CN116942706A - Akkermansia muciniphila在制备预防、治疗和/或辅助治疗肠炎的产品中的应用 - Google Patents
Akkermansia muciniphila在制备预防、治疗和/或辅助治疗肠炎的产品中的应用 Download PDFInfo
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- CN116942706A CN116942706A CN202311049048.7A CN202311049048A CN116942706A CN 116942706 A CN116942706 A CN 116942706A CN 202311049048 A CN202311049048 A CN 202311049048A CN 116942706 A CN116942706 A CN 116942706A
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- enteritis
- akkermansia muciniphila
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- fermentation broth
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Abstract
本发明涉及微生物技术领域,具体涉及具体涉及Akkermansia muciniphila在制备预防、治疗和/或辅助治疗肠炎的产品中的应用。所述的Akkermansia muciniphila菌的保藏编号为CGMCC No.20955。能够显著提高结肠炎小鼠的体重和摄食量,降低小鼠的病活动指数(DAI)和肝脏指数,增加结肠的长度,可显著改善结肠炎小鼠的生理损伤,对肠炎的预防或治疗具有重要的作用。
Description
技术领域
本发明涉及微生物技术领域,具体涉及Akkermansia muciniphila在制备预防、治疗和/或辅助治疗肠炎的产品中的应用。
背景技术
嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila,Akk)是一种革兰氏阴性厌氧菌,在含有黏蛋白的琼脂培养基上,菌落呈不透明的纯白色,直径不超过1mm,最适的生长温度为37℃,pH为6.5,黏蛋白为该菌的主要碳源和氮源,在含有黏蛋白的培养基中该菌以单个或成对的形式存在,菌体呈球形或椭球形。嗜黏蛋白阿克曼氏菌是肠道非优势菌,其可通过降解黏蛋白和细胞通讯参与肠粘膜屏障保护。
炎症性肠病(Inflammatory Bowel Diseases,IBD)是一种慢性非特异性肠道炎性疾病,包括溃疡性结肠炎(Ulcerative Colitis,US)、克罗恩病(Crohn’s Disease,CD)。炎症性肠病具有较为复杂的病因和发病机制,多种因素参与其发生与发展,如环境因素、感染和遗传因素等。目前炎症性肠病的治疗方法主要包括药物治疗和手术治疗,药物治疗主要为使用氨基酸水杨酸类药物,包括美沙拉嗪制剂、奥拉沙嗪制剂和水杨酸柳氮磺胺吡啶等,药物治疗存在一定的副作用,采用手术治疗的方法对患者身体的伤害较大。益生菌是指活菌或死菌包含其产物的细菌,对宿主起到有益作用的微生态制剂。现有技术中发现嗜黏蛋白阿克曼氏菌可以预防和改善免疫性疾病、抗肥胖、高尿酸血症等。
中国专利CN113330109A中公开了嗜黏蛋白阿克曼氏菌菌株及其用途,所述的嗜黏蛋白阿克曼氏菌的保藏号为KCTC13530BP,该专利中提供了用于食欲控制或预防、改善、缓解或治疗代谢性疾病的组合物,所述组合物包含所述菌株、或其培养液等或由其分离的蛋白作为活性成分。该嗜黏蛋白阿克曼氏菌能够使体重减轻并且控制葡萄糖内稳态,而且还对褐色脂肪以及分泌食欲调节激素具有一定的抑制作用。
中国专利CN114369146A中公开了一种阿克曼氏菌Amuc_2172蛋白,并公开了阿克曼氏菌Amuc_2172蛋白在制备抑制Th17细胞分化或肠道炎症或肠道癌症的药物中的用途,Amuc_2172蛋白可以抑制Th17细胞,治疗Th17相关的多种自身免疫性疾病,包括克罗恩病、溃疡性结肠炎、多发性硬化、类风湿关节炎和系统性红斑狼疮等。该专利的安全性高,没有毒副作用,且制备工艺简单,成本低,药效高。
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目前现有技术中并未公开保藏编号为CGMCC No.20955的Akkermansiamuciniphila在肠炎中的应用。
