CN115192602B - 一种复合益生元及其在调节肠道功能中的应用 - Google Patents
一种复合益生元及其在调节肠道功能中的应用 Download PDFInfo
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Abstract
本发明公开了一种复合益生元及其在调节肠道功能中的应用,所述复合益生元有效成分包括透明质酸类物质和四氢嘧啶类物质,透明质酸类物质占这两者总质量的60~90%,四氢嘧啶类物质占这两者总质量的10~40%。本发明开拓性地第一次建立了以透明质酸类物质和四氢嘧啶类物质为主要有效成分的复合益生元与肠道菌群的关系。通过试验证明,本发明复合益生元可作为一种全新的益生元,用于调节肠道的功能,且在制备调节动物肠道菌群的食品、药品或保健品中得到应用。
Description
技术领域
本发明涉及一种对肠道有益的复合益生元,具体涉及一种含透明质酸类物质和四氢嘧啶类物质的复合益生元及其在调节肠道功能中的应用,属于医药生物技术领域。
背景技术
益生元通常被定义为“选择性发酵的、不易被消化的食品成分,这些食品成分通过选择性地刺激定殖在胃肠道中的一种或少数几种菌落中的细菌的生长与活性而对寄主产生有益的影响从而改善寄主健康”(Gibson and Roberfroid,1995)。益生元的这一定义表明,并不是所有饮食的碳水化合物都是益生元。益生元必须满足以下标准:(1)抗胃酸(低pH值)、哺乳动物酶水解和胃肠道吸收;(2)由肠道菌群发酵;(3)选择性地刺激肠道细菌的生长和/或活动,进而促进人或动物健康。益生元改善肠道功能,促进有益菌生长,抑制病原菌生长,增加短链脂肪酸(SCFAs),降低总胆固醇和低密度脂蛋白(LDL)胆固醇,并且增强免疫功能。
肠道稳态的建立与维持依赖于肠道的屏障——肠道上皮粘膜层。肠道上皮中的多种细胞(包括普通上皮细胞、杯状细胞、潘氏细胞等)通过分泌黏液及多种抗菌活性物质,构成肠道抵御病原微生物入侵的第一道防线(Bevins and Salzman,2011;Shan et al.,2013)。
透明质酸(hyaluronic acid,HA)是一种由双糖(葡糖醛酸及N-乙酰氨基葡糖)基本结构组成的高分子多糖物质,是细胞外基质的重要组成成分,主要表达在动物包括肠道在内的大部分软***中。HA能够对肠上皮细胞起保护作用,例如在辐射诱导的肠道上皮损伤模型中,辐射前腹腔注射HA能够缓解辐射引起的肠道上皮细胞凋亡(Riehl et al.,2012),在葡聚糖硫酸钠(DSS)诱导的急性结肠炎模型中,联合使用HA和胆红素可以调节肠道菌群,增加其丰富度和多样性,恢复紧密连接相关蛋白的表达和肠道屏障功能,从而对急性结肠炎有很强的抗炎作用(Yonghyun et al.,2019)。上述研究暗示了大分子质量的HA,一方面可能作为益生元为肠道共生菌提供多糖类物质促进肠道菌群共生,进而维持更好的肠道稳态;另一方面透明质酸可以吸附在黏膜表面形成生物膜,增强肠道屏障,抵抗病原微生物的进一步刺激,提高了对病原菌的控制能力。
依克多因(2-甲基-1,4,5,6,-四氢嘧啶-4-羧酸)来源于高嗜盐菌,故也把依克多因称“耐盐菌萃取液”。在高盐、高温、高紫外线辐射的极端条件下,依克多因使嗜盐菌免受伤害。在不同的体外和体内模型中,依克多因是一种具有抗炎特性的溶质(Buenger andDriller,2004;Abdel-Aziz et al.,2013;Sydlik et al.,2013;Graf et al.,2008)。在DSS诱导的结肠炎模型中,依克多因通过稳定连接结构,减少炎症、白细胞浸润和氧化应激来改善DSS诱导的肠上皮屏障功能障碍(Castro-Ochoa et al.,2018)。
