CN111588726A - 2′-岩藻糖基乳糖调节宿主肠道菌群及增强肠屏障的应用 - Google Patents
2′-岩藻糖基乳糖调节宿主肠道菌群及增强肠屏障的应用 Download PDFInfo
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Abstract
本发明公开了2'‑岩藻糖基乳糖调节宿主肠道菌群及增强肠屏障的应用,属于生物医药技术领域。该新应用为2'‑岩藻糖基乳糖在制备调节宿主肠道菌群及增强肠屏障的药物中的应用,2'‑岩藻糖基乳糖在制备调节宿主肠道菌群及增强肠屏障的保健食品中的应用,2'‑岩藻糖基乳糖在制备调节宿主肠道菌群及增强肠屏障的食品中的应用。本发明首次公开了2'‑岩藻糖基乳糖具有调节宿主肠道菌群及增强肠屏障的作用,可以用于由致病菌感染等引起的肠道菌群紊乱及肠屏障受损的预防及缓解。
Description
技术领域:
本发明涉及2′-岩藻糖基乳糖调节宿主肠道菌群及增强肠屏障的应用,属于生物医药技术领域。
背景技术:
近年来,随着基因测序技术的不断发展,测序的深度不断加深而测序的成本却不断降低,越来越多的研究表明肠道菌群健康对人体肠道乃至全身健康的重要性。出血型腹泻、病毒感染型腹泻、克罗恩病、溃疡性结肠炎等常见胃肠道疾病都发现与患者肠道菌群的失调有重要关系,因此,调节宿主肠道菌群健康,增强肠屏障是预防、缓解甚至治疗这些常见胃肠道疾病的最佳选择。
传统的调节宿主肠道菌群的方法主要是直接摄入益生菌,通过直接增加有益菌的丰度来达到调节肠道菌群的作用,但该方法由于益生菌定殖困难且容易在加工贮藏和食用过程中大量失活而效率低下。益生元作为肠道微生物的专属营养素,由于其大都是低聚糖结构而相对稳定并可以直接调节宿主肠道内原有菌群组成和丰度,成为了调节宿主肠道菌群的更优方案。但益生元作为肠道菌群公用的营养来源,其对菌群的调节往往是复杂和立体的,并非单一靶向性调节宿主体内某一菌株,因此对于不同益生元对宿主肠道菌群的具体调节作用成为了研究的热点。
近年来,大量调研表明,母乳喂养的婴幼儿腹泻和胃肠道感染频率上显著低于非母乳喂养的,而这其中的功效,很大程度上是因为母乳中含有大量不同长度或结构的低聚糖,这些低聚糖被称为母乳低聚糖(Human milk oligosaccharides,HMOs)。2’-岩藻糖基乳糖(2’-Fucosyllactose,2’-FL)作为母乳中最丰富的的一类人乳寡糖,其在母乳中的浓度约为2-5g/L,约占总人乳寡糖的25%。尽管母乳中2’-FL含量丰富,但在其他哺乳动物乳汁中却极其缺乏,所以并未被广泛研究,或普遍应用于食品组分。然而,随着生物技术和发酵工程的快速进步,2’-FL已经逐步能够工业化生产,其主要的功能作用也被广泛研究,并在2015年和2016年先后获得欧盟和FDA的批准,将2’-FL纳为婴儿配方奶粉的合法成分,甚至作为膳食补充剂和营养保健品。
2’-FL作为一种大多数婴幼儿从一出生就接触到的益生元,对宿主肠道菌群的形成过程起到重要作用。早期研究就通过采集母乳喂养和非母乳喂养的婴儿粪便,在结肠模拟器中分别模拟结肠菌群对GOS、乳糖以及2’-FL的利用情况,发现母乳喂养的菌群对2’-FL的利用度较高,利用速率也更快一些,这表明母乳喂养的婴幼儿肠道菌群中有部分能够优先利用2’-FL的菌株被特异性增殖了。在体外的发酵实验中,证实了部分双歧杆菌能优先利用2’-FL等小分子母乳低聚糖来增殖自身,这表明2’-FL可能是一类对宿主菌群健康极其重要的益生元。但目前对于2’-FL在体内对肠道菌群的调节与其益生效果的研究却是比较少的。
发明内容
本发明提供了一种2’-岩藻糖基乳糖的新应用,采用的技术方案如下:
2’-岩藻糖基乳糖在制备调节宿主肠道菌群的药物中的应用。
2’-岩藻糖基乳糖在制备增强肠屏障的药物中的应用。
2’-岩藻糖基乳糖在制备调节宿主肠道菌群保健食品中的应用。
2’-岩藻糖基乳糖在制备增强肠屏障的保健食品中的应用。
2’-岩藻糖基乳糖在制备调节宿主肠道菌群的食品中的应用。
2’-岩藻糖基乳糖在制备增强肠屏障的食品中的应用。
优选的,其中将所述2’-岩藻糖基乳糖以足以增加或减少在人类或人类患者体内肠道微生物的丰度而促进其健康的量施用于人类或人类患者,所述体内肠道微生物主要包括但不限于阿克曼菌或大肠杆菌,增加阿克曼菌或减少大肠杆菌。