本发明系发明人针对自主开发的微生物资源:保藏编号为CGMCC No.20955的Akkermansia muciniphila(已同日递交其他专利),所进行的下游应用技术开发。
发明人在获得Akkermansia muciniphila后,进行了包含肠炎、心血管疾病、止痛、抗肿瘤、认知疾病、代谢疾病、炎症疾病、骨关节疾病等多个领域应用实验并在部分领域获得了正向实验结果。
考虑到专利法单一性的相关规定,对其中不具备单一性的各适应症分别请求保护。
本发明为针对治疗、辅助治疗或预防肠炎中的应用技术的保护。
由于微生物鉴定、性能试验等相关证据公布于同日递交的微生物专利中,为便于本发明的审查工作,快速了解发明人的前期工作,在本发明发明内容中对Akkermansiamuciniphila的相关信息进行简要披露。
Akkermansia muciniphila:
本部分的结论性信息为便于对本发明的审查工作,而非对本发明保护范围的限制。具体实验过程、实验结果记载于与本发明同日递交的微生物专利中。
1、Akkermansia muciniphila经本发明人分离筛选获得。
2、Akkermansia muciniphila的保藏信息:保藏编号为:CGMCC No.20955。
3、Akkermansia muciniphila的16srRNA:SEQ ID NO.1。
4、Akkermansia muciniphila生理生化性质:
(1)疏水性:随时间的上升而上升,在60min时达到30%以上。
(2)自聚集性:随时间的上升而上升,在20h时趋于稳定,保持在52%左右。
(3)胃肠液耐受:
在胃液中的存活率随时间的延长呈下降趋势,在240min时存活率在85%左右;
在肠液中的存活率整体上呈下降趋势,在240min时存活率在80%以上。
(4)生物膜形成能力:弱性。
(5)急毒实验:
细菌回复突变试验结果显示,该菌株无致突变性;
小鼠通过急性灌胃高、中、低剂量的Akkermansia muciniphila,未出现死亡现象;
受试组小鼠每天的体重变化与对照生理盐水组之间无显著性差异;
在急性灌胃期间,每天受试小鼠的摄食量变化与对照生理盐水组小鼠之间无显著性差异;
在急性灌胃期间,每天受试小鼠的血糖变化与对照生理盐水组小鼠之间无显著性差异;
急性灌胃组与对照生理盐水组小鼠的各项血液指标无显著差异;
肝脏中,受试小鼠肝脏中甘油三酯水平均极显著低于其对照生理盐水组小鼠;
血清中甘油三酯水平在受试小鼠与对照小鼠中无显著差异;
受试小鼠与其对照组小鼠的胆固醇水平在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的胆汁酸水平在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的葡萄糖水平在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的总蛋白水平在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的谷丙转氨酶酶活力在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的谷草转氨酶酶活力在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的肌酐含量在血清中均无显著性差异;
受试小鼠与其对照组小鼠的尿素氮浓度在血清中均无显著性差异;
受试小鼠与其对照组小鼠的心脏、肝脏、脾脏、肾脏、胸腺、大脑、睾丸、肺、胃及肠等主要器官重量基本无显著性差异;
受试小鼠与其对照组小鼠的肝脏和肾脏无显著病理损伤。
(6)亚慢性毒性试验:
小鼠通过连续90天灌胃高、中、低剂量的Akkermansia muciniphila,未出现死亡现象;
受试组小鼠每周的体重变化与对照生理盐水组之间无显著性差异;
在连续灌胃期间,每周受试小鼠的摄食量变化与对照生理盐水组小鼠之间无显著性差异;
在连续灌胃期间,每周中剂量灌胃小鼠的血糖变化与对照生理盐水组小鼠之间存在显著差异,其他组与对照组之间无显著性差异;
灌胃组与对照生理盐水组小鼠的各项血液指标无显著差异;
受试小鼠与其对照组小鼠的甘油三酯水平在肝脏和血清中均无显著性差异;
受试小鼠与其对照组小鼠的胆固醇水平在肝脏和血清中均无显著性差异;
