CN117919270A - 口服透明质酸及其盐在缓解急性炎症或急性炎症引起肠道损伤中的应用 - Google Patents
口服透明质酸及其盐在缓解急性炎症或急性炎症引起肠道损伤中的应用 Download PDFInfo
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- CN117919270A CN117919270A CN202311781553.0A CN202311781553A CN117919270A CN 117919270 A CN117919270 A CN 117919270A CN 202311781553 A CN202311781553 A CN 202311781553A CN 117919270 A CN117919270 A CN 117919270A
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- salts
- hyaluronic acid
- intestinal
- acid
- acute inflammation
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了口服透明质酸及其盐在缓解急性炎症或急性炎症引起肠道损伤中的应用,属于益生元领域。本发明口服250‑500kDa透明质酸及其盐的组合物可以通过靶向恢复急性炎症引起的肠道双歧杆菌、拟杆菌及其有益代谢物紊乱,来降低小鼠血液和肠组织中的促炎因子的含量和基因表达水平,抵消由脂多糖引起急性炎症的小鼠肠道菌群结构和代谢物的变化。所述的口服组合物在治疗或者缓解急性炎症引起的肠道菌群失调及炎症因子紊乱的病症中具有广泛的应用前景。
Description
技术领域
本发明涉及口服透明质酸及其盐在缓解急性炎症或急性炎症引起肠道损伤中的应用,属于益生元领域。
背景技术
脂多糖(LPS)是革兰氏阴性菌(病原菌和共生菌)外膜的主要成分,主要由脂质和多糖构成。它是一种常见的内毒素,能引起动物败血症休克,全身包括肠道的急性炎症反应。其中,肠道功能障碍在败血症的发生发展过程中至关重要,这表明肠道在全身炎症反应中起着“马达”的作用。肠道不仅仅是机体消化吸收的地方,更是人体最大的免疫器官:人体70%的免疫细胞分布在肠道,肠道是保护人体健康的第一道防线。肠道上皮的完整与否直接影响肠道健康,肠黏膜屏障的损伤可导致肠通透性增加,激活免疫细胞合成与释放大量的促炎细胞因子和炎性介质,进而诱发异常的黏膜免疫反应。近年来研究发现肠屏障功能受损与肠易激综合征(IBS)、炎症性肠病(IBD)等肠道疾病密切相关。促炎细胞因子可以激活与炎症相关的信号通路,进而引起肠道乃至周身炎症和症状。
有文献研究表明,一些肠道菌及其代谢物可以有效的缓解宿主的炎症反应。拟杆菌属(Bacteroides)是人体肠道中优势细菌,并被认为在维持健康的肠道生态系统中发挥着重要作用。作为下一代益生菌的候选菌种,拟杆菌受到了人们的广泛关注。已有研究表明,某些拟杆菌种可以调节机体代谢,抑制病原菌定植,减轻肠道炎症和脂多糖诱导的全身性炎症等。此外,Cell最新发表的一项研究表明,缺乏双歧杆菌及其母乳寡糖利用基因与生命早期的系统性炎症和免疫失衡相关,但补充婴儿双歧杆菌(Bifidobacteriuminfantis)可缓解这一问题。