CN117018039A - Akkermansia muciniphila在制备预防、治疗和/或辅助治疗代谢疾病的产品中的应用 - Google Patents
Akkermansia muciniphila在制备预防、治疗和/或辅助治疗代谢疾病的产品中的应用 Download PDFInfo
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- CN117018039A CN117018039A CN202311048077.1A CN202311048077A CN117018039A CN 117018039 A CN117018039 A CN 117018039A CN 202311048077 A CN202311048077 A CN 202311048077A CN 117018039 A CN117018039 A CN 117018039A
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- akkermansia muciniphila
- fermentation broth
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明属于微生物技术领域,具体涉及Akkermansia muciniphila在制备预防、治疗和/或辅助治疗代谢疾病的产品中的应用。本发明提供了一种Akkermansia muciniphila,已于2020年10月26日保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏编号为:CGMCC No.20955。本发明的Akkermansia muciniphila可以有效降低血糖水平,降低TC、TG、LDL‑C水平,升高HDL‑C水平,尤其在提高HDL‑C水平上具有显著的功效,表明Akkermansia muciniphila对糖尿病小鼠具有良好的降血糖、降血脂、调节胆固醇的作用。
Description
技术领域
本发明属于微生物技术领域,具体涉及Akkermansia muciniphila在制备预防、治疗和/或辅助治疗代谢疾病的产品中的应用。
背景技术
代谢性疾病即因代谢问题引起的疾病,包括代谢障碍和代谢旺盛等原因。在体内生物化学过程发生障碍时,某些代谢物质如糖、脂肪、蛋白质、嘌呤、钙铜等堆积或缺乏而引起的疾病。症状轻重不一,诊断依靠临床表现及血、尿等生物化学检查。尚无有效的根治方法,主要是消除病因和对症处理。预后取决于病因、症状的轻重和治疗效果。常见的高发病率代谢性疾病有肥胖、糖尿病、脂代谢紊乱等。
糖尿病是一组由多病因引起的以慢性高血糖为特征的代谢性疾病,是由于胰岛素分泌和(或)利用缺陷所引起的。长期的高血糖水平会引起多系统的损害,导致眼、肾、神经、心脏、血管等组织器官出现慢性进行性病变、功能减退及衰竭。病情严重或者应激时,可引起急性的严重代谢紊乱,如糖尿病酮症酸中毒、高渗高血糖综合征等。目前治疗糖尿病的药物主要为西药制剂,包括胰岛素制剂、磺酰脲制剂、双胍制剂、胰岛素抵抗改良剂、α-葡萄糖苷酶抑制剂等。这些药物作用于血糖调控的某一环节而发挥血糖控制作用,起效快,但副作用大,且疗效单一,容易产生抗性。
研究表明,菌群失调造成内毒素入血所致的慢性炎症,是肥胖、糖尿病等代谢性疾病发展的重要因素之一。菌群紊乱失衡可引发全身慢性反应炎症,从而导致胰岛β细胞损伤和胰岛素抵抗下降,同时影响体内其他细胞对糖分的吸收用以转化能量,造成人体机能难以正常运转,最后引发一系列并发症。研究表明益生菌能有效抑制前期糖尿病发展成2型糖尿病,益生菌有助于人体降低血糖浓度,从而抑制前期糖尿病的症状[1]。
专利CN113330109A涉及嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila)SNUG61027菌株(保藏号KCTC13530BP)及其用途。具体地,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,用于食欲控制或预防、改善、缓解和治疗代谢性疾病的用途,以及使用该组合物进行食欲控制或预防、改善、缓解和治疗代谢性疾病的方法,所述组合物包含所述菌株、或其培养液等或由其分离的B2UM07蛋白作为活性成分,所述代谢性疾病为葡萄糖耐量受损、糖尿病、动脉硬化、高脂血症、高胆固醇血症、脂肪肝、心血管疾病或肥胖症。
随着生活方式的变化,糖尿病患病率逐年升高,且越来越多的患者合并有其他代谢性疾病,这严重影响了患者的生活质量和生命健康,也形成了巨大的临床需求。因此,为患者提供安全有效、可及且可负担的创新药物至关重要。
[1]朱丽丽等.益生菌制剂治疗2型糖尿病临床疗效的Meta分析[J].中国微生态学杂志.2019,31(02).
