-3g/kg体重变化。在一个实施方案中,本发明的组合物包含足够的蛋白质以提供建议的每日摄入量的60-100重量%,建议的每日摄入量如医学研究委员会(Medical Research Council,MRC)在关于苯丙酮尿症的膳食管理的建议(Recommendations on the dietarymanagement of phenylketonuria).医学研究委员会工作组关于苯丙酮尿症的报告(Report of Medical Research Council Working Party on Phenylketonuria).ArchDis Child,1993Mar.63(3):p.426-427中所建议的。在替代性实施方案中,本发明的组合物包含足够的蛋白质以提供如MRC所列出的建议的每日摄入量的高达60重量%,如果本发明的组合物为补充剂形式,这是特别优选的。
脂质
本发明的组合物优选还包含脂质部分。脂质是儿童的重要能量来源,并且能够利用氨基酸。某些脂肪酸(例如长链多不饱和脂肪酸(LCPUFA))被认为对蛋白质受限的饮食有益。患有先天性氨基酸代谢缺陷的儿童的LCPUFA的摄入通常是受限的,因为LCPUFA主要存在于动物源食品中,并且膳食疗法要求从饮食中排除这种天然丰富的蛋白质源。脂质还贮存脂溶性维生素,并且是必需脂肪酸的来源。优选实施方案的总脂质含量优选为2.5-9g脂质/100kcal,更优选3-7.5g脂质/100kcal,甚至更优选3.5-6g脂质/100kcal以及最优选约4.5g脂质/100kcal或约12.5-25g脂质/100g组合物的干重。优选地,脂质源为植物油的共混物(例如菜籽油-葵花籽油-棕榈仁油-椰子油共混物),其提供百分比的饱和脂肪酸(16.6重量%的脂肪)、多不饱和脂肪酸(15.0重量%的脂肪)和单不饱和脂肪酸(68.4重量%的脂肪)。优选本发明的营养组合物包含必需脂肪酸、亚油酸(C18:2(n-6))和α-亚麻酸(C18:3(n-3),并且优选以符合目前建议的量(脂质总重量的3-10重量%和0.5-4.5重量%)存在。n-6与n-3脂肪酸的比例优选为6:1-1:1,更优选3:1-2:1,最优选约2.6:1。二十二碳六烯酸(22:6n-3,DHA)是重要的Ω-3长链多不饱和(LCP)脂肪酸,因为它是神经组织中最主要的脂肪酸。它占大脑中所有脂肪酸的约20%,并占视网膜(眼睛)中所有脂肪酸的高达60%。DHA对于神经膜的形成、膜的完整性、电绝缘、囊泡运输和突触传递至关重要。研究表明,DHA从其前体必需脂肪酸ALA的转化的效率低于通常假设的。由于已经发现在受限的饮食后,PKU受试者的饮食和血浆中缺乏DHA,而且在患有其他先天性代谢缺陷的受试者中也缺乏DHA,因此包含在本发明的组合物中的DHA水平为20-120mg/100kcal,优选30-90mg/100kcal,甚至更优选35-85mg/100kcal,最优选约65mg/100kcal。DHA的来源优选是海藻,其与来自鱼油的来源相比,对最终产品的味道影响最小。
可消化碳水化合物
优选本发明的组合物还包含可消化碳水化合物部分。碳水化合物被分类为单糖、二糖、低聚糖和多糖。可消化碳水化合物包括为重要能量来源的重要生物分子。优选地,本发明的组合物的总碳水化合物含量为0-50g/100kcal,优选20-40g/100kcal,最优选约30g/100kcal。优选地,本发明组合物中的碳水化合物的来源包括,优选为麦芽糖糊精。与例如葡萄糖或蔗糖相比,麦芽糖糊精的使用增加了溶解性并且降低了对配方物的重量摩尔渗透压浓度的贡献。
微量营养素
优选本发明的组合物还包含微量营养素。优选地,基于典型产品用法(例如参见Institute of Medicine,Dietary Reference Intakes for Calcium and Vitamin D,National Academy Press,Editor 2010:Washington D.C.),本发明的组合物包含维生素、矿物质和微量元素,其量满足1-3岁的RDA/DRI和DRV。具体而言,维生素D和钙根据新建议的摄入量而增加,如下所讨论。有意减少钠和钾以优化味道。