双歧杆菌属发挥免疫调节功能并不局限于幼儿时期,通过研究成人阶段针对金黄色葡萄球菌、表皮葡萄球菌和婴儿长双歧杆菌的抗菌T细胞反应,结果显示双歧杆菌预刺激的T细胞通过诱导FoxP3+CD4+T细胞、增加IL-10和galectin-1分泌及CTLA依赖性抑制,以细胞依赖性方式抑制葡萄球菌特异性Th细胞的活化。短链脂肪酸是肠道菌群重要的代谢产物,有研究人员报道,丙酸、丁酸可抑制组蛋白去乙酰化酶来缓解神经炎症。通过大肠靶向释放短链脂肪酸,丁酸可以缓解慢性不可预知温和应激诱导的机体LPS、IL-6和IL-1β的紊乱。研究表明,DL乳酸能够调节肠道微生物代谢物、维持肠道黏膜屏障功能完整性及抑制肠道炎症,能够保护小鼠抵抗三硝基苯磺酸(TNBS)诱导的肠道炎症反应。水杨酸可抑制炎症因子的表达,加强炎症反应相关信号通路,以起到缓解炎症反应及相关疾病的作用。肉豆蔻酸又称十四烷酸,是一种14碳长饱和脂肪酸,通过LPS刺激巨噬细胞的体外实验和佛波酯(TPA)诱导的动物炎症实验均证明,肉豆蔻酸可以通过IL-10发挥抗炎作用。丙烯酸又称压克力酸,是最简单的不饱和羧酸,肠道中需要有害微生物的过度繁殖可以大量积累此物质,可以对人体肠道上皮细胞产生刺激,破坏肠道粘膜,降低肠道通透性,从而诱导炎症反应、对人体产生危害。
目前,尚未发现能够靶向调节肠道中拟杆菌、双歧杆菌丰度和丙酸、丁酸与肉豆蔻酸、DL-乳酸、水杨酸以及丙烯酸含量的物质。
透明质酸(HA)作为一种内源性的酸性粘多糖,是由D-葡萄糖醛酸和N-乙酰氨基葡糖的双糖单位组成的非硫酸化的高分子线性多糖,存在于滑液和许多组织的细胞外基质中。值得关注的是,HA还是肠道固有碳源,并且是肠道微生物可以利用的碳源。
YeojungKim等利用35kDa透明质酸钠处理小鼠肠道鼠柠檬酸杆菌感染,对小鼠远端结肠组织的裂解液进行ZO-1印迹分析,检测粪便菌落总数,结果表明35kDa透明质酸改善肠屏障功能,减少鼠柠檬酸杆菌定植,改善鼠柠檬酸杆菌引发的结肠炎。专利公开号CN114191447A提出了20-35kDa的透明质酸钠能降低健康人群和肠炎患者厚壁菌门/拟杆菌门的比例,提高疣微菌门比例,显著提高艾克曼菌属(Akkermansias)和拟杆菌属(Bacteroides)的丰度,虽然该发明提供了透明质酸和肠道菌群的关系,但是基于的动物模型是致病菌感染,依赖于通过III型分泌系注入效应物激活免疫,而不是LPS诱导的急性炎症模型。2023年徐东等发表的核心期刊“痛风的诊疗规范”(中华内科杂志2023年9月第62卷第9期)也说明了口服秋水仙碱可以治疗急性痛风性关节炎,但是对慢性痛风性关节炎没有治疗作用,所以口服一定物质对慢性炎症与急性炎症的作用不能相互推及。此外,以上方法并未对肠道菌群的关键抗炎代谢产物进行深度分析,有一定局限性。通过对比,本发明专利申请与上述公开专利和文献存在本质的不同。
已有的研究表明,不同分子量的透明质酸在免疫调节方面发挥着不同的作用,在多样的生理条件下,透明质酸及其盐是否发挥抗炎或促炎功能均不可预料。目前,现有研究和技术暂未明确口服不同分子量透明质酸及其盐在急性炎症中是否能够发挥免疫调节作用,也不知晓口服何种分子量的透明质酸及其盐可以对LPS导致的肠道急性炎症起到有效缓解或治疗作用,以及对引起急性肠道炎症中的菌群和代谢产物的靶向作用,更不知晓不同分子量透明质酸对急性炎症的调节作用是否具有普遍性或特异性。
发明内容