灌胃中剂量小鼠与其对照组小鼠的胆汁酸水平在肝脏中具有显著性差异,而其他组与对照组在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的葡萄糖水平在肝脏和血清中均无显著性差异;
受试小鼠与其对照组小鼠的总蛋白含量在肝脏和血清中均无显著性差异;
受试小鼠与其对照组小鼠的谷丙转氨酶酶活力在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的谷草转氨酶酶活力在血清和肝脏中均无显著性差异;
受试小鼠与其对照组小鼠的肌酐含量在血清中均无显著性差异;
受试小鼠与其对照组小鼠的尿素氮浓度在血清中均无显著性差异;
受试小鼠与其对照组小鼠的心脏、肝脏、脾脏、肾脏、胸腺、大脑、睾丸、肺、胰腺、胃及肠等主要器官重量基本无显著性差异;
受试小鼠与其对照组小鼠的肝脏和肾脏无显著病理损伤;
受试小鼠与其对照组小鼠的血糖调节能力无显著性差异。
(7)Akkermansia muciniphila的药物敏感性分析:
经测定Akkermansia muciniphila对氨苄西林、头孢曲松、头孢噻污、美罗培南、四环素、莫西沙星、氯霉素均敏感。
发明内容
本发明的目的是提供Akkermansia muciniphila在肠炎中的应用,本发明的Akkermansia muciniphila对结肠炎有明显的调节作用,可以缓解结直肠长度缩短,可以显著降低血清中促炎因子IL-1β、IL-6、IFN-γ、iNOS和NF-κB的表达水平;在基因层面上可显著下调结肠组织中p50、p52、p65和IκBβ的mRNA表达水平。
一方面,本发明系针对Akkermansia muciniphila的下游应用技术请求保护。
具体为Akkermansia muciniphila在肠炎中的应用。
具体地,从应用领域而言,前述应用包括:
1、以治疗方法、制药用途将Akkermansia muciniphila应用于肠炎的预防、治疗、辅助预防、辅助治疗;
2、以食品制备用途将Akkermansia muciniphila应用于肠炎的辅助预防、辅助治疗或维持肠道菌群平衡;
3、以保健品制备用途将Akkermansia muciniphila应用于肠炎的辅助预防、辅助治疗或维持肠道菌群平衡;
4、以原料制备用途将Akkermansia muciniphila应用于肠炎的预防、治疗、辅助预防、辅助治疗。
本发明以模型小鼠为例,验证了Akkermansia muciniphila在肠炎中的应用,不应基于动物实验在医药领域的常用性而将本发明的用途范围限制于治疗方法或制药用途。
具体地,从肠炎种类而言,前述应用包括但不限于:结肠炎、小肠炎和/或直肠炎。
基于各种肠炎的发生均是由个体易感性,肠道菌群和黏膜免疫的三种必需共同因素的交互作用所致。本领域技术人员根据Akkermansia muciniphila在某种具体的肠炎(化学性肠炎)的实验,可以合理归纳或推测其能够等同的应用于或至少具备应用潜力于其他肠炎疾病中。
更具体地,所述的结肠炎为治疗相关肠炎、炎性肠炎、缺血性肠炎、伪膜性肠炎、感染性肠炎和/或不明原因的肠炎。
进一步具体地,所述的治疗相关肠炎可以是化学性结肠炎和/或放射性结肠炎。
优选地,所述的治疗相关肠炎为化学性肠炎。
更具体地,所述的炎性肠炎可以是溃疡性结肠炎、克罗恩病、未定型结肠炎。
更具体地,所述的缺血性肠炎是由结肠某段血供减少,不足以维持细胞正常代谢,将引起缺血性肠炎。
更具体地,所述的伪膜性肠炎是由难辨梭状芽孢杆菌引起,临床常见于抗生素治疗后,多见于免疫功能低下患者。
更具体地,所述的感染性肠炎可以是细菌性痢疾和/或急性阿米巴痢疾。
具体地,从原料形式而言,前述应用包含使用Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌、死菌和/或任何直接或间接来源于Akkermansiamuciniphila的成分、组分、组成物、代谢物;以及含有或不含有在某项具体应用领域上所允许的当前的、未来的辅料。
更具体地,所述的发酵液是指将菌种接种于培养基,培养一段时间的液体。
更具体地,所述的发酵液上清是指发酵液经离心后的上层的澄清液体;内含细菌生长繁殖过程丰富的代谢产物及一部分菌体碎片,细菌分泌的酸性物质及细菌素对有害菌有拮抗、杀灭作用;细菌分解食物后的氨基酸,以及合成的维生素都在培养液内,还包括细菌分泌的对人体有用的酶;而部分的菌体成分对人体也有免疫促进作用。
更具体地,所述的发酵液沉淀是指离心出来的液体沉淀,包括游离的蛋白,残留的菌体,破碎的细胞,培养基质的残渣,主要就是蛋白,细胞内的基质。