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,进行了包含代谢性疾病、心血管疾病、止痛、抗肿瘤、认知疾病、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、辅助治疗或预防代谢性疾病应用技术的保护。
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AKK PROBIO,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
为了解决上述问题,本发明提供了一种Akkermansia muciniphila,其特征在于,于2020年10月26日保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏编号为:CGMCC No.20955。Akkermansia muciniphila可以有效降低血糖水平,降低TC、TG、LDL-C水平,升高HDL-C水平,尤其在提高HDL-C水平上具有显著的功效。
本发明系针对Akkermansia muciniphila的下游应用技术请求保护。
具体为Akkermansia muciniphila在代谢性疾病中的应用。
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应用于代谢性疾病的预防、治疗、辅助预防、辅助治疗;
2、以食品制备用途将Akkermansia muciniphila应用于代谢性疾病的辅助预防、辅助治疗或调节代谢或者平衡代谢;
3、以保健品制备用途将Akkermansia muciniphila应用于代谢性疾病的辅助预防、辅助治疗或调节代谢或者平衡代谢;
4、以原料制备用途将Akkermansia muciniphila应用于代谢性疾病的预防、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在代谢性疾病中的应用,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,从代谢性疾病种类而言,前述应用包括但不限于:糖代谢异常、脂代谢异常、钙磷代谢异常、骨代谢异常和/或嘌呤代谢异常。
基于各种代谢性疾病的发生均是由物质合成代谢和分解代谢障碍所导致的疾病。本领域技术人员根据Akkermansia muciniphila在某种具体的代谢性疾病(糖尿病)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代谢性疾病疾病中。
更具体地,所述的糖代谢异常为糖尿病和/或低血糖。
优选地,所述的糖代谢异常为糖尿病。
更具体地,所述的脂代谢异常可以是肥胖症、脂肪肝、高脂血症和/或厌食症。
更具体地,所述的钙磷代谢异常可以是高钙血症、低钙血症、甲状旁腺功能亢进、甲状旁腺功能减退和/或甲状旁腺瘤。
更具体地,所述的骨代谢异常可以是骨质疏松、骨软化和/或骨营养不良。
更具体地,所述的嘌呤代谢异常可以是高尿酸血症、急性痛风性关节炎和/或慢性痛风性关节炎。
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,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。
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,所述的药物的剂型为片剂、胶囊剂、颗粒剂或注射剂。
更具体地,所述的药物包含其他治疗代谢性疾病的药物。
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代谢性疾病的方法,该方法为向代谢性疾病患者施用Akkermansia muciniphila。
具体地,所述的代谢性疾病患者为经过临床诊断患糖代谢异常、脂代谢异常、钙磷代谢异常、骨代谢异常和/或嘌呤代谢异常的患者。
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,向代谢性疾病患者施用包含下述(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,所述的药物包含其他治疗代谢性疾病的药物。
再一方面,本发明还提供了基于上述应用所产生、派生、衍生出的Akkermansiamuciniphila对代谢性疾病的预防、治疗方法。
具体地,基于Akkermansia muciniphila治疗或预防代谢性疾病的用途,还可以对菌株进行改良,产生、派生、衍生出治疗或预防代谢性疾病效果更好的Akkermansiamuciniphila,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,获得治疗或预防代谢性疾病效果更好的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代谢性疾病效果更优的菌株。
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代谢性疾病效果。
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,以获得治疗或预防代谢性疾病效果更好的菌株。
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,以获得治疗或预防代谢性疾病效果更好的菌株。
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,以获得治疗或预防代谢性疾病效果更好的菌株。