在优选的实施方案中,本发明的组合物包含维生素D和/或钙,优选维生素D。
人体维生素D的主要来源是暴露在阳光下,任何阻止日光照射或干扰UVB渗透到皮肤中的情况都会影响维生素D的合成。提供维生素D的饮食来源很少。主要来源是多脂鱼、鱼油、肝脏和其他器官肉以及饲喂维生素D的鸡的蛋黄,这些通常从患有先天性代谢缺陷的患者的受限的饮食中被排除。儿童维生素D缺乏会导致生长迟缓和佝偻病的典型体征和症状。维生素D对骨骼健康至关重要,并且由于早年奠定了成年人骨骼健康的基础,因此在儿童时期适当摄取维生素D是至关重要的。次优的维生素D状况和/或次优的暴露在阳光下还与肌无力、功能缺陷、心血管疾病、癌症死亡率以及住院患者可能更长的住院时间相关。此外,维生素D对在窄的范围内支持血清钙浓度具有关键作用,并且对于最大化小肠中钙的吸收至关重要。据估计,与当维生素D状况不足时将钙吸收增加至10-15%相比,适当的维生素D状况将钙吸收增加至30-40%。影响维生素D状况的因素包括种族、营养不良、高龄、使用多种维生素和紫外线照射。预期患有先天性代谢缺陷的患者从他们正常饮食中摄入的维生素D将非常有限。因此,本发明的组合物优选包含2-20μg/100kcal,更优选4-17μg/100kcal,最优选5-14μg/100kcal(200-560IU/100kcal)的维生素D。
钙是用于骨骼和牙齿矿化的必需的营养素。此外,钙被用作许多细胞过程(例如激素、酶和神经系统的分泌)的信号。钙和维生素D彼此紧密联系。维生素D的主要生理功能是将血清钙和磷水平维持在正常范围内,以支持例如代谢功能、骨骼矿化。如果钙摄入不足,维生素D有助于维持钙稳态。然而,当维生素D缺乏时,这会阻止钙的有效吸收。优选地,本发明的组合物包含的钙的水平为200-600mg/100kcal,更优选250-500mg/100kcal,最优选约375mg/100kcal。每100g的组合物干重,钙含量优选为500-1500mg,更优选为800-1200mg,最优选为约980mg。
热量密度
在优选的实施方案中,本发明的组合物是仅包含膳食纤维的补充剂。因此,纤维构成了组合物的约90-100能量%。在另一个优选的实施方案中,本发明的组合物是仅包含膳食纤维和蛋白质的补充剂。在后一个实施方案中,蛋白质的能量密度优选为4-98能量%,膳食纤维的能量密度优选为2-96能量%。在另一个优选的实施方案中,本发明的组合物为包含膳食纤维、蛋白质、可消化碳水化合物和脂质的全营养组合物,其中能量密度优选如下:10-60能量%脂质,10-65能量%可消化碳水化合物,2.0-15能量%膳食纤维和10-40能量%蛋白质。全营养组合物的能量密度优选为0.4-3.5kcal/ml,更优选0.7-3.0kcal/ml,甚至更优选0.8-2.6kcal/ml以及最优选0.9-2.4kcal/ml。在本文中,“仅包含”意指基本上不存在其他组分,并且组分的所有能量密度以组合物的总能量含量的百分比给出。
特别优选的组合物
在本发明的一方面,本发明涉及如上所定义的组合物本身。在该方面的上下文中,本发明的组合物优选包含膳食纤维和由游离氨基酸组成的蛋白质部分。特别优选的本发明的组合物包含低聚半乳糖、抗性淀粉、阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种,优选与由游离氨基酸组成的蛋白质部分结合,更优选其中游离氨基酸基本上不含缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸。另一个优选的组合物包含至少一种膳食纤维,其选自低聚果糖、菊粉、抗性淀粉、纤维素、甲基纤维素、麦麸、阿拉伯胶、大豆多糖、燕麦纤维、低聚半乳糖、刺槐豆胶、果胶、瓜尔胶及其混合物,并且游离氨基酸基本上不含缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸。优选地,膳食纤维至少包含GOS。优选地,组合物还包含乳酸菌。特别优选的,本方面的组合物还包含10-60能量%脂质和10-65能量%可消化碳水化合物,其中膳食纤维以总组合物的2.0-25能量%存在并且蛋白质以总组合物的10-40能量%存在,其中组合物的能量密度为0.7-3.5kcal/ml.