本发明申请的目的旨在解决目前关于口服透明质酸及其盐在调节肠道急性炎症领域存在的技术问题。目的之一是揭示口服不同分子量透明质酸钠对肠道急性炎症及肠组织损伤的缓解和治疗作用,并获得针对急性炎症缓解效果最好的口服透明质酸分子量范围。目的之二是提供一种基于口服透明质酸及其盐缓解脂多糖引起的急性炎症症状的肠道菌群及代谢物的应用。本发明披露了口服透明质酸和/或其盐在靶向调节肠道菌群中拟杆菌和/或靶向调节肠道菌群代谢物缓解脂多糖引起的急性肠道损伤炎症中的作用。口服一定分子量的透明质酸钠可以显著提高急性炎症肠道中Bacteroides和Bifidobacteriums的丰度,同时显著增加了有益代谢物丙酸、丁酸和肉豆蔻酸、水杨酸、DL-乳酸的含量。目前还未见到关于口服透明质酸及其盐靶向调节肠道菌群及其代谢物缓解或者治疗急性炎症症状的研究。
本发明提供了透明质酸及其盐在制备缓解肠道急性炎症和/或靶向调节急性炎症引起的肠道菌群失调的口服产品中的应用。
在一种实施方式中,所述透明质酸及其盐的分子量包括但不限于250-500kDa,具体地,所述的透明质酸及其盐的分子量可以为250kDa、260kDa、270kDa、280kDa、290kDa、300kDa、310kDa、320kDa、330kDa、340kDa、350kDa、360kDa、370kDa、380kDa、390kDa、400kDa、410kDa、420kDa、430kDa、440kDa、450kDa、460kDa、470kDa、480kDa、490kDa、500kDa及其中任一值。
具体的,所述透明质酸及其盐包括钠盐、钾盐、镁盐、钙盐、锌盐、铋盐或者它们中的两种以上的组合,更具体的,所述的透明质酸盐为钠盐。
在一种实施方式中,所述肠道急性炎症和/或急性炎症引起的肠道菌群失调是由脂多糖(LPS)介导引起的。
在一种实施方式中,所述脂多糖包括来源于革兰氏阴性菌。
在一种实施方式中,所述脂多糖来源于大肠杆菌。
在一种实施方式中,所述口服产品具有如下至少一种功能:
(1)缓解体重减少;
(2)缓解免疫因子紊乱;
(3)靶向调节肠道菌群;
(4)靶向调节肠道代谢物。
在一种实施方式中,所述靶向调节肠道菌群包括提高拟杆菌和双歧杆菌的丰度。
在一种实施方式中,所述靶向调节肠道代谢物包括提高丙酸、丁酸和肉豆蔻酸、DL-乳酸、水杨酸以及丙烯酸的含量。
在一种实施方式中,所述缓解免疫因子紊乱包括降低IL-6、IL-1β、TNF-α和NF-κB的含量。
本发明还提供了一种缓解急性炎症引起的肠道菌群失调和/或相关炎症的口服产品,所述产品包含透明质酸及其盐,优选地,透明质酸及其盐的分子量包括但不限于250~500kDa。
在一种实施方式中,所述透明质酸及其盐包括钠盐、钾盐、镁盐、钙盐、锌盐、铋盐或者它们中的两种以上的组合,更优选地,所述的透明质酸盐为钠盐。
在一种实施方式中,所述的产品还含有其他成分,优选地,所述透明质酸及其盐的质量份为0.2-0.5份。
具体的,所述透明质酸及其盐的质量份可以为0.2份、0.3份、0.4份、0.5份以及其中任一质量份数。
具体的,所述的其他成分包括但不限于适用于口服产品的各种营养素、维生素、矿物质(电解质)、调味剂(例如合成和天然调味剂)、着色剂和增稠剂(奶酪、巧克力)等。还可以含有盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳酸化剂等。另外,本发明的口服产品可以含有用于生产天然果汁、果汁饮料和植物饮料的果肉。
本发明的口服产品可以制造加工成片剂、胶囊剂、粉剂、颗粒剂、液体剂、丸剂等形式。
