CN117618473A - Pb菌在预防、改善和治疗代谢性疾病中的应用 - Google Patents
Pb菌在预防、改善和治疗代谢性疾病中的应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域,具体涉及一种Paraclostridium benzoelyticum,并且提供了包含Paraclostridium benzoelyticum菌株的药物组合物和菌剂组合物以及食品组合物,并发现了上述菌剂可以显著激活治疗肥胖糖尿病的靶点GPR120,可以抑制体重增长,降低空腹血糖,改善脂代谢水平及非酒精性脂肪肝症状,具有非常大的临床应用价值,能够用于预防、改善或治疗代谢性疾病。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种Paraclostridium benzoelyticum菌及其在代谢性疾病中的应用。
背景技术
肠道微生物群驻留在胃肠道中长期与宿主共生,参与人体的代谢过程。代谢性疾病是以物质代谢异常为基础的症候,物质代谢异常会导致肠道微生物群紊乱,因此,代谢性疾病与肠道微生物群有密切联系。相关研究表明,肥胖、2型糖尿病、脂质紊乱等代谢性疾病的发生与微生物群组成异常有紧密联系。同时,肠道微生物群对药物代谢有较大影响,因此对药物的药代动力学产生影响。
Paraclostridium benzoelyticum (JC272T)是Jyothsna等人于2013年12月从古吉拉特邦(印度属)不同的海洋沉积物样品中分离而来,是杆状、产芽孢、革兰氏染色阳性的专性厌氧细菌。菌株JC272T与Clostridium bifermentans ATCC 638T(99.8%)、Clostridium ghonii JCM 1400T(98.0%)、Clostridium sordellii ATCC 9714T(97.9%)及其他梭菌属成员(<96.4%)序列相似性最高。C16: 0, C18:0, C17:0, C16: 1ω9c和iso-C16:0是主要的(>5 %)脂肪酸。菌株JC272T含有二磷脂酰甘油、磷脂酰甘油、磷脂酰乙醇胺、磷脂酰胆碱和两种未知的氨基脂。菌株JC272T与C. bifermentans ATCC 638T的平均核苷酸同源性(ANI)和计算机DNA-DNA杂交(DDH)的基因组分析结果分别为94.35%和58.5±2.8%。菌株JC272T的DNA G+C含量为28.3 mol%。菌株JC272T和C. bifermentans被发现在梭菌属rRNA集群I之外,被认为是严格敏感梭状芽胞杆菌。基于ANI值、计算机DDH和与先前描述的分类群明显的形态和生理差异,Jyothsna等人认为菌株JC272T代表了梭菌科一个新属的新种,并建议将其命名为Paraclostridium benzoelyticum。模式菌株为JC272T (=KCTC 15476T=LMG 28745T)(T.S. Sasi Jyothsna et al., Paraclostridium benzoelyticum gen. nov., sp. nov.,isolated from marine sediment and reclassification of Clostridium bifermentans as Paraclostridium bifermentans comb. nov. Proposal of a newgenus Paeniclostridium gen. nov. to accommodate Clostridium sordellii andClostridium ghonii. International Journal of Systematic and EvolutionaryMicrobiology (2016), 66, 1268–1274)。