施用
在第一方面,包含膳食纤维的本发明的组合物用于甲基丙二酸血症(MMA)和/或丙酸血症(PA)的膳食管理。换言之,本发明涉及膳食纤维在制备用于甲基丙二酸血症(MMA)和/或丙酸血症(PA)的膳食管理的组合物中的用途。换言之,本发明涉及一种用于膳食管理甲基丙二酸血症(MMA)和/或丙酸血症(PA)的方法,其包括将包含治疗量的膳食纤维的本发明的组合物施用至有需要的受试者。
此外,包含膳食纤维的本发明的组合物用于治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状。换言之,本发明涉及膳食纤维在制备用于治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状的组合物中的用途。换言之,本发明涉及一种用于治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状的方法,其包括将包含治疗量的膳食纤维的本发明的组合物施用至有需要的受试者。
此外,包含膳食纤维的本发明的组合物用于减少肠道菌群引起的丙酸产生。换言之,本发明涉及膳食纤维在制备用于减少肠道菌群引起的丙酸产生的组合物中的用途。换言之,本发明涉及一种用于减少肠道菌群引起的丙酸产生的方法,其包括将包含治疗量的膳食纤维的本发明的组合物施用至有需要的受试者。
本文所述的关于根据本发明的用途同样适用于根据本发明的方法和根据本发明使用的组合物。这些用途本质上是医学上的。这些用途的目标人群是患有MMA和/或PA的患者。根据本发明的用途通常涉及减少如在患者粪便中测量的肠道菌群所产生的丙酸。
根据第一方面的用途还可用于治疗和/或减轻MMA或PA,以及/或者治疗、减轻和/或预防与之相关的症状。在一个实施方案中,根据第一方面的用途还用于治疗和/或减轻MMA或PA。在一个实施方案中,根据第一方面的用途还用于治疗、减轻和/或预防与MMA和/或PA相关的症状。
在一个实施方案中,根据第二方面的用途用于治疗和/或减轻MMA和/或PA。在一个实施方案中,根据第二方面的用途用于治疗、减轻和/或预防与MMA和/或PA相关的症状。根据第二方面的用途还可用于MMA和/或PA的膳食管理。治疗、减轻和/或预防症状也可以称为缓解症状。
与MMA和/或PA相关的症状也可以称为与肠道中丙酸过量产生相关的症状,并且通常包括肠道疾病、与维生素D缺乏相关的疾病和与LC-PUFA缺乏相关的疾病。MMA和/或PA患者的肠道疾病通常包括以下一种或多种:微生物群失衡、细菌移位、大便松散性受损、肠道转运时间受损、SCFA产生失衡和便秘。在一个实施方案中,肠道疾病选自大便松散性受损、SCFA产生失衡和便秘。大便松散产物包括体积、稠度和粘性。减少失衡SCFA的产生优选包括沿结肠的长度方向平衡SCFA的产生。与MMA和/或PA患者的维生素D缺乏相关的疾病通常包括以下一种或多种:生长迟缓、佝偻病、骨骼健康受损、肌无力、功能缺陷、心血管疾病、癌症死亡率和钙摄入受损。与LC-PUFA缺乏(尤其是DHA缺乏)相关的疾病包括脑部疾病,例如神经膜完整性受损、电绝缘受损、囊泡运输受损和突触传递受损。与MMA和/或PA相关的这些症状通过施用本发明的组合物来治疗、减轻和/或预防。在优选的实施方案中,治疗、减轻和/或预防与MMA和/或PA相关的肠道疾病。
实施例1
发酵
在高通量厌氧结肠模型(I-screenTM平台,TNO,Zeist,荷兰)中孵育24小时后,测量表1的纤维混合物对SCFA产生的影响。该平台模拟肠道菌群条件,并使得在严格厌氧条件下确定化合物随时间对微生物群组成的影响。用标准的健康人类成年肠道菌群接种I-screenTM模型。肠道菌群采用以下方法获得:通过合并来自6名健康成年人志愿者的粪便样本并将合并的粪便样本在补料分批发酵罐中孵育40h,以产生标准化的微生物群。然后将合并的粪便样品在改良的标准回肠流出物培养基(standard ileal efflux medium,SIEM)中进行体外培养,并将pH调节至5.8。将该标准的成年人肠道菌群在-80℃下保存12%甘油中,直至进一步分析。这种合并方法旨在限制个体间变异,并提高人体结肠中具有更大潜在细菌种类代表的可能性。