更具体地,所述的活菌也称活性菌群,可在肠道内定植、繁衍,有利于增加有益菌的数。
更具体地,所述的死菌已经失去生命活力的微生物,无法进行生长和繁殖,由生产过程导致益生菌失去活力,如高温处理或过度干燥。
具体地,从食品领域而言,所述的食品包含:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、食品学上可接受的辅料。
更具体地,所述的食品学上可接受的辅料选自润湿剂、乳化剂、悬浮液稳定剂、赋形剂、稀释剂、润滑剂、防腐剂、甜味剂以及香料中的一种或两种以上的组合。
优选地,所述食品学上可接受的辅料为选自乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油中的至少一种。
更具体地,所述的食品包括但不限于:茶饮、咖啡、汽水、饮料、果汁、饼干、蛋糕、面包、月饼、乳制品、奶制品、糖果和/或巧克力。
具体地,从药物领域而言,所述的药物包含:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、药学上可接受的辅料。
更具体地,所述的药学上可接受的辅料选自润湿剂、乳化剂、防腐剂、抗氧化剂、缓冲剂、赋形剂、稀释剂、润滑剂、抑菌剂、悬浮剂、助悬剂、增溶剂、增稠剂、稳定剂、甜味剂以及香料中的一种或两种以上的组合。
优选地,所述药学上可接受的辅料为选自乳糖、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油中的至少一种。
更具体地,所述的药物的剂型可以是粉剂、片剂、胶囊或丸剂。
更具体地,所述的药物包含其他治疗肠炎的药物。
具体地,从保健品而言,所述的保健品包含:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、保健品中可接受的辅料。
更具体地,所述的辅料选自填充剂、胶囊壳材料、溶剂、稳定剂、赋味剂、甜味剂、色素一种或两种以上的组合。
优选地,所述的填充剂选自淀粉、玉米粉、葡萄中的至少一种;
所述的胶囊壳材料选自明胶、羟丙基甲基纤维素、聚乙烯醇中的至少一种;
所述的溶剂选自水、酒精、甘油、乙醇中的至少一种;
所述的稳定剂选自抗氧剂、防腐剂中的至少一种;
所述的赋味剂选自天然香料、人工香精中的至少一种;
所述的甜味剂选自天然甜味剂、人工甜味剂中的至少一种;
所述的色素选自天然色素、人工色素中的至少一种。
具体地,以上领域从活性剂量而言,所述的Akkermansia muciniphila的活菌数不低于1×108CFU/g或1×108CFU/mL。
优选地,所述Akkermansia muciniphila的活菌数为1×108-1×1012CFU/g或1×108-1×1012CFU/mL。
进一步优选地,所述Akkermansia muciniphila的活菌数为1×109-1×1012CFU/g或1×109-1×1012CFU/mL,如1×109CFU/g(CFU/mL)、2×109CFU/g(CFU/mL)、3×109CFU/g(CFU/mL)、4×109CFU/g(CFU/mL)、5×109CFU/g(CFU/mL)、6×109CFU/g(CFU/mL)、7×109CFU/g(CFU/mL)、8×109CFU/g(CFU/mL)、9×109CFU/g(CFU/mL)、10×109CFU/g等,该数值范围内的其他点值均可选择。
另一方面,本发明还提供了一种治疗肠炎的方法,所述的方法为向肠炎患者施用Akkermansia muciniphila。
具体地,所述的肠炎患者为经过临床诊断患结肠炎、小肠炎和/或直肠炎的患者。
具体地,所述的施用的方法选自口服给药、静脉注射给药、局部给药、皮内给药和/或皮下给药。
具体地,向肠炎患者施用包含下述(1)和(2)的药物:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、药学上可接受的辅料。
更具体地,所述的药学上可接受的辅料选自润湿剂、乳化剂、防腐剂、抗氧化剂、缓冲剂、赋形剂、稀释剂、润滑剂、抑菌剂、悬浮剂、助悬剂、增溶剂、增稠剂、稳定剂、甜味剂以及香料中的一种或两种以上的组合。
优选地,所述药学上可接受的辅料为选自乳糖、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油中的至少一种。
更具体地,所述的药物的剂型可以是粉剂、片剂、胶囊或丸剂。