目前,NCBI上仅公开在不同保藏机构有不同保藏号但属于同一来源的同一模式菌株Paraclostridium benzoelyticum——personal::JC272, KCTC:15476, BCCM/LMG:28745(包含了Jyothsna等人同时分离的其他22株Clostridium sp. JC245等菌株,https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi)。
关于该菌种的相关研究也极少,仅有WO2019169138A1公开了使用Paraclostridium benzoelyticum治疗癌症的组合物和方法,在说明书中公开了口服Paraclostridium benzoelyticum(以及和抗PD-L抗体联合)抑制结直肠癌肿瘤生长的数据结果图,但目前还尚未有Paraclostridium benzoelyticum关于代谢相关的疾病研究。
发明内容
本发明的目的是解决上述现有技术的不足,提供Paraclostridium benzoelyticum菌株、或所述菌株的培养物或加工物在制备用于预防、改善或治疗代谢性疾病药物中的应用。
本发明是通过以下技术方案实现的:
本发明涉及微生物菌株、或所述微生物菌株的培养物或加工物在制备用于预防、改善或治疗代谢性疾病的药物中的应用,所述微生物菌株属于Paraclostridium benzoelyticum种,所述代谢性疾病为糖尿病、肥胖及肥胖相关疾病、代谢综合征。
在本说明书中,术语“培养物”指在适合Paraclostridium benzoelyticum存活和/或生长条件下悬于培养基的Paraclostridium benzoelyticum群体。如本领域普通技术人员所清楚了解的,在一些方面,本文所用的这些术语涉及包含Paraclostridium benzoelyticum群体和该群体在其中悬浮的培养基的组合。在另一方面,本文所用的这些术语还涉及指将本发明的Paraclostridium benzoelyticum的培养完成后的培养上清液和培养成分。在本发明中,所述培养物包括但不限于:Paraclostridium benzoelyticum接种或移植于任意形态(液体或固体)的培养基中所得到的含菌溶液、培养上清或含菌培养基。
在本说明书中,术语“加工物”是指只要来自于培养物则不作特别限定,可以通过例如培养物的浓缩、糊化、喷雾干燥、冻结干燥、真空干燥、滚筒干燥、液化、稀释、粉碎等加工而得到。在这些加工中,可以适当使用公知的方法。
在本发明中,所述培养物中或所述加工物中,本发明的微生物菌株可以是活菌,也可以是死菌。
在本说明书中,术语“菌株”可以是由保藏的菌株直接培养获得,也可以是子代菌株(后代)或从原始菌株培养(亚克隆菌株)的菌株。
在本说明书中,术语“糖尿病”包括所有形式的糖尿病,如上所述,其特征为由于胰岛素激素水平不足而导致的代谢紊乱和异常高血糖(高血糖症)。该术语由此包括1型糖尿病(T1D)、2型糖尿病(T2D)、妊娠期糖尿病(GDM)以及葡萄糖耐受不良(IGT)。1型糖尿病是由于自身免疫损害或特发性原因引起的,以胰岛功能绝对破坏为特点的糖尿病,多发生在儿童和青少年,必须用胰岛素治疗才能获得满意疗效,否则将危及生命。2型糖尿病是一种以碳水化合物/脂肪代谢异常为特征的多因子综合征,通常包括高血糖、高血压和胆固醇异常。2型糖尿病是胰岛素不能有效发挥作用(与受体结合含量少)所致,因此不仅要检查空腹血糖,而且要观察餐后2小时血糖,特别应做胰岛功能检查。妊娠期间的糖尿病有两种情况,一种为妊娠前已确诊患糖尿病,称“糖尿病合并妊娠”;另一种为妊娠前糖代谢正常或有潜在糖耐量减退、妊娠期才出现或确诊的糖尿病,又称为“妊娠期糖尿病(GDM)”,糖尿病孕妇中80%以上为GDM。葡萄糖耐受不良(Imparired Glucose Tolerance,IGT)是与胰岛素抗性和心血管疾病风险增加有关的血糖代谢障碍的糖尿病前状态。根据世界卫生组织和美国糖尿病协会的标准,葡萄糖耐受不良被定义为75 g口服葡萄糖耐受试验中两小时的葡萄糖水平为140-199mg/dL(7.8至11.0mmol)。当所述患者在2小时后具有立即升高的葡萄糖水平,但低于2型糖尿病标准时,则被认为处于IGT状态。空腹葡萄糖可为正常或轻度升高。IGT可以早于2型糖尿病多年。IGT还是死亡的危险因素。