具体的,片剂形式的口服产品是通过将作为本发明的活性成分透明质酸及其盐与赋形剂、粘合剂、崩解剂和其他添加剂的混合物按常规方式造粒而制成的,然后添加润滑剂等。可以进行压缩成型,或者可以将混合物直接压缩成型。另外,片剂形式的口服产品可以根据需要含有调味剂等。
在胶囊型口服产品中,硬胶囊可通过将作为本发明的活性成分的透明质酸及其盐与添加剂如赋形剂的混合物填充到普通硬胶囊中来制造,软胶囊也可通过将本发明的活性成分透明质酸及其盐与赋形剂等添加剂的混合物填充到普通硬胶囊中而制备。它可以通过将与赋形剂等添加剂混合的混合物填充到胶囊中来制造基质,例如明胶。如果需要,软胶囊可以含有增塑剂例如甘油或山梨糖醇、着色剂、防腐剂等。
丸剂形式的口服产品可以通过将本发明的活性成分透明质酸及其盐与赋形剂、粘合剂、崩解剂等的混合物采用已知的方法成型来制备,如果需要,可以用白糖包衣。或者,表面可以涂有诸如淀粉或滑石粉之类的物质。
颗粒形式的口服产品可以通过使用已知的方法将本发明的活性成分与赋形剂、粘合剂、崩解剂等混合而制成颗粒,并且可以含有矫味剂、矫味剂等。
本发明的口服产品可以是含有本发明的透明质酸及其盐作为活性成分的药物口服产品,并且除了本发明的活性成分之外,还可以使用药学上合适的和生理学上可接受的辅料来制备。助剂可包括赋形剂、崩解剂、甜味剂、粘合剂、包衣剂、溶胀剂、润滑剂、润滑剂或调味剂。
具体的药物口服产品可以是颗粒剂、粉剂、片剂、包衣片剂、胶囊剂、溶液剂、糖浆剂、汁剂、混悬剂、乳剂、滴剂的形式。例如,对于片剂或胶囊形式的制剂,活性成分可以与口服、无毒、药学上可接受的惰性载体例如乙醇、甘油、水等组合。另外,如果需要或必要,混合物中还可以包含合适的粘合剂、润滑剂、崩解剂和着色剂。合适的粘合剂包括但不限于淀粉、明胶、天然糖如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶如阿拉伯树胶、白胶或油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。还可以根据需要添加其他常用添加剂,如抗氧化剂、缓冲剂、抑菌剂等。
在一个实施例中,透明质酸钠固体饮料含有0.2份透明质酸钠、5份蓝莓果粉、15份低聚果糖、15份麦芽糊精、0.1份葡萄糖酸锌。
在一个实施例中,透明质酸钠口服液含有0.3份透明质酸钠、山梨酸钾10-20份,异麦芽低聚糖20份、柠檬酸5份以及纯净水100份。
在一个实施例中,透明质酸钠益生元软糖含有浓缩果汁30份、透明质酸钠0.5份、低聚果糖1份、异麦芽低聚糖1份、柠檬酸0.5份、白砂糖40份、卡拉胶1份、果胶1.5份。
有益效果:
本发明表明,口服分子量为250~500kDa(HA2)的透明质酸可以缓解LPS感染导致的急性炎症或急性炎症引起肠道损伤症状,包括:
(1)抑制体重减少、缓解免疫因子紊乱;
(2)靶向调节肠道拟杆菌和双歧杆菌丰度,整体调节肠道菌群的物种丰富度;
(3)靶向提高肠道菌群有益代谢物丙酸、丁酸和肉豆蔻酸、DL-乳酸、水杨酸的含量,与模型组相比,分别提高9.44,11.14和12.86倍;
(4)靶向降低肠道菌群有害代谢物丙烯酸的含量,与模型组相比,降低3.49倍。
因此,分子量为250~500kDa的透明质酸及其盐可用于制备缓解急性炎症引起的肠道菌群失调和/或相关炎症的药品,还可用于制备靶向调节肠道菌群及代谢物的口服产品。
附图说明
图1不同分子量透明质酸对LPS小鼠体重的影响;A:实验设计的示意图;B:不同组小鼠体重增加量随着时间的变化曲线图;C:LPS诱导之后,不同组小鼠体重的下降的百分比;