透明质酸和依克多因单独作用,均具有肠道调节功能,但目前未见这两者共同用于肠道调节的报道。而且,从现有技术研究的益生元食品、药品和保健品来看,本领域的研究主要集中在以低聚糖为原料配方来对人体肠道中的菌群进行调节。因此,开发原料丰富、成本较低、功能更强的益生元对促进人体及动物的肠道菌群健康具有重要的意义,也为人体和动物体使用益生元提供更宽的市场选择。
发明内容
本发明的目的是提供一种复合益生元,该复合益生元以透明质酸类物质为主要成分,配以特定小剂量的四氢嘧啶类物质,能够在调节肠道功能方面表现出更为明显的增效作用,功能强大,且原料易得、成本低廉,能满足多样化的市场选择,具有重要意义。
本发明以特定比例的透明质酸类物质和四氢嘧啶类物质为有效成分,二者组合而成的复合益生元能够协同调节肠道菌群结构,通过动物试验发现,其不仅能够促进乳杆菌和双歧杆菌等益生菌增殖,效果能够与市面上公认的益生元聚葡萄糖相媲美,而且还能够显著抑制致病菌如肠杆菌、肠球菌和产气荚膜梭菌的生长,特别是,在试验研究过程中意外发现该组合物能促进动物肠道菌群中嗜粘蛋白-艾克曼菌的生长,将其制备成健康食品、保健食品或药品具有潜在应用价值。
本发明具体技术方案如下:
一种复合益生元,所述复合益生元的有效成分包括透明质酸类物质和四氢嘧啶类物质,其中,以透明质酸类物质和四氢嘧啶类物质的总质量为100%计,透明质酸类物质占这两者总质量的60%~90%,四氢嘧啶类物质占这两者总质量的10%~40%。
优选地,所述复合益生元中,透明质酸类物质占这两者总质量的75%,四氢嘧啶类物质占这两者总质量的25%。
进一步的,所述透明质酸类物质包括透明质酸、透明质酸盐和透明质酸衍生物中的至少一种。所述透明质酸衍生物可以为乙酰化透明质酸、硫酸化透明质酸、赖氨酸透明质酸、左旋透明质酸、硬脂酰透明质酸、二甲基甲硅烷醇透明质酸酯、透明质酸苄酯、透明质酸抗坏血酸酯、透明质酸交联聚合物等。所述透明质酸类物质的分子量为50 kDa~500kDa,优选为80kDa~120kDa。各透明质酸类物质在所限的范围内,均能满足本发明的要求,起到调节肠道的作用。
进一步的,所述四氢嘧啶类物质包括包括四氢嘧啶(依克多因)、四氢嘧啶医学领域可接受的盐、四氢嘧啶医学领域可接受的酯、羟基四氢嘧啶、羟基四氢嘧啶医学领域可接受的盐和羟基四氢嘧啶医学领域可接受的酯中的至少一种。各四氢嘧啶类物质均能与透明质酸类物质协同起到很好的条件肠道功能的作用。
进一步的,本发明选择的透明质酸类物质和四氢嘧啶类物质都对人体有益,安全无毒,且透明质酸类物质和四氢嘧啶类物质均可以通过微生物发酵制得,产量大,价格低廉。
进一步的,本发明所述的复合益生元除了有效成分外,还含有药剂学中可接受的辅料,以便将复合益生元制备成所需要的各种剂型;所述剂型可以为片剂、散剂、颗粒剂、胶囊剂或液体混悬液等常用剂型。
本发明复合益生元制备简单,将透明质酸类物质和四氢嘧啶类物质按照配比混合均匀即可。在使用时,本发明复合益生元可以加入到鲜乳、乳制品或其他食品中一起食用或直接用水稀释之后食用。
经试验验证,本发明复合益生元对动物体的肠道功能有很好的调节作用,且效果明显优于透明质酸类物质或四氢嘧啶类物质单用的效果,这两者复合具有明显的增效作用。尤其是,本发明复合益生元能够显著增殖动物肠道益生菌并抑制肠道条件致病菌生长,因此其能够调节动物肠道菌群,在制备调节动物肠道菌群的药物、食品或保健品中得到应用。
进一步的,本发明提供了上述复合益生元在制备调节动物肠道菌群的药物、食品或保健品中的应用。
