CN113662936A - Egcg在制备调节肠道菌群药物中的应用 - Google Patents
Egcg在制备调节肠道菌群药物中的应用 Download PDFInfo
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Abstract
本发明公开了EGCG在制备调节肠道菌群药物中的应用。本发明通过体外模拟体内环境，并收集人体粪便中的肠道微生物，进行EGCG体外干预实验，首次验证并发现了EGCG对于肠道菌群具有调节作用，尤其是可以显著或极显著上调多种肠道益生菌的丰度，包括：栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter和毛螺旋菌属Parasutterella，因此EGCG不仅可作为肠道菌群调节药物、功能食品或保健食品，有效预防和/或治疗肠道菌群紊乱；而且还可用于辅助治疗与上述益生菌相关的如痛风、肝硬化、克罗恩、便秘、抑郁症、2型糖尿病等疾病，对于维持肠道菌群稳定以及相关疾病的辅助治疗具有重要意义，具有较大的应用价值。
Description
技术领域
本发明属于医药保健技术领域，具体涉及EGCG在制备调节肠道菌群药物中的应用。
背景技术
EGCG，即表没食子儿茶素没食子酸酯，是绿茶茶多酚的主要组成成分，是从茶叶中分离得到的儿茶素类单体，研究发现其具有抗菌、抗病毒、抗氧化、抗动脉硬化、抗血栓形成、抗血管增生、抗炎以及抗肿瘤等多种有益作用，然而其对于肠道微生物的调节作用，目前未见相关报道。
人体肠道中存在的数量庞大的微生物，这群微生物依靠人体的肠道生活，同时帮助人体完成多种生理生化功能。肠道微生物不仅在膳食和宿主之间起到了重要的桥梁作用，其本身以及代谢产物也能调节人体健康，因此肠道微生物与人体健康密切相关。肠道微生物通过与宿主之间的动态性生理作用，达到微生态平衡，有效防止肠道内细菌及内毒素易位。当正常的微生物群落受到宿主及外环境影响时，原有的平衡遭到破坏，肠道菌群失调，肠道正常菌群的种类、数量和比例发生异常变化，转变为病理性组合状态，进而导致宿主致病。目前研究表明，人体的多种疾病都与肠道微生物具有密切关联，如栖粪杆菌属(Faecalibacterium)已有多篇文献报道其与痛风、肝硬化、肠道疾病或便秘、抑郁症和糖尿病等有关联，如文献Guo,Zhuang et al.Intestinal Microbiota Distinguish GoutPatients from Healthy Humans.Scientific Reports,2016中报道了在痛风患者体内，其肠道微生物Faecalibacterium prausnitzii被几乎耗尽，并且其肠道菌群变化与2型糖尿病患者和肝硬化类似，因此Faecalibacterium菌属可作为判断人体健康的指标之一；同时文献Fujimoto et al.Decreased abundance of Faecalibacterium prausnitzii in thegut microbiota of Crohn's disease.Journal of Gastroenterology and Hepatology,2013,28(4),613–619中报道了Faecalibacterium菌属与克罗恩疾病相关；文献Zhuang,Minet al.Abundance of Probiotics and Butyrate-Production Microbiome ManagesConstipation via Short-Chain Fatty Acids Production and HormonesSecretion.Molecular Nutrition&Food Research,2019.中报道了Faecalibacterium菌属与肠道功能相关，便秘会导致该菌丰度降低；文献Simpson,Carra A et al.The gutmicrobiota in anxiety and depression-Asystematic review.Clinical PsychologyReview,2020.