再一方面,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,一种治疗或预防代谢性疾病的保健品,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,一种治疗或预防代谢性疾病的药物,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,所述的药物的剂型为片剂、胶囊剂、颗粒剂或注射剂。
更具体地,所述的药物包含其他治疗代谢性疾病的药物。
具体地,一种治疗或预防代谢性疾病的食品,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。
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,用于治疗或预防代谢性疾病的食品原料,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,用于治疗或预防代谢性疾病的药物原料,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,用于治疗或预防代谢性疾病的工业原料,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。
本发明所取得的的技术效果:
(1)Akkermansia muciniphila可以有效降低血糖水平,具备良好的降血糖功能。
(2)Akkermansia muciniphila能降低TC、TG、LDL-C水平,升高HDL-C水平,尤其在提高HDL-C水平上具有显著的功效。
保藏说明:
菌株名称:AKK PROBIO;
保藏编号:CGMCC No.20955;
分类命名:Akkermansia muciniphila;
保藏日期: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;
保藏单位地址:北京市朝阳区北辰西路1号院3号。
附图说明
图1为小鼠血清中高密度脂蛋白胆固醇(HDL-C)水平。
具体实施方式
下面结合具体实施例,对本发明作进一步详细的阐述,下述实施例不用于限制本发明,仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明,实施例中未注明具体条件的实验方法,通常按照常规条件,下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
名词和术语:
甘油三酯(Triglyceride,TG):又称为中性脂肪,是甘油分子与脂肪酸反应所形成的脂类,为血脂的其中一种组成部分,具有为细胞代谢提供能量的功能。甘油三酯测定为血脂检查中的一项重要内容,是血浆中各脂蛋白所含甘油三酯的总和。
总胆固醇(Total Cholesterol,TC):血液中各种脂蛋白所含胆固醇的总和,胆固醇是细胞膜的主要成分,同时也是合成肾上腺皮质激素、性激素、胆汁酸及维生素D等生理活性物质的重要原料。人体血液中总胆固醇浓度可作为脂代谢的指标,用于评估动脉粥样硬化和缺血性心脑血管疾病的发病风险。
高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C):是一种抗动脉粥样硬化的脂蛋白,可将胆固醇从肝外组织转运到肝脏进行代谢,由胆汁排出体外,其血浆含量的高低与患代谢性疾病的风险呈负相关。
低密度脂蛋白胆固醇(Low density lipoprotein cholesterol,LDL-C):是空腹血浆中的主要脂蛋白,约占血浆脂蛋白的2/3,是运输胆固醇到肝外组织的主要运载工具。其浓度与代谢性疾病的发病率有明显正相关。
本发明中的Akkermansia muciniphila即为AKK PROBIO。
实施例1AKK PROBIO的培养
(1)培养基
固体平板培养:BHI(脑心浸出液(Brain Heart Infusion),OXOID,货号:CM1032B))+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。
实施例2动物实验
2.1动物
8周龄雌性C57BL/6小鼠(上海南方模式生物科技股份有限公司)共40只,体重18-22g,无特定病原体。实验前适应性饲养一周,自由进食和饮水,饲养环境符合SPF级要求。
2.2试剂与仪器
血糖仪:爱科莱动物血糖仪BS-7110。
阳性药:盐酸二甲双胍片,中美上海施贵宝制药有限公司,批准文号:H20023371。
链脲佐菌素(STZ),上海北诺生物科技有限公司,货号:Sigma 100mg。
高密度脂蛋白胆固醇(HDL-C)检测试剂盒,上海研尊生物科技有限公司,货号:YZ-P63995。
低密度脂蛋白胆固醇(LDL-C)检测试剂盒,上海研启生物科技有限公司,货号:YQ-2710。
甘油三酯(TG)检测试剂盒,上海烜雅生物科技有限公司,货号:XY-SJH-XS1465。
总胆固醇(TC)检测试剂盒,上海齐源生物科技有限公司,货号:QYS-234007。
2.3动物造模及药物干预
低脂饲料:Research Diets D12450B,上海华雅思创生物科技有限公司,货号:D12450J;高脂饲料:Research Diets D12451,上海华雅思创生物科技有限公司,货号:D12451。链脲佐菌素(STZ),溶于0.1mol/L,pH4.4的柠檬酸溶液中,0.22μm微孔过滤,保持冰浴;4℃保存,现用现配。
STZ诱导糖尿病小鼠模型的建立,对照组(10只)低脂饲料饲养,糖尿病模型组(50只)高脂饲料饲养,喂养4周后,注射STZ注射前禁食1h,糖尿病模型组连续5d小剂量70mg/kg腹腔注射STZ,对照组注射等体积的柠檬酸缓冲液。注射后,对照组喂低脂饲料;糖尿病模型组继续给予高脂饲料。小鼠禁食8h后第7天后尾静脉取血测空腹血糖,用灭菌小剪刀剪尾取血,应用血糖仪测定血糖,血糖≥11.1mmol/L确定为糖尿病模型成功。