更具体地,所述的药物包含其他治疗肠炎的药物。
又一方面,本发明还提供了基于上述应用所产生、派生、衍生出的Akkermansiamuciniphila对肠炎的治疗方法。
具体地,基于Akkermansia muciniphila治疗或预防肠炎的用途,还可以对菌株进行改良,产生、派生、衍生出治疗或预防肠炎效果更好的Akkermansia muciniphila,所述的改良方法为传统方法和遗传工程方法。
进一步具体地,所述的传统方法可以是物理方法,化学方法和/或选择方法。
更进一步具体地,所述的物理方法是指利用辐射或高压手段来诱发突变,从而实现菌种改良。
优选地,所述的辐射方法包括紫外线辐射和/X射线辐射;
所述的高压法可以是将微生物暴露在高压环境下,使其产生适应性变化。
更进一步具体地,所述的化学方法是指利用化学药剂来诱发菌种突变。
优选地,所述的化学药剂可以是亚硝酸盐、乙酰胆碱和/或氮芥。
更进一步具体地,所述的选择方法是指通过筛选出具有优良性状的微生物进行繁殖,从而实现菌种改良。
优选地,所述的选择方法是用于改良微生物的代谢途径和/或生长条件,获得治疗或预防肠炎效果更好的Akkermansia muciniphila。
进一步具体地,所述的遗传工程方法可以是基因克隆、基因敲除、基因编辑和/合成生物学,从而获得治疗或预防肠炎的效果更优的菌株。
更进一步具体地,所述的基因克隆是指将目标基因从一个细胞剪出来,并将其插入另一个细胞中,实现目标基因在新的宿主中的表达,以增强原有菌株的治疗或预防肠炎的效果。
更进一步具体地,所述的基因敲除是指通过技术手段将目标基因删除,实现对微生物性状的调控,以获得治疗或预防肠炎的效果更好的菌株。
更进一步具体地,所述的基因编辑是指通过技术手段精准地修改目标基因序列,实现对微生物性状的调控,以获得治疗或预防肠炎的效果更好的菌株。
更进一步具体地,所述的合成生物学是指利用化学合成机技术构建新型基因序列,并将其导入微生物中,实现对微生物性状的调控,以获得治疗或预防肠炎的效果更好的菌株。
又一方面,本发明还提供了基于上述应用所产生、派生、衍生出的包含Akkermansia muciniphila的产品。
具体地,一种治疗或预防肠炎的药物,所述的药物包含:
(1)、产生、派生、衍生出的Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、药学上可接受的辅料。
更具体地,所述的药学上可接受的辅料选自润湿剂、乳化剂、防腐剂、抗氧化剂、缓冲剂、赋形剂、稀释剂、润滑剂、抑菌剂、悬浮剂、助悬剂、增溶剂、增稠剂、稳定剂、甜味剂以及香料中的一种或两种以上的组合。
优选地,所述药学上可接受的辅料为选自乳糖、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油中的至少一种。
更具体地,所述的药物的剂型可以是粉剂、片剂、胶囊或丸剂。
更具体地,所述的药物包含其他治疗肠炎的药物。
具体地,一种治疗或预防肠炎的食品,所述的食品包含:
(1)、产生、派生、衍生出的Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、食品学上可接受的辅料。
更具体地,所述的食品学上可接受的辅料选自润湿剂、乳化剂、悬浮液稳定剂、赋形剂、稀释剂、润滑剂、防腐剂、甜味剂以及香料中的一种或两种以上的组合。
优选地,所述食品学上可接受的辅料为选自乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油中的至少一种。
更具体地,所述的食品包括但不限于:茶饮、咖啡、汽水、饮料、果汁、饼干、蛋糕、面包、月饼、乳制品、奶制品、糖果和/或巧克力。
具体地,一种治疗或预防肠炎的保健品,所述的保健品包含:
(1)、产生、派生、衍生出的Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、保健品中可接受的辅料。
更具体地,所述的辅料选自填充剂、胶囊壳材料、溶剂、稳定剂、赋味剂、甜味剂、色素一种或两种以上的组合。
优选地,所述的填充剂选自淀粉、玉米粉、葡萄中的至少一种;
所述的胶囊壳材料选自明胶、羟丙基甲基纤维素、聚乙烯醇中的至少一种;
所述的溶剂选自水、酒精、甘油、乙醇中的至少一种;
所述的稳定剂选自抗氧剂、防腐剂中的至少一种;
所述的赋味剂选自天然香料、人工香精中的至少一种;
所述的甜味剂选自天然甜味剂、人工甜味剂中的至少一种;
所述的色素选自天然色素、人工色素中的至少一种。