中报道了Faecalibacterium与抑郁症相关。又如布劳特氏菌属Blautia，研究报道其与痛风、便秘和抑郁症等疾病相关，又如丁酸弧菌属Anaerostipes，研究发现其主要与便秘和抑郁症等疾病相关。又如纺锤链杆菌属Fusicatenibacter，有研究报道其与多种肠道疾病相关，又如毛螺旋菌属Parasutterella，研究报道其与肝硬化疾病相关。基于此，通过改变肠道微生物菌群的构成，使某些益生菌在体内富集使其丰度增加，并进一步减少肠道有害菌，可能对某些疾病的治疗提供帮助，目前肠道微生物已被认为是多种疾病的治疗靶点之一。
发明内容
本发明针对现有技术的空白，提供了EGCG在制备调节肠道菌群药物中的应用，通过体外模拟进行EGCG干预实验，首次验证了EGCG具有调节肠道菌群的作用，尤其是显著上调了其中栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter，毛螺旋菌属Parasutterella的增殖，增加上述肠道益生菌的丰度，因此可用于制备调节肠道菌群的药物、功能食品或保健食品，不仅可有效预防和/或治疗肠道菌群紊乱，而且还可用于辅助治疗痛风、肝硬化、克罗恩、便秘、抑郁症、2型糖尿病等疾病。
为实现上述目的，本发明采用的技术方案是：
本发明提供了表没食子儿茶素没食子酸酯在制备调节肠道菌群药物中的应用。
本发明提供了包含表没食子儿茶素没食子酸酯的药物组合物在制备调节肠道菌群药物中的应用。
本发明提供了表没食子儿茶素没食子酸酯在制备调节肠道菌群的功能食品或保健食品中的应用。
进一步地，所述表没食子儿茶素没食子酸酯促进肠道益生菌的增殖，所述肠道益生菌选自：栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter，毛螺旋菌属Parasutterella中的一种或多种。
进一步地，所述表没食子儿茶素没食子酸酯通过增加栖粪杆菌属Faecalibacterium的丰度，达到改善痛风、肝硬化、克罗恩、便秘、抑郁症和/或2型糖尿病的作用。因此可将其制成用于辅助治疗痛风、肝硬化、克罗恩、便秘、抑郁症和/或2型糖尿病的药物。
进一步地，所述表没食子儿茶素没食子酸酯通过增加布劳特氏菌属Blautia的丰度，达到改善痛风、便秘和/或抑郁症的作用。因此可将其制成用于辅助治疗痛风、便秘和/或抑郁症的药物。
进一步地，所述表没食子儿茶素没食子酸酯通过增加丁酸弧菌属Anaerostipes的丰度，达到改善便秘和/或抑郁症的作用。因此可将其制成用于辅助治疗便秘和/或抑郁症的药物。
进一步地，所述药物中还包括药学上可接受的辅料。
进一步地，所述药物组合物为片剂、胶囊剂、粉剂、丸剂、颗粒剂或溶液剂。
进一步地，所述功能食品或保健食品为饼干、糕点、饮料、口服液、冲剂、饮料、液体乳类、奶粉。
与现有技术相比，本发明的有益效果是：本发明通过体外模拟体内环境，并收集正常人体粪便中的肠道微生物，进行EGCG体外干预实验，首次验证并发现了EGCG对于肠道菌群具有调节作用，尤其是可以显著上调多种肠道益生菌的丰度，包括：栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter，毛螺旋菌属Parasutterella等，因此EGCG不仅可作为肠道菌群调节药物、功能食品或保健食品，有效预防和/或治疗肠道菌群紊乱；而且还可用于辅助治疗与上述益生菌相关的如痛风、肝硬化、克罗恩、便秘、抑郁症、2型糖尿病等疾病，对于维持肠道菌群稳定以及相关疾病的辅助治疗具有重要意义，具有较大的应用价值。
附图说明
图1为本发明实施例1中试验组和对照组中部分肠道微生物的丰度测定分析结果。
具体实施方式
下面将结合本发明中的实施例，对本发明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条件下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