优选的,其中由阿克曼菌丰度上调而导致黏蛋白和紧密连接蛋白表达量的上调。
优选的,其中所述黏蛋白包括但不限于MUC2,紧密连接蛋白包括但不限于Occludin。
优选的,其中所述2’-岩藻糖基乳糖以足以增加或减少在人类或人类患者体内肠道微生物的丰度而促进其健康的量是在小鼠实验中相当于1毫克/天到20毫克/天的2’-岩藻糖基乳糖;优选地相当于5毫克/天到15毫克/天的2’-岩藻糖基乳糖;更优选地相当于10毫克/天的2’-岩藻糖基乳糖的量。
本发明首次公开2′-岩藻糖基乳糖可以调节肠道微生物群,特别是增加阿克曼菌和减少大肠杆菌在体内的丰度,并促进宿主黏蛋白和紧密连接蛋白的表达,以达到预防及缓解由致病菌包括但不限于大肠杆菌染等引起的肠道菌群紊乱及肠屏障受损。
本发明有益效果:
本发明对2’-岩藻糖基乳糖进行了研究,通过动物实验,用2’-岩藻糖基乳糖提前对小鼠进行每日灌胃干预以预防及缓解由大肠杆菌感染而引起的肠道菌群紊乱及肠屏障受损。实验周期3个月分别对小鼠肠组织黏蛋白和紧密连接蛋白相关基因mRNA的表达量、小鼠结肠组织切片和肠道菌群16S rDNA等检测后发现:灌胃2’-岩藻糖基乳糖的小鼠结肠组织黏蛋白MUC2和紧密连接蛋白Occludin mRNA的表达量显著增加,肠绒毛相对整齐致密,隐窝结构较为完整,黏液层更为厚实,肠道内壁总体较为健康,肠道菌群中门水平疣微菌门(Verrucomicrobia)等显著增加,变形菌门等(Proteobacteria)显著减少,在属水平中,阿克曼菌等有益菌丰度显著增加,而大肠杆菌属等显著减少,菌群功能上寡糖转运及代谢和部分氨基酸代谢功能显著提高。由此可知:2’-岩藻糖基乳糖能提高肠道屏障功能,上调黏蛋白和紧密连接蛋白的表达量,保护肠道上皮组织,以及提高阿克曼菌属相对丰度,减少大肠杆菌属相对丰度,能有效预防或缓解宿主体内肠道菌群紊乱及肠屏障受损。2’-岩藻糖基乳糖对菌群具有综合作用,不仅能减少致病菌,还能增加有益菌,而增加有益菌会增强肠屏障,进一步减少有害菌,调节宿主代谢等等作用。因此,本发明首次公开了2′-岩藻糖基乳糖可以调节肠道微生物群,特别是增加阿克曼菌和减少大肠杆菌在体内的丰度,并提高肠道屏障功能,以达到预防及缓解由致病菌包括但不限于大肠杆菌感染等引起的肠道菌群紊乱及肠屏障受损。
附图说明
图1为不同组小鼠结肠组织切片经HE染色的效果图。
图2为不同组小鼠结肠黏蛋白和紧密连接蛋白相关基因mRNA表达量的结果图。*表示两组之间P<0.05,具有显著性差异。
图3为不同组小鼠肠道菌群门水平物种堆叠图。
图4为不同组小鼠肠道菌群属水平物种堆叠图。
图5为不同组小鼠肠道菌群阿克曼菌属和大肠杆菌属丰度的对比图。图a为阿克曼菌属,图b为大肠杆菌属。
图6为不同组小鼠肠道菌群功能热图。*表示两组之间P<0.05,具有显著性差异,**表示两组之间P<0.01,具有极显著性差异。
具体实施方式
下面结合具体实施例对本发明做进一步说明,但本发明不受实施例的限制。
实施例1
一、动物侵染模型的建立
将购入的BALB/c小鼠随机分为三组,每组10只,分别为2’-FL组、MC组和CK组,适应期1周后进入干预期。干预期2’-FL组灌胃50mg/mL的2’-岩藻糖基乳糖,每只每天200μL。MC组和CK组在干预期内灌胃等量的生理盐水。干预期8周后进入造模期,造模期3周,其中2’-FL组和MC组灌胃大肠杆菌O157,每只每天约109CFU,CK组灌胃等体积生理盐水。造模期间2’-FL组保持灌胃2’-岩藻糖基乳糖,其余组保持灌胃生理盐水。造模期结束后统一组织扑杀。扑杀后将小鼠组织分装后按需贮藏。
二、小鼠肠组织切片分析
取无粪便段新鲜肠组织0.5cm,置于2mL组织固定液中,常温固定24h,随后石蜡包埋,切片,HE染色,制作病理切片,拍照分析。结果见图1。
由实验结果可知,2’-FL组相较于MC组肠绒毛相对整齐致密,隐窝结构较为完整,黏液层更为厚实,肠道内壁总体较为健康。这表明2’-岩藻糖基乳糖能够保护肠道上皮组织,提高肠道屏障功能。
三、小鼠黏蛋白和紧密连接蛋白表达量分析
取新鲜肠组织0.5cm,用TRIzol试剂盒提取肠组织RNA,再将RNA反转录为cDNA,用微量分光测定cDNA浓度,并用DEPC水归一化,最后用实时定量荧光PCR仪测定黏蛋白MUC2基因和紧密连接蛋白Occludin基因的表达量。结果如图2。