需要说明的是,上述制药用途针对糖尿病的应用包括不限于1型糖尿病(T1D)、2型糖尿病(T2D)、妊娠期糖尿病(GDM)和葡萄糖耐受不良(IGT)的治疗或预防。
在本说明书中,术语“肥胖”与体重指数(BMI)相关联。体重指数(BMI)(用以千克为单位的体重除以以米为单位的身高的平方来计算)是最普遍接受的用于超重和/或肥胖的计算方法。BMI超过25认为是超重。将BMI为30或更高定义为肥胖,BMI为35或更高认为是严重的同病性(comorbidity)肥胖,将BMI为40或更高认为是病态肥胖。
如上所述,本文所使用的术语“肥胖”包括超重、肥胖、同病性肥胖和病态肥胖。因此,本文所使用的术语“肥胖”可以定义为BMI大于或等于25的受试者。在一些实施方式中,合适地,肥胖受试者的BMI可大于或等于30、合适地为35、合适地为40。
虽然本发明的组合物特别适用于同时患有糖尿病和肥胖的患者,但本发明的组合物还适于患有糖尿病但无肥胖的患者,其还适用于具有糖尿病风险因素但尚未处于糖尿病状态的肥胖患者。可以预期,肥胖的人(但非糖尿病)可能限制了其肥胖的代谢后果,即形成糖尿病或至少为胰岛素抗性。
另外,用于本发明的Paraclostridium benzoelyticum物种的微生物菌株可用于治疗哺乳动物的代谢综合征。代谢综合征是增加患心血管疾病和糖尿病的风险的医学病症的总称。代谢综合征还被称为代谢综合征X、综合征X、胰岛素抗性综合征、雷文综合征(Reaven's syndrome)或CHAOS综合征(澳大利亚)。
对于代谢综合征目前还没有单独被接受的定义。世界卫生组织标准(1999)要求存在糖尿病、葡萄糖耐受不良、空腹葡萄糖耐受不良或胰岛素抗性,以及下列两种:
血压:≥140/90mmHg;
血脂异常:甘油三酯(TG):≥1.695mmol/L,高密度脂蛋白胆固醇(HDL-C)≤0.9mmol/L(雄性),≤1.0mmol/L(雌性);
中心性肥胖:腰:臀比>0.90(雄性),>0.85(雌性),和/或体重指数>30kg/m2。
微白蛋白尿:尿白蛋白排泄率≥20mg/min,或白蛋白:肌酸酐比≥30mg/g。
欧洲胰岛素抗性研究小组(1999)要求将胰岛素抗性定义为在非糖尿病个体中空腹胰岛素值为25%以上,以及下列的两种或多种:
中心性肥胖:腰围≥94cm(雄性),≥80cm(雌性);
血脂异常:TG≥2.0mmol/L,和/或HDL-C<1.0mg/dL,或被作为血脂障碍进行治疗;
高血压:血压≥140/90mmHg,或进行抗高血压药物治疗;
空腹血糖≥6.1mmol/L。
美国国家胆固醇教育计划(NCEP)成人治疗方案 III(2001)要求下列至少三种:
中心性肥胖:腰围≥102cm或40英寸(雄性),≥88cm或36英寸(雌性);
血脂异常:TG≥1.695mmol/L(150mg/dl);
血脂异常:HDL-C<40mg/dL(雄性),<50mg/dL(雌性);
血压:≥130/85mmHg;
空腹血糖≥6.1mmol/L(110mg/dl)。
优选地,所述肥胖相关疾病包括如下疾病中的至少一种:心血管疾病、高脂血症、胰岛素抵抗综合征和脂肪性肝炎。
根据本发明可使用Paraclostridium benzoelyticum种的微生物菌株治疗的心血管疾病的实例包括动脉瘤、心绞痛、动脉粥样硬化、脑血管意外(中风)、脑血管疾病、充血性心力衰竭(CHF)、冠心病、心肌梗塞(心脏病发作)以及外周血管性疾病。