考虑到来源于人体的肠道菌群无法完全在小鼠体内进行定殖，导致菌群丰度测定结果不准确的问题，在体外进行体内模拟实验，取人体粪便作为肠道菌群样品，观察EGCG干预对于肠道菌群的作用，具体操作过程如下：
1、粪便样品处理
(1)PBS缓冲液配制
以1000ml为例，用电子分析天平分别称取下列药品，倒入1000ml烧杯中，包括：KH2PO4 0.24g，Na2HPO4·12H2O 2.90g，NaCl 8.00g，KCl 0.20g。
用量筒量取800ml超纯水倒入烧杯中，放入搅拌转子，并放到磁力加热搅拌器上搅拌至完全溶解，然后用校准后的PH计测量上述溶液的PH，用0.1M的HCl或NaOH调整PH＝7.4±0.05。
将上述完全溶解并调节pH后的溶液用玻璃棒引流至1000ml容量瓶中，用少量超纯水冲洗烧杯后倒入容量瓶，重复3次。将容量瓶中的液体用超纯水定容至刻度线，塞上盖子后上下颠倒10次，确保溶液充分混匀。
将定容后的溶液倒入洁净黄色盖子的玻璃瓶，每1000ml的瓶子内放500ml溶液，防止高压灭菌时喷出。将黄色玻璃瓶盖子拧松后，放入高压灭菌锅，121℃，15分钟。取出后迅速拧紧盖子。待降至室温后，将溶液需存于4℃冰箱中，可保存6个月。
(2)粪便样品处理
以10g为例，最终浓度为5％。
用百分之一的天平称量出10g粪便样品，用自动移液枪取适量上述PBS缓冲液加至离心管中，在振荡器上充分混匀。然后将完全混匀的样品平均分装至新50ml离心管中，每管再加适量PBS缓冲液。
混匀后在生物安全柜内进行过滤，把稀释好的样品依次通过20目、50目、100目、200目的滤网。收集滤液至离心管中，将离心管放入离心机，配平，6000G，4℃离心15min，弃上清。将沉淀称量之后，以终浓度为5％用PBS溶液定容，得到肠道微生物样品。
2、EGCG干预实验
(1)基础培养基配制
配制用于培养肠道微生物的基础培养基：GAM培养基，以1000ml为例。用电子分析天平称取60g改良GAM肉汤药品，倒入1000ml烧杯中。用量筒量取800ml超纯水倒入烧杯中，放入搅拌转子，并放到磁力加热搅拌器上搅拌至完全溶解。将上述完全溶解的溶液用玻璃棒引流至1000ml容量瓶，并用少量超纯水冲洗烧杯后倒入容量瓶，重复3次。将容量瓶中的液体用超纯水定容至刻度线，塞上盖子后上下颠倒10次，确保溶液充分混匀。
将定容后的溶液倒入洁净黄色盖子的玻璃瓶，每1000ml的瓶子内放500ml培养基，防止高压灭菌时喷出。将装有培养基的黄色盖子的玻璃瓶，瓶盖拧松，放入脉冲高压灭菌锅，使用液体程序，121℃，15分钟。灭菌完后，立即把瓶盖拧紧，冷却至室温。
(2)EGCG-GAM培养基配制
于无菌操作台上，用1ml的移液枪取上述GAM培养基分装至玻璃管中，每管2ml。将黑色盖子放在瓶口上微掩。接着用1ml移液器取EGCG溶液(EGCG购于盛恒生物科技有限公司，纯度90％，用PBS缓冲液溶解至质量百分浓度为：5％)，加入上述装有GAM培养基的玻璃管中，每管2ml，作为试验组。同时还设置有空白对照组，每组3个重复，分组具体如下：
试验组：2ml GAM培养基+2ml EGCG溶液+1mL PBS缓冲液；
对照组：2ml GAM培养基+3mL PBS缓冲液；
确认好每个玻璃管盖拧紧后，转移至厌氧箱传递箱中，放置之前需用84消毒液消毒处理。放入厌氧箱后，拧松瓶盖，置换氧气，需置换12个小时。
将上述处理后得到的肠道微生物样品分别接种至试验组(EGCG-GAM培养基)以及空白对照组(GAM培养基-PBS缓冲液)中，每管1ml。
于厌氧箱中培养72小时后，观察菌群的生长状况，拍照留存。
接着分别将试验组样品和对照组样品，10000rpm，3min离心，弃上清，将沉淀用液氮处理，并送至武汉艾康健生物科技有限公司，分别测定试验组和对照组中的肠道菌群丰度，即不同肠道微生物在检测到的所有菌种中所占的百分比，其中部分肠道菌群的丰度测定结果如表1所示。
并对部分肠道菌群经EGCG干预前后的丰度变化进行显著性分析。