进一步的,本发明提供了上述复合益生元在制备促进动物肠道中的有益菌的药物、食品或保健品中的应用,所述有益菌为嗜粘蛋白-艾克曼菌(Akkermansia)、乳杆菌(Lactobacillus)和双歧杆菌(Bifidobacterium)。目前报道的益生元均是对常规的乳杆菌、双歧杆菌等常见肠道有益菌有利,目前未见益生元对嗜粘蛋白-艾克曼菌也有促进作用的相关报道,本发明是首创。
进一步的,本发明提供了上述复合益生元在制备抑制动物肠道中的条件致病菌的药物、食品或保健品中的应用,所述条件致病菌为肠杆菌(Enterobacteriaceae)、肠球菌(Enterococcus)和产气荚膜梭菌(Clostridium perfringens)。
进一步的,本发明提供了一种药品,其包括上述的复合益生元。
进一步的,本发明提供了一种食品,其包括上述的复合益生元。
进一步的,本发明提供了一种保健品,其包括上述的复合益生元。
本发明的创造性贡献在于以透明质酸类物质为主要成分,配以特定小剂量的四氢嘧啶类物质,首次发现四氢嘧啶类物质可以促进透明质酸类物质的功效及利用率(促进动物肠道中嗜粘蛋白—艾克曼菌、乳酸杆菌和双歧杆菌等益生菌增殖,抑制条件致病菌如肠杆菌、肠球菌和产气荚膜梭菌的生长),并意外发现添加了四氢嘧啶类物质的透明质酸类物质具有与聚葡萄糖相媲美的调节肠道菌群的功效。
与现有技术相比,本发明的有益效果主要体现在:
1、本发明开拓性地第一次建立了以透明质酸类物质和四氢嘧啶类物质为主要有效成分的复合益生元与肠道菌群的关系。本发明首次阐明透明质酸类物质和四氢嘧啶类物质作为复合益生元有复配增效作用,对肠道菌群有调节作用,拓展了透明质酸类物质和四氢嘧啶类物质在食品和医药领域中的应用范围。
2、本发明以透明质酸类物质和四氢嘧啶类物质为主要有效成分的复合益生元不仅表现在其可以促进嗜粘蛋白-艾克曼菌、乳杆菌和双歧杆菌的生长,还表现在其能够显著抑制肠杆菌、肠球菌和产气荚膜梭菌的生长。
3、本发明所述透明质酸类物质和四氢嘧啶类物质原料丰富,制备工艺产业化,产品无毒副作用,具有广阔的开发应用前景。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的试验方法,若无特别指明,实施例中的试验条件均为常规试验条件。实施例中所用的试验材料、试剂等,如无特殊说明,均可从商业途径得到。
透明质酸的来源:华熙生物科技股份有限公司。
依克多因的来源:华熙生物科技股份有限公司。
聚葡萄糖的来源:济南德乐生物技术有限公司。
实施例1
称取粉末状的透明质酸(分子量为80kDa)60克和粉末状的依克多因40克,将二者混合、搅拌均匀,即得复合益生元。
实施例2
称取粉末状的透明质酸(分子量为80kDa)75克和粉末状的依克多因25克,将二者混合、搅拌均匀,即得复合益生元。
实施例3
称取粉末状的透明质酸(分子量为120kDa)90克和粉末状的依克多因10克,将二者混合、搅拌均匀,即得复合益生元。
实施例4
按照实施例2的方式制备复合益生元,不同的是:透明质酸的分子量为50kDa。
实施例5
按照实施例2的方式制备复合益生元,不同的是:透明质酸的分子量为500kDa。
实施例6
按照实施例2的方式制备复合益生元,不同的是:透明质酸的分子量为300kDa。
对比例1
称取粉末状的透明质酸(分子量为80kDa)95克和粉末状的依克多因5克,将二者混合、搅拌均匀,即得复合益生元。
对比例2
称取粉末状的透明质酸(分子量为80kDa)55克和依克多因45克,将二者混合、搅拌均匀,即得复合益生元。
对比例3