具体地,以上领域从活性剂量而言,所述的产生、派生、衍生出的Akkermansiamuciniphila的活菌数不低于1×108CFU/g或1×108CFU/mL。
优选地,所述Akkermansia muciniphila的活菌数为1×108-1×1012CFU/g或1×108-1×1012CFU/mL。
进一步优选地,所述Akkermansia muciniphila的活菌数为1×109-1×1012CFU/g或1×109-1×1012CFU/mL,如1×109CFU/g(CFU/mL)、2×109CFU/g(CFU/mL)、3×109CFU/g(CFU/mL)、4×109CFU/g(CFU/mL)、5×109CFU/g(CFU/mL)、6×109CFU/g(CFU/mL)、7×109CFU/g(CFU/mL)、8×109CFU/g(CFU/mL)、9×109CFU/g(CFU/mL)、10×109CFU/g等,该数值范围内的其他点值均可选择。
具体地,用于治疗或预防肠炎的食品原料,所述的食品原料为产生、派生、衍生出的Akkermansia muciniphila发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌。
具体地,用于治疗或预防肠炎的药物原料,所述的药物原料为产生、派生、衍生出的Akkermansia muciniphila发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌。
具体地,用于治疗或预防肠炎的工业原料,所述的工业原料为产生、派生、衍生出的Akkermansia muciniphila发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌。
本发明的有益效果为:
Akkermansia muciniphila能够显著提高结肠炎小鼠的体重和摄食量,降低小鼠的病活动指数(DAI)和肝脏指数,增加结肠的长度,以上结果均表明Akkermansiamuciniphila可显著改善结肠炎小鼠的生理损伤,对结肠炎具有较好的干预作用。
保藏说明
菌株名称:AKK PROBIO;
保藏编号:CGMCC No.20955;
分类命名:Akkermansia muciniphila;
保藏时间:2020年10月26日;
保藏单位:中国微生物菌种保藏管理委员会普通微生物中心;
保藏单位简称:CGMCC;
保藏地址:北京市朝阳区北辰西路1号院3号。
附图说明
图1为各组小鼠体重(body weight)变化趋势。
图2为各组小鼠摄食量(Food intake)变化趋势。
图3为各组小鼠DAI得分(DAI Score)。
图4为各组小鼠肝脏指数(Liver index)。
图5为各组小鼠结肠长度(Colon length)。
上图中,Blank为对照组,DSS为模型组;AKK PRO为灌胃活菌组;mAKK PRO组为灌胃灭活菌组。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例,进一步阐明本发明,但下述实施例仅为本发明的优选实施例,并非全部。基于实施方式中的实施例,本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例,都属于本发明的保护范围。下述实施例中,若无特殊说明,所用的操作方法均为常规操作方法,所用设备均为常规设备,各个实施例所用设备材料均相同。
名词和术语:
葡聚糖硫酸钠(Dextran Sulfate Sodium Salt,DSS):是一种化学合成的多糖硫酸酯,主要由葡糖醛酸单位通过硫酸酯键连接而成。DSS本身对人体几乎无毒,不能被结肠上皮细胞吸收,但是可以损伤结肠上皮细胞的紧密连接和基底膜,从而增加肠道渗透性,导致肠道菌群和其他抗原进入黏膜下层和体循环,激活免疫炎症反应,诱导结肠炎症状。
本发明中的Akkermansia muciniphila即为AKK PROBIO,简称AKK PRO。
实施例1
1.1动物及其管理
雄性C57BL/6J小鼠(6-10周龄,体重18-24g)购自北京华阜康生物科技有限公司,涉及小鼠的程序严格按照国际动物护理标准进行,并经由吉林农业大学动物保护机构和管理委员会批准。进行1周的适应性培养,室温(25℃±1℃)光照12h黑暗12h循环下将小鼠进行培养。
1.2动物实验设计