分析结果如图1所示，其中**表示P＜0.01，即丰度变化有极显著差异；*表示P＜0.05，即丰度变化有显著差异。
表1不同处理组的肠道菌群丰度
结果显示，经EGCG干预后，肠道菌群中的部分益生菌，包括：栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter的丰度相较于对照组均有极显著地提高，此外，毛螺旋菌属Parasutterella的丰度也有小幅度增长，与对照组存在显著性差异。上述结果说明，EGCG具有调节肠道菌群，有效预防和/或治疗肠道菌群紊乱，并可用于辅助治疗与上述益生菌相关的，如痛风、肝硬化、克罗恩、便秘、抑郁症、2型糖尿病等疾病。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。
Claims (10)
1.表没食子儿茶素没食子酸酯在制备调节肠道菌群药物中的应用。
2.包含表没食子儿茶素没食子酸酯的药物组合物在制备调节肠道菌群药物中的应用。
3.表没食子儿茶素没食子酸酯在制备调节肠道菌群的功能食品或保健食品中的应用。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述表没食子儿茶素没食子酸酯促进肠道益生菌的增殖，所述肠道益生菌选自：栖粪杆菌属Faecalibacterium，布劳特氏菌属Blautia，丁酸弧菌属Anaerostipes，纺锤链杆菌属Fusicatenibacter，毛螺旋菌属Parasutterella中的一种或多种。
5.根据权利要求4所述的应用，其特征在于，所述表没食子儿茶素没食子酸酯通过增加栖粪杆菌属Faecalibacterium的丰度，达到改善痛风、肝硬化、克罗恩、便秘、抑郁症和/或2型糖尿病的作用。
6.根据权利要求4所述的应用，其特征在于，所述表没食子儿茶素没食子酸酯通过增加布劳特氏菌属Blautia的丰度，达到改善痛风、便秘和/或抑郁症的作用。
7.根据权利要求4所述的应用，其特征在于，所述表没食子儿茶素没食子酸酯通过增加丁酸弧菌属Anaerostipes的丰度，达到改善便秘和/或抑郁症的作用。
8.根据权利要求2所述的应用，其特征在于，所述药物中还包括药学上可接受的辅料。
9.根据权利要求8所述的应用，其特征在于，所述药物组合物为片剂、胶囊剂、粉剂、丸剂、颗粒剂或溶液剂。
10.根据权利要求3所述的应用，其特征在于，所述功能食品或保健食品为饼干、糕点、饮料、口服液、冲剂、饮料、液体乳类、奶粉。
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| CN114164154A (zh) * | 2021-12-14 | 2022-03-11 | 美益添生物医药(武汉)有限公司 | 一种利用鳖甲提取物制备的fmt供体菌液及方法和应用 |
| CN114181855A (zh) * | 2021-12-07 | 2022-03-15 | 美益添生物医药(武汉)有限公司 | 一种定向增殖用于肠道菌群移植的肠道菌群制剂和制作方法及应用 |
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| CN114146099A (zh) * | 2021-12-07 | 2022-03-08 | 美益添生物医药(武汉)有限公司 | 一种含有多种低丰度菌的fmt供体菌液及其制备方法和应用 |
| CN114181855A (zh) * | 2021-12-07 | 2022-03-15 | 美益添生物医药(武汉)有限公司 | 一种定向增殖用于肠道菌群移植的肠道菌群制剂和制作方法及应用 |
| CN114164154A (zh) * | 2021-12-14 | 2022-03-11 | 美益添生物医药(武汉)有限公司 | 一种利用鳖甲提取物制备的fmt供体菌液及方法和应用 |
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