动脉瘤是由血管壁病变或减弱导致的血管局部充血性膨胀(气球样膨凸)。动脉瘤最常见于脑基底部(大脑动脉环)的动脉和主动脉(出心脏的主要动脉,所谓的主动脉瘤)。随着动脉瘤增大,破裂的风险增加,这可导致严重的出血或包括猝死在内的其他并发症。
心绞痛(angina pectoris,通常称为angina)是由于心肌缺血(血液缺乏和由此的氧供应缺乏)而导致的,通常是由于冠状动脉(心脏的血管)阻塞或痉挛而导致的严重胸痛。冠心病(心绞痛的主要病因)是由于心脏动脉的动脉粥样硬化而导致的。
动脉粥样硬化是由于脂肪物质(例如胆固醇)累积而导致的动脉壁增厚的病症。它是一种影响到动脉血管的综合征,是动脉壁的慢性炎症反应,很大程度上归因于巨噬细胞白细胞累积,且由低密度(特别是小颗粒)脂蛋白(携带胆固醇和甘油三酯的血浆蛋白)促进,而不能通过功能性高密度脂蛋白(HDL)从巨噬细胞适当地去除脂肪和胆固醇。动脉粥样硬化通常被称为动脉硬化或“毛状物附着(furring)”,通常因动脉内形成多发性斑块而导致。
中风是由于脑供血障碍导致的快速发生的脑功能丧失。这可能是由于血栓形成或栓塞引起的缺血(血液供应缺乏)或由于出血而导致的。因此,受影响的脑区不能发挥作用,从而导致机体一侧的一个或多个肢活动不能,语言理解或描述能力缺乏,或一侧视野不能看见并最终死亡。
脑血管疾病是一组与供应脑的血管疾病相关的脑机能障碍。高血压是损害与下层的胶原接触的血管内侧膜内皮的最重要原因,其中血小板在下层胶原累积而启动并不总是完整和完美的修复过程。持续性高血压永久改变血管结构,使其狭窄、僵硬、变形以及不平,使得较易受血压波动影响。睡眠过程中的血压降低可导致窄化血管中的血流显著降低,导致早晨缺血性中风,而血压突然升高则可引起血管破裂,导致日间兴奋过程中颅内出血。主要是老年、糖尿病、抽烟者或具有缺血性心脏病的人群患有脑血管疾病。所有动脉机能障碍相关的疾病都可归类在称为大血管疾病的疾病。这是过分简单的研究,由其使脂肪沉积物或血栓阻塞动脉。脑血管疾病的结果可包括中风,或者甚至有时包括出血性中风。在脑血管意外过程中,缺血或其他血管机能障碍可影响一者。
心力衰竭是其中的心排血量不足以用于机体需要的生理状态的通用术语。这可在心输出量低的情况下发生(常称为“充血性心力衰竭”)。心力衰竭的常见病因包括心肌梗塞和其他形式的缺血性心脏病、高血压、瓣膜性心脏病以及心肌病。
冠心病(或冠状动脉心脏病)是指冠状动脉循环不能向心肌和周围组织供应恰当的循环。它通常等同于动脉粥样硬化性冠状动脉心脏病,但冠状动脉疾病可归因于其他原因,例如冠状血管痉挛。狭窄可能是由于痉挛引起的。
当到达心脏部分的血液供应被阻断而导致某些心脏细胞死亡时,发生心肌梗塞(通常称为心脏病发作)。这最常归因于易损的动脉粥样硬化斑块(动脉壁中脂质(如胆固醇)和白细胞(特别是巨噬细胞)的不稳定积聚)破裂之后冠状动脉阻塞(阻滞)。所导致的缺血(血液供应受限)和氧不足,如果足够长的时间不处理,则可导致心肌损伤和/或坏死(梗塞)。
外周血管性疾病(PVD),也称为外周动脉性疾病(PAD)或外周动脉闭塞性疾病(PAOD),包括由手臂和腿中的大动脉闭塞引起的所有疾病。PVD 可归因于动脉粥样硬化,导致狭窄的炎症过程、栓塞或血栓形成,其导致急性或慢性缺血(血液供应缺乏),通常发生在腿部。
在本发明中,所述肥胖相关疾病与所述代谢综合征的症状会有相同或相似之处,但在本发明中均属于代谢相关疾病,不会影响保护范围的确定。
在本发明的范围内考虑到本发明的实施方式可以组合,使得本文所述的任何特征的组合也包括在本发明的范围内。特别地,在本发明的范围内考虑到可同时体现所述细菌的任何治疗效果。
优选地,所述功能性菌剂或药物用于如下至少一种用途:
预防或治疗肥胖引起的糖尿病;
预防或治疗Ⅱ型糖尿病;
减轻哺乳动物的体重;
减轻哺乳动物脂肪组织重量;
降低哺乳动物的空腹血糖;
降低哺乳动物血液中甘油三酯和/或低密度脂蛋白-胆固醇水平;
