CN113796545B - 调节肠道免疫功能的母乳低聚糖组合物及其应用 - Google Patents
调节肠道免疫功能的母乳低聚糖组合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种调节肠道免疫功能的母乳低聚糖组合物及其应用,其中包括中性母乳低聚糖2’‑FL(2’‑岩藻糖基乳糖)和酸性母乳低聚糖3’‑SL(3’‑唾液酸乳糖),其中2’‑FL与3’‑SL的重量比例为2~7:1。本发明发现,以特定质量比的2’‑FL(2’‑岩藻糖基乳糖)和3’‑SL(3’‑唾液酸乳糖)的组合,可以显著协同促进婴儿结肠产短链脂肪酸、减少气体产生并维持双歧杆菌优势地位,并降低肠道炎症反应,调节肠道免疫功能。本发明的母乳低聚糖组合物能显著改善肠道微环境健康,可用于添加在婴幼儿食品(包括婴幼儿配方粉、辅食、营养补充剂),以及3岁以上儿童、青少年和成人的营养补充剂或食品中,具有广阔的应用前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于调节肠道免疫功能母乳低聚糖组合物及其应用。
背景技术
肠道菌群结构和组成与婴儿的健康息息相关,稳定的肠道菌群组成有助于有效的肠道屏障的建立以及平衡的粘膜免疫系统的组成。婴儿的肠道菌群结构对于成人来说相对简单,以双歧杆菌属、拟杆菌属、梭菌属、乳杆菌属、链球菌属、粪杆菌属等为主。影响其肠道菌群的因素也相对可控,有利于研究单一因素对其肠道菌群的影响。对于婴儿来说,其肠道菌群容易受各种遗传因素和环境因素的影响。而且饮食的改变或者抗生素的使用等都可能会导致婴儿获得免疫相关的疾病,如过敏、肠绞痛或者肠炎。因此,健康的肠道菌群环境有助于促进婴儿的健康发展。
母乳低聚糖(human milk oligosaccharides,HMOs)是母乳中重要的生物活性成份,也是影响婴儿肠道菌群组成的重要因素之一,具有结构多样性,目前已检测出超过200种结构。由于它在婴儿的肠道当中能够发挥益生元效应并且引导婴儿肠道菌群稳定以及建立更健康的肠屏障功能和促进粘膜免疫系统的发育,近几年来备受科学家们关注。HMOs在上消化道当中是不被消化的,所以HMOs会直接到达婴儿的大肠并且刺激婴儿肠道中的有益菌,比如双歧杆菌或者乳酸菌的生长,并产生对婴儿健康有益的短链脂肪酸和乳酸。除了刺激肠道中有益菌的生长外,HMOs还可以直接影响到婴儿粘膜免疫系统和肠屏障功能的建立。
近年来国内外众多研究已经阐明了HMOs对婴儿肠道的有益影响,但是由于HMOs结构众多,性质复杂,不同结构的HMOs对肠道的影响是不同的,目前关于不同结构的HMOS对婴儿肠道的发酵特性以及肠屏障功能的评价并不全面,缺乏HMOs对不同类型的婴儿肠道菌群作用的深入研究。
中国专利申请CN112514997A公开了改善肠道微环境健康的母乳低聚糖及其应用。具体地,本发明提供了母乳低聚糖特别是岩藻糖基类低聚糖2’-FL或3-FL在制备用于改善肠道微环境健康的食品中的应用,其中,所述改善肠道微环境健康包括:在肠道系统中作为益生元被肠道菌群利用并产气,降低pH以维持肠道微环境健康,和/或减少支链脂肪酸如异丁酸和/或异戊酸。本发明的母乳低聚糖用于添加在婴幼儿食品(包括婴幼儿配方粉、辅食、营养补充剂),以及3岁以上儿童、青少年和成人的营养补充剂或食品中,具有广阔的应用前景。该专利申请关注的是单一母乳低聚糖的作用。
中国专利申请CN112075637A公开了一种减少肠道气体产生的组合物途,所述组合用于制备一营养组合物或制剂,所述营养组合物用于:(a)减少婴幼儿肠道气体的产生;和/或(b)抑制婴幼儿肠道产气梭菌的过度生长;其中,所述营养组合物中包括:(i)一种母乳低聚糖(HMO);和(ii)一种益生菌微生物,所述益生菌微生物包括双歧杆菌。本发明的组合或营养组合物可以显著降低婴幼儿肠道产气、可较优的改善腹胀以及腹绞痛婴儿的肠道菌群。但该专利申请重点关注的是肠道产气,而没有涉及肠道短链脂肪酸和支链脂肪酸的平衡以及维持双歧杆菌优势地位。
发明内容
基于上述背景技术,本发明所要解决的技术问题在于提供能促进婴儿结肠产短链脂肪酸、减少气体产生并维持双歧杆菌优势地位,调节肠道免疫功能的益生元母乳低聚糖组合物。为了实现本发明的发明目的,拟采用如下技术方案:
本发明一方面涉及一种母乳低聚糖组合物,其中包括2’-FL(2’-岩藻糖基乳糖)和3’-SL(3’-唾液酸乳糖),其中2’-FL与3’-SL的重量比例为2-7:1;优选为2.8-3.2:1;最优选为3:1。
在本发明的另一个优选实施方式中,所述的母乳低聚糖组合物还包括瑞士乳杆菌(Lactobacillus helveticus R52)、婴儿双歧杆菌(Bifidobacterium infantis R33)和/或两歧双歧杆菌(Bifidobacterium bifidum R71)。
在本发明的另一个优选实施方式中,所述的母乳低聚糖组合物还包括婴儿双歧杆菌(Bifidobacterium infantis R33);优选的,所述婴儿双歧杆菌(Bifidobacteriuminfantis R33)与2’-FL(2’-岩藻糖基乳糖)的重量比为0.4-0.6:1,其中婴儿双歧杆菌的浓度为106~1011CFU/g。
在本发明的一个优选实施方式中,所述组合物还包括中性低聚糖:LNT、LNnT和GOS(低聚半乳糖)中的一种或者多种的组合以及酸性低聚糖6’-SL(6’-唾液酸乳糖)
本发明另一方面涉及一种食品,其包括上述母乳低聚糖组合物,所述低聚糖组合物在食品中的终浓度为100mg/100g~104mg/100g。
在本发明的一个优选实施方式中,所述食品为营养补充剂、婴幼儿配方粉、辅食。
本发明另一方面还涉及上述母乳低聚糖组合物在制备改善微环境健康的食品中的应用。
在本发明的一个优选实施方式中,所述改善微环境健康包括能促进婴儿结肠产短链脂肪酸、减少气体产生并维持双歧杆菌优势地位,以及调节肠道免疫功能。
有益效果
本发明发现,以特定质量比的2’-FL(2’-岩藻糖基乳糖)和3’-SL(3’-唾液酸乳糖)的组合,可以显著协同促进婴儿结肠产短链脂肪酸、减少气体产生并维持双歧杆菌优势地位,以及调节肠道免疫功能。本发明的母乳低聚糖组合物能显著改善肠道微环境健康,可用于添加在婴幼儿食品(包括婴幼儿配方粉、辅食、营养补充剂),以及3岁以上儿童、青少年和成人的营养补充剂或食品中,具有广阔的应用前景。
附图说明
图1为示出益生元在发酵过程的产气动态的图;
图2为示出发酵24小时短链脂肪酸产量的图;
图3为示出发酵24h时样本中双歧杆菌属的相对丰度的图。
具体实施方式
为了进一步理解本发明,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均可以通过商业渠道购买获得。
实施例1:
1.1研究方法
研究对象:从妇幼医院收集60位婴儿志愿者。
参加实验的婴儿母亲都将签定知情协议书,并保证在实验期间纯母乳喂养。
1.2.入组标准:
1)健康、足月儿(胎龄≥37周)、阴道分娩;
2)经过医学上证明是健康婴儿:无症状和无疾病体征;
1.3.实验方法和实验结果:
通过在婴儿年龄第1个月T1(30d±3d),第2个月T2(60d±3d),第3个月T3(90d±3d)第6个月(180d±3d)时收集母亲母乳样本。
分别测定上述4个时期母亲母乳中中性低聚糖和酸性低聚糖的总量。
结果显示:天然人乳中,随着泌乳时间的改变,中性HMO与酸性HMO的比例为:2~7:1,如表1所示。
表1:中性HMO与酸性HMO的比例变化
月份 | 1月 | 2月 | 3月 | 6月 |
中性HMO(g) | 3.261 | 2.563 | 2.388 | 1.912 |
酸性HMO(g) | 1.316 | 0.639 | 0.456 | 0.302 |
中性HMO:酸性HMO(比例) | 2.5:1 | 4:1 | 5.2:1 | 6.3:1 |
实施例2:
2.1研究方法
研究对象:招募10名月龄为3-7月、无抗生素摄入的健康顺产的母乳喂养的婴儿并收集其粪便,粪便中优势菌群为双歧杆菌(相对丰度>50%)。
益生元:A:2’-FL(2’-岩藻糖基乳糖),B:3’-SL(3’-唾液酸乳糖),C:2’-FL+3’-SL(3:1),D:2’-FL+3’-SL(4:1),E:2’-FL+FOS(低聚果糖)(3:1)。
益生元与益生菌的组合:F:2’-FL+3’-SL+婴儿双歧杆菌(Bifidobacteriuminfantis R33)(3:1:1.5),G:2’-FL+3’-SL+瑞士乳杆菌(Lactobacillus helveticus R52)(3:1:1.5)