图2不同分子量透明质酸对LPS小鼠血清免疫因子的调节作用;
图3不同分子量透明质酸对LPS小鼠空肠免疫因子及组织病理学影响;A:小鼠空肠组织免疫因子mRNA的转录水平分析;B:空肠组织切片;
图4不同分子量透明质酸对LPS小鼠结肠免疫因子及组织病理学影响;A:小鼠结肠组织免疫因子mRNA的转录水平分析;B:结肠组织切片;
图5不同分子量透明质酸对LPS小鼠肠道菌群属水平的影响;A:菌群的α多样性,包括Shannon和Simpson指数分析;B:菌群β多样性分析,使用NMDS主成分分析;C:菌群的柱状堆积图分析;D:菌群随机森林预测模型,分析不同组中差异菌属;E:拟杆菌属相对丰度;F:双歧杆菌属相对丰度;
图6不同分子量透明质酸对LPS小鼠肠道菌群代谢产物的影响;A:乙酸;B:丙酸;C:丁酸;D:总短链脂肪酸;E:肉豆蔻酸;F:DL-乳酸;G:水杨酸;H:丙烯酸。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚,我们进一步对说明书和权利要求书中的一些词汇进行解释说明。本说明书及权利要求并不以名词的差异来作为区分组件的方式,而是以组件在功能上的差异来作为区分的准则。如在通篇说明书及权利要求当中所提及的“包含”或“包括”为一开放式用语,故应解释成“包含但不限定于”。说明书后续描述为实施本发明的较佳实施方式,然所述描述乃以说明书的一般原则为目的,并非用以限定本发明的范围。本发明的保护范围当视所附权利要求所界定者为准。同时我们也将结合附图对本发明的优选实施例进行详细的描述。
下述实施例中涉及的小鼠为8周龄雄性SPF级(Specific pathogen free,无特定病原体)C57BL/6J,购自北京维通利华实验动物技术有限公司;下述实施例ELISA试剂盒购自上海酶联生物科技有限公司;下述实施例中涉及的RNA提取试剂盒购自南京诺唯赞有限公司;下述实施例中使用的qPCR引物合成于生工生物工程(上海)股份有限公司;下述实施例中涉及的微生物组学和代谢组均是在本单位完成。测定方法按照常规分析,与其他公司测定无任何差异。动物实验符合伦理要求,严格按照伦理内容来进行实验。动物实验操作按照动物房要求在特定的动物屏障中进行所有的实验操作。送检样本经4%多聚甲醛固定,固定状态良好后,严格按照病理实验检测程序进行修剪、脱水、包埋、切片、染色、封片最后镜检合格的样片。其中,本发明所用试剂均为常用试剂,均可在常规试剂生产销售公司购买。
实施例1:不同分子量透明质酸对脂多糖感染小鼠的体重及血清免疫因子的影响
具体步骤如下:
1、透明质酸灌胃液的制备
将三种不同分子量范围的透明质酸钠(HA1,平均分子量40kDa(范围在30-50kDa);HA2,平均分子量375kDa(范围在250-500kDa);HA5,平均分子量1750kDa(范围在1500-2000kDa)),分别用生理盐水进行溶解,放置摇床孵育12h,使其完全溶解,至清澈透明,配制成5.5mg/mL的溶液,并保存在4℃下直至使用。
2、实验动物
SPF级8周龄雄性C57BL/6J小鼠,购于北京维通利华实验动物技术有限公司;饲养于25±2℃、相对湿度50±5%、12h光照12h黑暗的标准化实验室中,适应性喂养一周后开始干预实验。
3、实验方法
取适应性喂养一周后健康雄性C57BL/6J小鼠50只,随机分为5组,每组10只,5组分别为:空白组、造模组和分别灌胃HA1、HA2和HA5干预组。