由实验可知,2’-FL组MUC2基因和Occludin基因的表达量均显著高于MC组和CK组,表明2’-FL组肠黏液层更加厚实,细胞紧密连接也更加健康。这表明2’-岩藻糖基乳糖能够上调黏蛋白和紧密连接蛋白的表达,增强肠屏障功能。
四、小鼠肠道菌群16S rDNA测序分析
取新鲜小鼠盲肠,用试剂盒提取盲肠内容物的微生物基因组DNA并使用凝胶电泳检测其有效性。再用带有barcode的特异引物扩增DNA样本16S rDNA的V3+V4区,然后对扩增产物切胶回收,用Qubit3.0荧光计进行定量。将纯化的扩增产物进行等量混合,连接测序接头,根据Illumina官方说明构建测序文库,Hiseq2500的PE250模式上机测序。过滤并合并原始数据后,根据OTU比对结果,注释物种信息,最后使用Omicsmart数据实时交互式在线平台进行生物信息学分析。结果见图3、图4、图5。
由实验可知,灌胃2’-岩藻糖基乳糖的小鼠门水平物种信息与MC组有较大差异,灌胃2’-岩藻糖基乳糖的小鼠厚壁菌门(Firmicutes)和髌骨杆菌门(Patescibacteria)丰度相对降低,而疣微菌门丰度与CK组或MC组相比均极显著提升。在属水平上,灌胃2’-岩藻糖基乳糖的小鼠阿克曼菌属和瘤胃球菌属(Ruminococcaceae)丰度显著增加,大肠杆菌属和毛螺菌属_NK4A136(Lachnospiraceae_NK4A136)丰度显著降低。在菌群功能预测上,ABC转运蛋白表达、精氨酸/脯氨酸代谢、氮素代谢、甲基代谢、淀粉/蔗糖代谢、丙氨酸/天冬氨酸/谷氨酸代谢、氨糖和核糖代谢、果糖/甘露糖代谢和嘌呤代谢能力均显著增强。这表明2’-岩藻糖基乳糖能有效调节肠道菌群,显著增加阿克曼菌属的丰度,降低大肠杆菌属的丰度,提高肠道寡糖转运及代谢和部分氨基酸代谢功能,促进肠道微生物环境往更健康的方向发展。
综上可知:2’-岩藻糖基乳糖能够调节肠道微生物群,特别是增加阿克曼菌和减少大肠杆菌在体内的丰度,提高肠道寡糖转运及代谢和部分氨基酸代谢功能,并促进宿主黏蛋白和紧密连接蛋白的表达,保护肠道上皮组织,提高肠道屏障功能。因此,本实验得知2’-岩藻糖基乳糖具有调节宿主肠道菌群及增强肠屏障的作用,可以用于由致病菌感染等引起的肠道菌群紊乱及肠屏障受损的预防及缓解。
虽然本发明已以较佳的实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可以做各种改动和修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.2'-岩藻糖基乳糖在制备调节宿主肠道菌群的药物中的应用。
2.2'-岩藻糖基乳糖在制备增强肠屏障的药物中的应用。
3.2'-岩藻糖基乳糖在制备调节宿主肠道菌群保健食品中的应用。
4.2'-岩藻糖基乳糖在制备增强肠屏障的保健食品中的应用。
5.2'-岩藻糖基乳糖在制备调节宿主肠道菌群的食品中的应用。
6.2'-岩藻糖基乳糖在制备增强肠屏障的食品中的应用。
7.根据权利要求1到6中任一项所述的应用,其特征在于,其中将所述2’-岩藻糖基乳糖以足以增加或减少在人类或人类患者体内肠道微生物的丰度而促进其健康的量施用于人类或人类患者,所述体内肠道微生物主要包括但不限于阿克曼菌或大肠杆菌。
8.根据权利要求7所述的应用,其特征在于,其中由阿克曼菌丰度上调而导致黏蛋白和紧密连接蛋白表达量的上调。
9.根据权利要求8所述的应用,其特征在于,其中所述黏蛋白包括但不限于MUC2,紧密连接蛋白包括但不限于Occludin。
10.根据权利要求7所述的应用,其特征在于,其中所述2’-岩藻糖基乳糖以足以增加或减少在人类或人类患者体内肠道微生物的丰度而促进其健康的量是在小鼠实验中相当于1毫克/天到20毫克/天的2’-岩藻糖基乳糖;优选地相当于5毫克/天到15毫克/天的2’-岩藻糖基乳糖;更优选地相当于10毫克/天的2’-岩藻糖基乳糖的量。
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Application publication date: 20200828 |