将糖尿病模型组小鼠随机分为3组:模型对照,阳性药组,AKK PROBIO组,每组10只。阳性药组给予盐酸二甲双胍片,灌胃量为150mg/kg;AKK PROBIO组,灌胃量为1×109CFU/只。所有药物每天按照相应剂量灌胃2次(早晚各一次),对照组和模型组灌胃等量的柠檬酸溶液,均给药5周。
2.4指标检测
2.4.1小鼠血糖
检测小鼠给药前和5周给药后,各组小鼠空腹血糖值。
2.4.2血清指标检测
在第5周给药后禁食8h,心脏取血方式采集小鼠新鲜血液,将各组小鼠血液室温放置1h后,1000×g离心20min,获得血清标本。参考试剂盒说明书,检测血清甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平。
2.5实验结果
2.5.1小鼠血糖和体重
小鼠血糖见表1,模型组的血糖水平显著高于对照组,说明了小鼠高血糖模型构建成功。阳性药组和AKK PROBIO组与模型组相比均显著降低了血糖水平,AKK PROBIO组几乎达到了与阳性药组相当的水平,说明了AKK PROBIO具有良好的降血糖作用。
表1
2.5.2血清检测指标
血清检测指标见表2,与对照组相比,模型组小鼠血清中的清TC、TG、LDL-C水平显著升高,HDL-C水平显著降低。阳性药组和AKK PROBIO组与模型组相比均有效降低了TC、TG、LDL-C水平,升高了HDL-C水平,并且AKK PROBIO组的HDL-C水平高于阳性药组。表明了AKKPROBIO具有调节糖尿病小鼠血脂和总胆固醇的作用,并有效降低低密度脂蛋白,提高高密度脂蛋白。
表2
对比例
参照实施例1的培养方法,实施例2中的血清检测指标实验,将本发明的AKKPROBIO替换为阿克曼氏菌的ATCC标准菌株(ATCC BAA 835),进行实验,具体结果见表3。
表3
以上结果表明阿克曼氏菌的ATCC标准菌株也能够提高糖尿病小鼠血清中的HDL-C水平,但是效果远不如本申请的AKK PROBIO。
应用实施例1:AKK PROBIO活菌制备
AKK PROBIO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 PROBIO死菌制备
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 PROBIO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 PROBIO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 (21)
1.Akkermansia muciniphila在制备预防、治疗和/或辅助治疗代谢疾病的产品中的应用,其特征在于,所述的Akkermansia muciniphila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所述的应用,其特征在于,所述的代谢性疾病为糖代谢异常、脂代谢异常、钙磷代谢异常、骨代谢异常和/或嘌呤代谢异常。
6.根据权利要求5所述的应用,其特征在于,所述的糖代谢异常为糖尿病和/或低血糖。
7.根据权利要求6所述的应用,其特征在于,所述的糖代谢异常为糖尿病。
8.一种治疗代谢性疾病的方法,其特征在于,向代谢性疾病患者施用Akkermansiamuciniphila。
9.根据权利要求8所述的方法,其特征在于,所述的代谢性疾病患者为经过临床诊断患糖代谢异常、脂代谢异常、钙磷代谢异常、骨代谢异常和/或嘌呤代谢异常的患者。
10.根据权利要求8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。
11.根据权利要求8-10任意一项所述的方法,其特征在于,向代谢性疾病患者施用包含下述(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。
12.一种治疗和/或预防代谢性疾病的药物,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。
13.根据权利要求12所述的药物,其特征在于,所述的药物的剂型为片剂、胶囊剂、颗粒剂或注射剂。
14.根据权利要求12所述的药物,其特征在于,所述的药物中Akkermansiamuciniphila的活菌数不低于1×108CFU/g或1×108CFU/mL。
15.根据权利要求12所述的药物,其特征在于,所述的药物包含其他治疗代谢性疾病的药物。
16.根据权利要求12-15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、使制剂与接受者的血液等渗的溶质、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。
17.一种医药原料、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。
18.一种辅助治疗和/或预防代谢性疾病的食品,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。
19.根据权利要求18所述的食品,其特征在于,所述的食品为巧克力、固体饮料、液体饮料、冰激淋、软糖、压片糖果、果冻、凝胶颗粒和/或晶球。
20.根据权利要求18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。
21.根据权利要求18-20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。
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