实验过程为:空白组和造模组小鼠按照0.2mL的剂量每天灌胃一次无菌生理盐水,HA1、HA2和HA5干预组小鼠按照0.2mL的剂量每天灌胃一次透明质酸钠溶液,干预4周共28天时间。期间每间隔4天测一次小鼠体重。在第29天,按照10mg脂多糖(以下简称“LPS”)/kg小鼠体重的剂量,给造模组和干预组(HA1、HA2和HA5)小鼠腹腔注射由无菌生理盐水配制的脂多糖(LPS,来源于大肠杆菌,Sigma,货号:L2630)溶液(1mg/mL),空白组不做任何处理,注射8h后,测定小鼠的体重,处死小鼠并采取小鼠的血液离心收集血清。使用ELISA试剂盒测定相关血清中的免疫因子的含量。
如图1所示,与空白组相比,口服透明质酸钠的干预并不会导致小鼠体重显著的增加。但是LPS造模之后,与空白组相比,小鼠体重出现显著的下降。同时与造模组相比,透明质酸钠干预组HA1、HA2和HA5组的小鼠体重下降程度显著降低。与LPS组相比,HA2缓解体重下降的效果最好,是LPS体重下降的42.03%。
进一步使用ELISA试剂盒测定了小鼠血清中IL-6和TNF-α的含量。实验结果如图2所示,LPS的感染显著提高了小鼠血清中促炎因子白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α);与空白组相比,IL-6含量增加3.23倍,TNF-α含量提高3.44倍。而口服透明质酸钠干预后可以有效调节由于LPS刺激引起的细胞因子的变化情况,主要表现在降低促炎因子的分泌。其中HA2的缓解效果最为显著,IL-6含量恢复至空白组的2.09倍,TNF-α含量恢复至空白组的2.04倍。
实施例2:不同分子量透明质酸对脂多糖感染小鼠肠组织细胞因子和肠道病理状态的影响
具体步骤如下:
具体实施方法同实施例1,处死小鼠并取部分它们的空肠和结肠组织置于RNA提取保存液中,提取肠组织的RNA,进行qPCR测定免疫因子转录水平的情况。同时取一段肠组织放入液氮中保存,用于后面测定肠组织中的免疫因子的含量。最后取一小段无内容物的肠组织置于4%多聚甲醛溶液中用于组织切片观察。采用苏木精-伊红染色法对LPS刺激引起的小鼠肠组织损伤以及口服透明质酸钠干预对于肠组织的保护作用进行评价。
实验结果如图3所示,造模组小鼠空肠免疫因子的转录水平与空白组相比具有显著差异。IL-1β,TNF-α和NF-κB基因的表达水平显著高于空白组,分别是空白组1.88,1.78和2.00倍。而透明质酸干预组可以显著的降低这些变化,使其更接近于空白组。其中效果最好的HA2,IL-1β,TNF-α和NF-κB分别是空白组1.30,1.22和1.19倍。组织病理切片分析可知造模组小鼠空肠组织切片存在炎症浸润区域及杯状细胞凋亡,出现严重的空洞现象。透明质酸干预后,炎症小鼠肠道状态显著改善,几乎无炎症浸润与粘膜出血状况。综上分析,口服透明质酸钠可以有效缓解脂多糖引起的小鼠空肠组织的急性炎症和病理损伤,其中HA2的缓解效果最佳。
实验结果如图4所示,造模组小鼠结肠免疫因子的转录水平与空白组相比具有显著差异。IL-6,TNF-α和NF-κB基因的表达水平显著高于空白组。分别是空白组的1.79,1.75和1.54倍。而口服透明质酸钠干预组可以显著的降低IL-6,TNF-α和NF-κB的变化,使其更接近于空白组。其中效果最好的HA2,IL-6,TNF-α和NF-κB分别是空白组的1.29,1.22和1.22倍。组织病理切片分析可知造模组小鼠结肠组织切片存在炎症浸润区域及杯状细胞凋亡。透明质酸干预后,炎症小鼠肠道状态显著改善,几乎无炎症浸润与粘膜出血状况。综上分析口服透明质酸钠可以有效缓解脂多糖引起的小鼠结肠组织的急性炎症和病理损伤,其中HA2的缓解效果优于HA1和HA5。