在小鼠的饮用水中加入5.0%(wt/vol)DSS(分子量为36,000-50,000),持续3天以诱导结肠炎。从服用DSS第一天开始,每天灌胃AKK PRO(活菌或灭活,浓度为1×1010CFU/mL),持续9天。将C57BL/6J小鼠随机分为4组:对照组、DSS模型组、AKK PRO组、灭活AKK PRO组(mAKK PRO组)。观察每组小鼠生理指标。
1.3生理指标
生理指标用于评估小鼠的健康状况,将每只小鼠的个体得分合并,生成疾病活动指数(DAI),包括体重变化、摄食量和粪便稠度。评分标准见表1。小鼠实施安乐死后,测量每组小鼠的结肠长度,测量各组小鼠肝脏的重量,并根据以下公式计算免疫器官指数:肝脏指数=肝脏重量(mg)/体重(g)。
表1疾病活动指数(DAI)评分表
Table 1 Disease Activity Index(DAI)Score Table
1.4统计学分析
采用GraphPad对数据进行统计分析,所有数据均以平均±标准差(SD)表示。两组间的统计学意义采用t检验,多组的比较采用双向方差分(ANOVA),P<0.05表示差异具有显著性。
1.5结果
为了确定AKK PRO是否对结肠炎有改善作用,用5.0% DSS,在添加或不添加AKKPRO的情况下诱导急性结肠炎。由图所知,同时用DSS和AKK PRO治疗的小鼠比模型组小鼠体重(图1)和摄食量(图2)降低的更少,DAI得分更低(图3)。同时,免疫器官指数(肝脏指数)的增加和结肠长度的减少表明炎症增加。结果显示,DSS组的免疫器官指数显著增加(P<0.05),但在AKK PRO处理后显著下降(图4)。DSS组小鼠的结肠长度显著降低(P<0.05),但在摄入AKK PRO后显著增加(P<0.05)(图5)。上述结果表明AKK PRO可显著改善结肠炎小鼠的生理损伤。
对比例
参照实施例1中的疾病活动指数(DAI)评分标准,将AKK PRO菌株替换为ATCC标准菌株(ATCC BAA 835),ATCC标准菌株组小鼠灌胃的剂量为活菌或灭活,浓度为1×1010CFU/mL,其余皆与实施例1相同,结果见表2。
表2
结果表明,同时用DSS和ATCC标准菌株(ATCC BAA 835)治疗的小鼠比模型组肝脏指数也有所降低,但效果并不如AKK PRO组、灭活AKK PRO组(mAKK PRO组)。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
应用实施例1:AKK PRO活菌制备方法
AKK PRO活菌的培养方法
(1)培养基
固体平板培养:BHI+5%羊血
按成品要求称取一定体积所需的BHI粉末,以20g/L的比例加入琼脂粉末,定容至相应体积,121℃20min灭菌。灭菌完成后冷却至53℃(手握不烫)时加5%无菌脱纤维羊血,摇匀倾注15-20mL至平皿备用。
(2)培养条件
培养温度:37℃;
培养条件:完全厌氧;
液体发酵液培养:BHI;
培养温度:37℃;
培养条件:8层纱布完全厌氧培养。
(3)菌种扩大培养
一级:取一支2mL甘油管,以10%的接种量接种至含有9mL BHI试管中,37℃厌氧培养24-48h。
二级:取一级发酵试管,以5%的接种量接种至含有90mL BHI的三角瓶中,37℃厌氧培养24h。
三级:取二级三角瓶发酵液,以5%的接种量接种至含有300mL BHI的三角瓶中,37℃厌氧培养13h,20%甘油管-80℃冷冻保藏。
(4)发酵罐培养
将活化好的菌种于大型发酵罐中,培养条件如上。培养结束后离心获得湿菌体。
应用实施例2:AKK PRO死菌制备方法
将应用实施例1制备得到的湿菌体用化学或物理方法将菌体杀死,获得死菌;
所述的化学方法可以是气体杀菌和/或液体杀菌;
具体地,所述的气体杀菌可以是臭氧、环氧乙烷、甲醛、丙二醇、甘油或过氧乙酸蒸汽;
所述的液体杀菌为化学试剂,如乙醇;
所述的物理方法可以是热力杀菌,光照杀菌和/或微波杀菌;
具体地,所述的热力杀菌法可以是燃烧法、干烤法、煮沸法和/或压力蒸汽灭菌法;
所述的光照杀菌可以是日光暴晒、紫外照射和/或电离辐射。
应用实施例3:一种包含AKK PRO的口服药物
将应用实施例1制备得到的湿菌体按照一定的比例与辅料混合,将混合物通过冷冻干燥或喷雾干燥、压片等工艺制成活菌片,或者制成胶囊、颗粒等;
或者将实施例1制备得到的湿菌体进行细胞破碎,然后以适当的技术提取有益成分;提取方式包括离心,蒸馏,浸提,萃取等,具体选择取决于益生菌中所含的成分;将提取的成分按照临床使用需要,药物可以制成胶囊、口服液、颗粒剂、注射液等不同剂型。
应用实施例4:一种包含AKK PRO的酸奶