称取聚葡萄糖75克和粉末状的依克多因25克,将二者混合、搅拌均匀,即得复合益生元。
对比例4
称取粉末状的透明质酸(分子量为80kDa)75克和聚葡萄糖25克,将二者混合、搅拌均匀,即得复合益生元。
对上述实施例和对比例制备的复合益生元的肠道调节功能进行验证,方法如下:
受试样品:本发明上述实施例和对比例制得的复合益生元。
对照样品:单一的透明质酸(分子量为80kDa),单一的依克多因,单一的聚葡萄糖。
试验动物:8周龄、SPF级雄性C57BL/6J小鼠。
动物处理:小鼠饲养4周适应环境后,进行试验处理。将小鼠随机分为14组,3只/笼,每组6只:第一组每天给予正常饮食并灌胃200μL PBS溶液;第二至十一组每天给予正常饮食,并分别灌胃200μL 本发明实施例1-6和对比例1-4的复合益生元,灌胃量为300mg/kg体重;第十二组每天给予正常饮食并灌胃200μL 透明质酸(分子量为80kDa),灌胃量为300mg/kg体重;第十三组每天给予正常饮食并灌胃200μL 依克多因,灌胃量为300mg/kg体重;第十四组每天给予正常饮食并灌胃200μL聚葡萄糖,灌胃量为300mg/kg体重;整个动物试验过程持续2周,试验结束后收集小鼠粪便于无菌的器皿中。
检测方法:每个样品称重取200mg小鼠粪便,放在新的高压灭菌过的1.5mL EP管内,采用Fast DNA SPIN试剂盒(MP Biomedicals,USA)抽提小鼠粪便中的DNA。小鼠粪便DNA抽提成功后,对小鼠粪便中的微生物组成进行分析。
检测结果:微生物多样性检测结果见表1。从表1结果可以看出,本发明实施例的复合益生元以透明质酸为主要成分,配以特定小剂量的依克多因,对小鼠肠道中的嗜粘蛋白—艾克曼菌、乳酸杆菌和双歧杆菌等益生菌具有显著的促进增殖的作用,对于肠杆菌、肠球菌和产气荚膜梭菌等的条件致病菌的生长具有显著的抑制作用,能够对肠道菌群起到调节作用。本发明复合益生元的效果与单一的透明质酸和依克多因相比,有明显的提升,且从实施例和对比例的对比看,采用透明质酸为主(透明质酸类物质占这两者总质量的60~90%)、依克多因为辅(四氢嘧啶类物质占这两者总质量的10~40%)的搭配方式效果更佳,依克多因可以促进透明质酸的功效及利用率,本发明复合益生元具有与聚葡萄糖相媲美的调节肠道菌群的功效。
Claims (7)
1.一种复合益生元,其特征是:有效成分包括透明质酸类物质和四氢嘧啶类物质,透明质酸类物质占这两者总质量的60~90%,四氢嘧啶类物质占这两者总质量的10~40%;透明质酸类物质的分子量为80kDa~120kDa;所述透明质酸类物质为透明质酸和透明质酸盐中的至少一种,所述四氢嘧啶类物质为四氢嘧啶和四氢嘧啶医学领域可接受的盐中的至少一种。
2.根据权利要求1所述的复合益生元,其特征是:透明质酸类物质占这两者总质量的75%,四氢嘧啶类物质占这两者总质量的25%。
3.根据权利要求1所述的复合益生元,其特征是:还包括制成不同的剂型所需的辅料。
4.权利要求1-3中任一项所述的复合益生元在制备调节动物肠道菌群的药物中的应用。
5.权利要求1-3中任一项所述的复合益生元在制备促进动物肠道中的有益菌的药物中的应用,其特征是:所述有益菌为嗜粘蛋白-艾克曼菌、乳杆菌和双歧杆菌。
6.权利要求1-3中任一项所述的复合益生元在制备抑制动物肠道中的条件致病菌的药物中的应用,其特征是:所述条件致病菌为肠杆菌、肠球菌和产气荚膜梭菌。
7.一种药品,其特征是:包括权利要求1-3中任一项所述的复合益生元。
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