实施例3:不同分子量透明质酸对脂多糖感染小鼠肠道菌群的影响
具体步骤如下:
具体实施方法同实施例1,在小鼠处死前收集了小鼠粪便用于微生物总DNA提取及16SrRNA基因测序。称取一定量的粪便,采用Fast DNA Spin Kit for Feces试剂盒提取样品离心所得沉淀的细菌基因组后,使用通用引物对16s V3-V4区序列(F-5’-CCTAYGGGRBGCASCAG-3’,R-5’-GGACTACNNGGGTATCTAAT-3’)进行PCR扩增后,通过二代测序仪(MiSeq PE300)测定粪便样品中肠道菌群多样性。
结果如图5所示,与空白组相比,LPS的刺激会显著的影响小鼠的肠道菌群的多样性和菌群结构。与空白组相比,LPS组的Shannon和Simpson指数分别下降了1.37和1.18倍。主成分分析表明,LPS的干预使菌群结构组成发生了很大的偏移,而口服一定分子量透明质酸钠的干预会缓解脂多糖带来的肠道菌群的变化情况,进而维持肠道菌群结构,保护小鼠健康。其中最为显著的是拟杆菌属和双歧杆菌属的变化情况:与空白组相比,LPS组的拟杆菌、双歧杆菌的丰度分别下降5.92、4.25倍。透明质酸钠尤其是HA2可以显著的逆转这些菌属丰度的降低。与LPS组相比,HA2使拟杆菌,双歧杆菌的丰度分别增加了23.18,9.90倍。拟杆菌和双歧杆菌可参与人体肠道中许多重要的代谢活动,且还可以在一定程度上保护机体免受侵入性病原体的侵害。是一种生理性有益菌,对人体健康具有生物屏障、免疫增强作用、改善胃肠道功能和抑制炎症等多种重要的生理功能。由HA2组结果可知,口服250-500kDa分子量的透明质酸钠可以显著改善因急性炎症引起的有益菌群的偏移,整体菌群结构更类似于空白组,优于HA1和HA5。
实施例4:不同分子量透明质酸对脂多糖感染小鼠代谢物的影响
具体步骤如下:
具体实施方法同实施例1和3,采集脂多糖造模后小鼠的粪便,进行代谢产物短链脂肪酸测定。在通风橱内向粪便溶液中准确加入1mL乙醚溶液,震荡30s后离心(8000rpm,15min,4℃),移取上清液至含有0.25g无水硫酸钠的离心管中,震荡均匀,离心(8000rpm,15min,4℃),取上清至气质上样瓶中,通过GC-MS检测短链脂肪酸含量。取一定量的血清,加入0.4mL甲醇与乙腈的混合溶液(v:v=1:1,-20℃预冷),涡旋30s,冰水浴超声10min,-20℃孵育1h,离心(15000rpm,15min,4℃)取上清液。将上清用旋转蒸发仪蒸发至干再加入200μL甲醇:水(v:v=4:1)复溶,随后离心(15000rpm,15min,4℃),用0.22μm滤膜将上清液过滤到注射瓶中。将提取得到的样品转入液相小瓶,进行LC-MS分析。使用Compound Discoverer初步筛选并导出样品代谢物结果,通过VIP和p值分析筛选得到差异代谢物,检测结果见图6。