在测试纤维混合物之前,通过将标准的成年人微生物群在改良的SIEM培养基中在厌氧条件下,在37℃下并以300rpm震动孵育过夜来活化。以浓度为6mg/ml(纤维水平浓度)测试了4种条件,对应于纤维混合物和组分的不同结合(表1)。包括阴性对照(SIEM培养基未暴露的微生物群)和空白(不含微生物群的SIEM培养基)。每种条件(包括对照)均一式三份进行测试。表1总结了实验设置。加入测试化合物(的组合)、阴性对照或空白后,将微生物群在37℃下厌氧孵育24小时。然后收集样品并进行进一步分析。
短链脂肪酸(SCFA)测量
为了分析短链脂肪酸,对由I-screenTM孵育所产生的物质进行采样并在4,000g下离心5分钟。将上清液用0.45pm过滤器过滤灭菌。加入甲酸(20%)、甲醇和2-乙基丁酸的混合物(内标,2mg/ml的甲醇溶液)。在岛津GC-2014气相色谱仪中,将分流比为75.0的3皮升(pl)样品注入GC柱(ZB-5HT inferno,ID 0.52mm,膜厚0.10um;Zebron;phenomenex,美国)。分析的SCFA为乙酸、丙酸、异丁酸、正丁酸和异戊酸。
结果
用成年人微生物组厌氧体外发酵24小时后,纤维混合物所产生的丙酸的量和相对于总SCFA的丙酸百分比如表2所示。与对照相比,混合物A、B、D、E和F减少了丙酸的形成并增加了形成的SCFA的总量,而混合物C引起了丙酸形成的增加。而且,就丙酸形成和SCFA形成两者而言,混合物B(GOS)相对于混合物A和C显示出最大的作用。接着是该混合物D——与混合物A相比,其抗性淀粉水平量增加(以纤维素为代价)——表明丙酸相对于混合物A有所降低。与混合物A相比,混合物D的SCFA的总量也更高。向混合物D中加入10重量%的GOS进一步降低了所得混合物F中丙酸的量。
当存在相对大量的抗性淀粉时,GOS对丙酸的作用似乎更高。相较于混合物E对比混合物A,混合物F对比混合物D表现出改善的效果。
结论
发明人已经发现,本发明的纤维混合物导致成年人微生物组中较低水平的丙酸产生。具体而言,混合物B、D和F的丙酸产量出乎意料地低,而保持其他SCFA的高产量。这表明包含纤维的本发明的纤维组合物可在患有甲基丙二酸血症(MMA)和丙酸血症(PA)的患者的临床特征中发挥重要作用。
表1:测试的纤维混合物的组成(每种纤维相对于总纤维的重量百分比)。
表2:体外发酵时产生的丙酸(3次测量的平均值)。
实施例2:本发明的组合物
本发明的以下组合物是适合于通过调节肠道菌群使得丙酸产量降低而治疗MMA和PA的组合物。基于组合物的总重量计,补充剂包含以重量%计的以下成分:
·1.5-28.4%低聚果糖
·1.5-25.5%菊粉
·1.5-50%抗性淀粉
·1-15%阿拉伯胶
·0-0.5%大豆多糖
·0-3%瓜尔胶
·5-79.5%低聚半乳糖
·任选地补充有产乳酸菌,优选双歧杆菌和/或乳杆菌。
实施例3:本发明的组合物
本发明的以下组合物是适合于通过调节肠道菌群使得丙酸产量降低而治疗MMA和PA的组合物。基于组合物的总重量计,补充剂包含以重量%计的以下成分:
·5-100%低聚半乳糖
·0-70%抗性淀粉
·任选地补充有产乳酸菌,优选双歧杆菌和/或乳杆菌。
·任选地脂质源和可消化碳水化合物源。
实施例4:本发明的组合物
本发明的以下组合物是这样的组合物:其通过调节肠道菌群并补充蛋白质使得血液中的毒性代谢物水平降低而用于MMA或PA患者的治疗和/或膳食管理。组合物包含实施例2的纤维共混物和氨基酸共混物,该氨基酸共混物包含以g/每10克蛋白质当量计的以下氨基酸:
实施例5:本发明的组合物
本发明的以下组合物是全营养组合物,其通过调节肠道菌群和补充蛋白质使得血液中的毒性代谢物水平降低而用于MMA或PA患者的治疗和/或膳食管理。该组合物可用作唯一饮食(exclusive diet)。该补充剂包含实施例3的纤维和蛋白质共混物、脂质、可消化碳水化合物和微量营养素。
注释
*术语“蛋白质当量”在本领域中是公知的,并且是指游离氨基酸的量,犹如它们是蛋白质的一部分,即氨基酸的重量值应被理解为蛋白质当量重量值。氨基酸对蛋白质的贡献表示各个氨基重量的约81%。
Claims (17)