原材料:实施例1制备得到的湿菌体,牛奶、酸奶、豆浆或牛奶粉(新鲜的),酸奶发酵剂(保加利亚乳杆菌和嗜热链球菌);
以牛奶制备为例:
新鲜牛奶、酸奶发酵剂和湿菌体按照一定的比例混合,搅拌均匀,保鲜膜覆盖后于温暖的地方(最好30-40℃)发酵6-8小时(或过夜),发酵后冰箱冷藏。
Claims (23)
1.Akkermansia muciniphila在制备预防、治疗和/或辅助治疗肠炎的产品中的应用,其特征在于,所述的Akkermansia muciniphila的保藏编号为CGMCCNo.20955。
2.根据权利要求1所述的应用,其特征在于,所述的产品包含Akkermansiamuciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌。
3.根据权利要求2所述的应用,其特征在于,所述的发酵液沉淀包含蛋白质、核酸和/或脂质。
4.根据权利要求1-3任意一项所述的应用,其特征在于,所述的产品为药物、食品、保健品、医药原料、工业原料、食品原料或保健品原料。
5.根据权利要求1-4任意一项所述的应用,其特征在于,所述的肠炎为结肠炎、小肠炎和/或直肠炎。
6.根据权利要求5所述的应用,其特征在于,所述的结肠炎为治疗相关肠炎、炎性肠炎、缺血性肠炎、伪膜性肠炎、感染性肠炎和/或不明原因的肠炎。
7.根据权利要求6所述的应用,其特征在于,所述的治疗相关肠炎为化学性肠炎和/或放射性肠炎。
8.根据权利要求7所述的应用,其特征在于,所述的治疗相关肠炎为化学性肠炎。
9.一种治疗和/或预防肠炎的药物,其特征在于,所述的药物包含:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、药学上可接受的辅料。
10.根据权利要求9所述的药物,其特征在于,所述的药物的剂型为粉剂、片剂、胶囊或丸剂。
11.根据权利要求9所述的药物,其特征在于,所述的药物中Akkermansia muciniphila的活菌数不低于1×108CFU/g或1×108CFU/mL。
12.根据权利要求11所述的药物,其特征在于,所述的药物中Akkermansiamuciniphila的活菌数为1×108-1×1012CFU/g或1×108-1×1012CFU/mL。
13.根据权利要求9所述的药物,其特征在于,所述的药物包含其他治疗肠炎的药物。
14.根据权利要求9-13任意一项所述的药物,其特征在于,所述的药学上可接受的辅料选自润湿剂、乳化剂、防腐剂、抗氧化剂、缓冲剂、赋形剂、稀释剂、润滑剂、抑菌剂、悬浮剂、助悬剂、增溶剂、增稠剂、稳定剂、甜味剂以及香料中的一种或两种以上的组合。
15.一种治疗肠炎的方法,其特征在于,向肠炎患者施用Akkermansia muciniphila。
16.根据权利要求15所述的方法,其特征在于,所述的肠炎患者为经过临床诊断患结肠炎、小肠炎和/或直肠炎的患者。
17.根据权利要求15所述的方法,其特征在于,所述的施用的方法选自口服给药、静脉注射给药、局部给药、皮内给药和/或皮下给药。
18.根据权利要求15-17任意一项所述的方法,其特征在于,向肠炎患者施用包含下述(1)和(2)的药物:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、药学上可接受的辅料。
19.一种辅助治疗和/或预防肠炎的食品,其特征在于,所述的食品包含:
(1)、Akkermansia muciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌;
(2)、食品学上可接受的辅料。
20.根据权利要求19所述的食品,其特征在于,所述的食品为茶饮、咖啡、汽水、饮料、果汁、饼干、蛋糕、面包、月饼、乳制品、奶制品、糖果和/或巧克力。
21.根据权利要求19所述的食品,其特征在于,所述的食品中Akkermansiamuciniphila的活菌数不低于1×108CFU/g或1×108CFU/mL。
22.根据权利要求19-21任意一项所述的食品,其特征在于,所述的食品学上可接受的辅料料选自润湿剂、乳化剂、悬浮液稳定剂、赋形剂、稀释剂、润滑剂、防腐剂、甜味剂以及香料中的一种或两种以上的组合。
23.一种医药原料、工业原料、食品原料或保健品原料,其特征在于,包含Akkermansiamuciniphila的发酵液、发酵液上清、发酵液沉淀、活菌和/或死菌。
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