说明:上述比例指重量比
实验方法:1)体外结肠发酵:在厌氧环境下,分别将每份婴儿粪便与碳酸磷酸盐缓冲液按1:4(w/v)的比例混合并通过4层滤布过滤,制成粪便匀浆。将粪便浆液(1mL)、碳酸磷酸盐缓冲液(3mL)、50mg益生元或益生元与益生菌的组合(干基)分别加入厌氧瓶中并密封,于37℃恒温酵解4h、8h、12h和24h后取出,用于后续产气、产酸及菌群分析。2)代谢物含量测定:产气——使用标有刻度的注射器收集发酵气体进行气体产量测量;产酸——用气相色谱法测量发酵液中短链脂肪酸含量;菌群组成——通过16S rRNA序列分析法分析发酵前后的粪便菌群组成。
2.2结果分析
2.2.1发酵产气速率
益生元在发酵过程的产气动态如图1所示,A-G在发酵0-24h不断释放气体,不同组别的益生元在各发酵时间段的产气速率不同,其中C、F和G组合能够有效的降低产气速率,由此说明2’-FL+3’-SL以特定的比例进行组合有助于降低产气速率,特别是F组合具有更加明显的气体缓释作用,有助于减少婴儿肠胀气等不适症状。
2.2.2短链脂肪酸产量
益生元在发酵24h时的短链脂肪酸产量如图2所示,A-G组发酵过程中产生的SCFAs主要为乙酸、少量丙酸和丁酸,其中C、F和G组合能够更有效促进肠道系统中对人体有益的乙酸、丙酸等短链脂肪酸的产生,由此说明2’-FL+3’-SL以特定的比例进行组合有助于短链脂肪酸的产生。
2.2.3益生元的肠道菌群调节作用
益生元对肠道菌群调节作用如图3所示,发酵前,10个婴儿个体粪便菌群以双歧杆菌为优势菌群,双歧杆菌属相对丰度>50%;A-G组益生元组合发酵24h后,可能由于发酵环境的影响,E组双歧杆菌丰度上升不显著,A-D,F-G组双歧杆菌都有显著的提升。但C、F和G组双歧杆菌作为各处理组中的优势菌属,上升最显著。由此说明C、F和G组对于显著升高双歧杆菌丰度,维持双歧杆菌优势地位具有改善作用,但三组之间没有实质性差异。
实施例3:
实验方法:1)体外结肠发酵:根据实施例2进行体外结肠发酵获得发酵上清液即发酵代谢物。2)肠上皮细胞免疫功能测定:购买自美国典型菌种保藏中心(ATCC)的人Caco-2细胞。在37℃、5%CO2环境中,用含有10%FBS,1%双抗的1640培养基培养Caco-2细胞。在实验当天,将用体外发酵收集的发酵代谢产物与1μg/mL LPS共干预Caco-2细胞。干预24h后,将细胞裂解提取RNA,转录成DNA后用RT-qPCR检测各细胞因子表达量。
3.2结果分析
3.2.1细胞因子表达量
益生元组合对细胞因子的表达量如表2所示,A-G组均能促进抑炎因子(IL-10)的表达并且抑制促炎因子(IL-8和TNF-α)的表达。其中C、F和G组合能够有效的促进IL-10的表达和抑制IL-8和TNF-α的表达,由此说明2’-FL+3’-SL以特定的比例进行组合有助于调节免疫功能,特别是C、F和G组合具有更加明显的调节作用,有助于调节肠道免疫功能,维持肠道健康。
表2
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
1.一种母乳低聚糖组合物在制备改善微环境健康的婴幼儿食品中的应用,所述改善微环境健康包括能同时促进婴儿结肠产短链脂肪酸乙酸和丙酸、减少婴幼儿肠道气体产生并维持婴幼儿肠道双歧杆菌优势地位、以及调节婴幼儿肠道免疫功能,其中所述母乳低聚糖组合物中的低聚糖由中性低聚糖2’-岩藻糖基乳糖和酸性低聚糖3’-唾液酸乳糖组成,其中2’-岩藻糖基乳糖与3’-唾液酸乳糖的重量比为2.8-3.2:1。
2.根据权利要求1所述的应用,所述2’-岩藻糖基乳糖与3’-唾液酸乳糖的重量比为3:1。
3.根据权利要求1所述的应用,所述的母乳低聚糖组合物还包括瑞士乳杆菌R0052或婴儿双歧杆菌R0033。
4.根据权利要求1所述的应用,所述的母乳低聚糖组合物还包括婴儿双歧杆菌R0033。
5.根据权利要求1所述的应用,所述母乳低聚糖组合物在婴幼儿食品中的终浓度为100mg/100g~104mg/100g。
6.根据权利要求5所述的应用,所述婴幼儿食品为营养补充剂、婴幼儿配方粉或辅食。
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