1.包含低聚半乳糖的组合物,其在年龄为至少3岁的人类受试者中用于:
-治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状;
-MMA和/或PA的膳食管理;以及/或者
-减少肠道菌群引起的丙酸产生。
2.根据权利要求1所述的用于所述用途的组合物,其中所述受试者的年龄至少为12岁,优选至少为18岁。
3.根据前述权利要求中任一项所述的用于所述用途的组合物,其中所述组合物还包含抗性淀粉。
4.根据前述权利要求中任一项所述的用于所述用途的组合物,其中所述组合物还包含阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种。
5.包含低聚半乳糖、抗性淀粉、阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种的组合物,其在患有MMA或PA的患者中用于:
-治疗和/或减轻甲基丙二酸血症(MMA)和/或丙酸血症(PA),以及/或者治疗、减轻和/或预防与之相关的症状;
-MMA和/或PA的膳食管理;以及/或者
-减少肠道菌群引起的丙酸产生。
6.根据权利要求1-5中任一项所述的用于所述用途的组合物,其中所述组合物包含至少10重量%,优选至少20重量%,最优选至少30重量%的抗性淀粉,基于膳食纤维总重量计。
7.根据权利要求1-6中任一项所述的用于所述用途的组合物,其中所述组合物包含至少20重量%,优选至少30重量%,最优选至少50重量%的抗性淀粉和低聚半乳糖的组合,基于膳食纤维总重量计。
8.根据权利要求1-7中任一项所述的用于所述用途的组合物,其中所述组合物还包含产乳酸菌,其优选选自双歧杆菌属和乳杆菌属。
9.根据权利要求1-8中任一项所述的用于所述用途的组合物,其中所述组合物还包含瓜尔胶。
10.根据权利要求1-9中任一项所述的用于所述用途的组合物,其中所述组合物包含小于5重量%的纤维素,基于膳食纤维总重量计,优选所述组合物不包含纤维素。
11.根据权利要求1-10中任一项所述的用于所述用途的组合物,其中所述组合物为以下形式:
(i)营养补充剂,优选其中补充剂还包含氨基酸;或者
(ii)全营养组合物,其中营养组合物还包含蛋白质部分、可消化碳水化合物、维生素和矿物质,优选所述蛋白质部分以氨基酸的形式。
12.根据权利要求1-11中任一项所述的用于所述用途的组合物,其中所述组合物还包含基本上由游离氨基酸和二肽组成的蛋白质部分,优选其中所述蛋白质部分基本上不含缬氨酸、异亮氨酸、甲硫氨酸和苏氨酸。
13.根据权利要求1-12中任一项所述的用于所述用途的组合物,其中所述组合物包含DHA。
14.根据权利要求1-13中任一项所述的用于所述用途的组合物,其中所述组合物包含维生素D和/或钙,优选维生素D。
15.组合物,其包含低聚半乳糖、抗性淀粉、阿拉伯胶、大豆多糖,以及低聚果糖和菊粉中的至少一种。
16.根据权利要求15的组合物,其中GOS的量为组合物中膳食纤维的至少5重量%,并且抗性淀粉为组合物中膳食纤维的至少10重量%,优选至少20重量%,最优选至少30重量%。
17.根据权利要求15或16的组合物,其中所述组合物包含小于5重量%的纤维素,基于膳食纤维总重量计,优选其中所述组合物不包含纤维素。
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ALBERTO BURLINA ET AL.: "The potential role of gut microbiota and its modulators in the management of propionic and methylmalonic acidemia", 《EXPERT OPINION ON ORPHAN DRUGS》, pages 1 - 33 * |
姚圣蜜: "FODMAPs在健康人群体内外发酵的对比研究", 《中国硕士学位论文全文数据库 医药卫生科技辑》, no. 1, pages 1 - 56 * |
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