降低哺乳动物肝脏中总胆固醇和/或甘油三酯水平。
在本发明中,所述改善是指降低超过正常范围的水平和/或提高低于正常范围的水平。
优选地,所述微生物菌株为能够在生理生化水平和/或分子生物学水平鉴定为Paraclostridium benzoelyticum的任一菌株。
优选地,所述微生物菌株与选自包括P. benzoelyticum JC272、P. benzoelyticum KCTC 15476、P. benzoelyticum LMG 28745和P. benzoelyticum CCTCC M20232265的P. benzoelyticum菌株组中的至少一种具有至少98.65%、99.85%、99.93%或100%一致性的16s rRNA基因序列、重要功能性基因序列、调控子序列、重要的分子标志物序列、分化性能更高的基因序列或全基因组序列。或者针对上述菌株中的至少一种,针对全基因组序列的任一段特定序列或任意多种特定或不特定序列,利用PCR扩增进而测序,若某微生物菌株的扩增子中至少一个具有至少98.65%、99.85%、99.93%或100%一致性,也认为是本发明的所述微生物菌株。
在本发明的一些实施方案中,所述微生物菌株选自包括P. benzoelyticum JC272、P. benzoelyticum KCTC 15476、P. benzoelyticum LMG 28745和P. benzoelyticum CCTCC M 20232265的P. benzoelyticum菌株组中的至少一种。
在本发明中,所述P. benzoelyticum CCTCC M 20232265菌株在中国典型培养物保藏中心保藏,地址为湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心,保藏日期2023年11月17日。
优选地,所述功能性菌剂或药物还包括药学上可接受的辅料。
辅料在制剂中的分类方式有多种,可从来源、作用和用途、给药途径等进行分类。按来源可分为天然产物、半合成产物和全合成产物。按辅料在制剂中的作用和用途分类有65种,分别是pH调节剂、螯合剂、包合剂、包衣剂、保护剂、保湿剂、崩解剂、表面活性剂、病毒灭活剂、补剂、沉淀剂、成膜材料、调香剂、冻干用赋形剂、二氧化碳吸附剂、发泡剂、芳香剂、防腐剂、赋形剂、干燥剂、固化剂、缓冲剂、缓控释材料、胶黏剂、矫味剂、抗氧剂、抗氧增效剂、抗黏着剂、空气置换剂、冷凝剂、膏剂基材、凝胶材料、抛光剂、抛射剂、溶剂、柔软剂、乳化剂、软膏基质、软胶囊材料、润滑剂、润湿剂、渗透促进剂、渗透压调节剂、栓剂基质、甜味剂、填充剂、丸芯、稳定剂、吸附剂、吸收剂、稀释剂、消泡剂、絮凝剂、乙醇改性剂、硬膏基质、油墨、增稠剂、增溶剂、增塑剂、黏合剂、中药炮制辅料、助滤剂、助溶剂、助悬剂、着色剂。
所述在药学上可接受的辅料包括佐剂、稳定剂或保护剂、抑菌剂、赋形剂、助溶剂、矫味剂、稀释剂、缓冲剂中的至少一种。
佐剂:是与一种疫苗抗原结合以增强[如加强、加快、延长和(或)可能的定向]其特异性免疫反应和疫苗临床效果的一种或多种成分混合的物质。
稳定剂或保护剂:用于稳定或保护生物制品有效成分、防止其降解或失去活性的物质。
抑菌剂:用于抑制微生物生长、防止微生物污染的物质。赋形剂:用于冻干制品中使药品成型、起支架作用的物质。助溶剂:用于增加药品溶解性的物质。矫味剂:用于改善口服药品口感的物质。稀释剂、缓冲剂:用于溶解、稀释制品,调整制品酸碱度的溶剂,如注射用水、氯化钠注射液、磷酸盐缓冲生理氯化钠溶液(PBS)等。