由图6可知,造模组的短链脂肪酸总体水平与空白组之间差异明显。透明质酸钠HA2干预可以显著提高短链脂肪酸的水平,尤其是特异性调节丙酸和丁酸的含量,使其与空白组更为接近甚至高于空白组。HA2组的丙酸约是模型组的1.49倍,丁酸约是模型组的1.91倍。LPS的刺激会显著降低有益物质肉豆蔻酸(Myristic acid),DL-乳酸(DL-lacticacid),水杨酸(Salicylic acid)的含量,增加有害物质丙烯酸(Acrylic acid)的含量。而透明质酸的干预会显著调节这些差异代谢物的变化,其中HA2的调节效果最为显著。与模型组相比,HA2组肉豆蔻酸,DL-乳酸,水杨酸的相对含量分别提高了9.44,11.14和12.86倍,丙烯酸的相对含量降低了3.49倍。
实施例5:透明质酸钠固体饮料的制备
透明质酸可用于制备固体饮料,固体饮料中各组分的重量如下:0.2份透明质酸钠、5份蓝莓果粉、15份低聚果糖、15份麦芽糊精、0.1份葡萄糖酸锌。采用常规制剂方法将各组分制备成粉剂,分别准确称取各原料粉,充分混合均匀,分装。
实施例6:透明质酸钠口服液的制备
透明质酸可用于制备口服液,口服液中各组分的重量如下:将0.3份透明质酸钠、山梨酸钾10-20份,异麦芽低聚糖20份、柠檬酸5份以及纯净水100份。将上述各组分按重量份数分别准备好,于纯净水中充分溶解后过滤、杀菌、装罐后即制得。
实施例7:透明质酸钠益生元软糖的制备
透明质酸可用于制备益生元软糖,益生元软糖各组分的重量如下:浓缩果汁30份、透明质酸钠0.5份、低聚果糖1份、异麦芽低聚糖1份、柠檬酸0.5份、白砂糖40份、卡拉胶1份、果胶1.5份。按照常规制软糖方法制得混合凝胶溶液,浇注成型,包装,得到成品。
虽然本发明已以较佳实施例公开如上,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,都可做各种的改动与修饰,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.透明质酸及其盐在制备缓解急性炎症引起的肠道菌群失调和/或相关炎症的口服产品中的应用。
2.如权利要求1所述的应用,其特征在于,所述透明质酸及其盐的分子量包括但不限于250~500kDa。
3.如权利要求1或2所述的应用,其特征在于,所述透明质酸及其盐包括钠盐、钾盐、镁盐、钙盐、锌盐、铋盐或者它们中的两种以上的组合,优选地,所述的透明质酸盐为钠盐。
4.如权利要求1-3任一所述的应用,其特征在于,所述应用包括下述任一种或一种以上:
(1)缓解体重减少;
(2)缓解免疫因子紊乱;
(3)靶向调节肠道菌群;
(4)靶向调节肠道代谢物。
5.如权利要求4所述的应用,其特征在于,所述靶向调节肠道菌群包括提高拟杆菌属(Bacteroides)和双歧杆菌属(Bifidobacteriums)的丰度。
6.如权利要求5所述的应用,其特征在于,所述靶向调节肠道代谢物包括提高丙酸、丁酸、肉豆蔻酸、水杨酸、DL-乳酸和/或丙烯酸任一种或一种以上的含量。
7.如权利要求6所述的应用,其特征在于,所述缓解免疫因子紊乱包括降低IL-6、IL-1β、TNF-α和NF-κB任一种或一种以上的含量。
8.一种缓解急性炎症引起的肠道菌群失调和/或相关炎症的口服产品,其特征在于,所述产品包含透明质酸及其盐,优选地,透明质酸及其盐的分子量包括但不限于250~500kDa。
9.如权利要求8所述的产品,其特征在于,所述透明质酸及其盐包括钠盐、钾盐、镁盐、钙盐、锌盐、铋盐或者它们中的两种以上的组合,更优选地,所述的透明质酸盐为钠盐。
10.如权利要求8或9所述的产品,其特征在于,所述的产品还含有其他成分,优选地,所述透明质酸及其盐的质量份为0.2-0.5份。
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