例示性辅料包括但不限于:丁基化羟基甲苯(BHT)、碳酸钙、磷酸钙(一氢)、硬脂酸钙、交联羧甲纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交联聚维酮、半胱氨酸、乙基纤维素、明胶、羟基丙基纤维素、羟基丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露糖醇、蛋氨酸、甲基纤维素、对羟基苯甲酸甲酯、微晶纤维素、聚乙二醇、聚维酮、预胶化淀粉、对羟基苯甲酸丙酯、视黄醇棕榈酸酯、虫胶、二氧化硅、羧基甲基纤维素钠、柠檬酸钠、乙醇酸淀粉钠、山梨糖醇、淀粉(玉米)、硬脂酸、硬脂酸、蔗糖、滑石、二氧化钛、维生素A、维生素E、维生素C及木糖醇。
所述药物可呈注射制剂的形式或口服制剂形式经制备。所述的注射制剂依据物态分类包括液体注射剂、注射用粉剂、注射用片剂;依据注射部分分类包括皮内注射剂、皮下注射剂、肌肉注射剂、静脉注射剂、脊椎腔注射剂;优选的所述注射制剂的溶剂包括注射用水或生理盐水。
用于口服使用的制剂包括含有与无毒的药学上可接受的赋形剂混合的活性成分的片剂。这些赋形剂可以是例如惰性稀释剂或填充剂(例如,蔗糖、山梨糖醇、糖、甘露糖醇、微晶纤维素、包括马铃薯淀粉的淀粉、碳酸钙、氯化钠、乳糖、磷酸钙、硫酸钙或磷酸钠);制粒剂及崩解剂(例如,包括微晶纤维素的纤维素衍生物、包括马铃薯淀粉的淀粉、交联羧甲纤维素钠、藻酸盐或藻酸);粘合剂(例如,蔗糖、葡萄糖、山梨糖醇、阿拉伯胶、藻酸、藻酸钠、明胶、淀粉、预胶化淀粉、微晶纤维素、硅酸镁铝、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮或聚乙二醇);以及润滑剂、助流剂及抗粘剂(例如,硬脂酸镁、硬脂酸锌、硬脂酸、二氧化硅、氢化植物油或滑石)。用于口服使用的制剂也可呈可咀嚼片剂形式,或呈硬明胶胶囊形式,其中活性成分与惰性固体稀释剂(例如,马铃薯淀粉、乳糖、微晶纤维素、碳酸钙、磷酸钙或高岭土)混合,或呈软明胶胶囊形式,其中活性成分与水或油介质(例如,花生油、液体石蜡或橄榄油)混合。粉剂、颗粒剂及丸剂可以使用上文在片剂或胶囊下提到的成分以常规方式使用例如混合器、流化床设备或喷雾干燥设备来制备。
用于口服制剂的其他药学上可接受的赋形剂包括但不限于着色剂、调味剂、增塑剂、保湿剂及缓冲剂。用于口服使用的制剂也可呈可咀嚼片剂形式,或呈硬明胶胶囊形式,其中活性成分与惰性固体稀释剂(例如,马铃薯淀粉、乳糖、微晶纤维素、碳酸钙、磷酸钙或高岭土)混合,或呈软明胶胶囊形式,其中活性成分与水或油介质(例如,花生油、液体石蜡或橄榄油)混合。粉剂、颗粒剂及丸剂可以使用上文在片剂或胶囊下提到的成分以常规方式使用例如混合器、流化床设备或喷雾干燥设备来制备。
在一些实施方案中,施用包括经肌肉内、静脉内(例如,呈无菌溶液形式且在适用于静脉内使用的溶剂系统中)、皮内、动脉内、腹膜内、病变内、颅内、关节内、前列腺内、胸膜内、气管内、鼻内、玻璃体内、阴道内、直肠内、经表面、肿瘤内、经腹膜、皮下、结膜下、囊内、经粘膜、心包内、脐内、眼内、经口(例如,片剂、胶囊、囊片、囊形片或糖浆)、经表面(例如,呈乳膏、凝胶、洗剂或软膏形式)、经局部、通过吸入、通过注射或通过输注(例如,以乳膏或脂质组合物形式连续输注、直接地浸泡靶标细胞的局部灌注、置管、灌洗)施用本文所述的药物。
优选地,所述功能性菌剂或药物还包括其他与Paraclostridium benzoelyticum起到协同作用的药物。
本发明还保护一种微生物菌株,所述微生物菌株是以保藏号CCTCC M 20232265保藏的Paraclostridium benzoelyticum ibiome015菌株,所述Paraclostridium benzoelyticum ibiome015菌株在中国典型培养物保藏中心保藏,地址为湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心,保藏日期2023年11月17日。
本发明还保护一种药物,包含上述的菌株,或与上述的微生物菌株16s rRNA序列一致性达到至少98.65%、99.85%、99.93%或100%的菌株,或上述菌株的培养物或加工物,和药学上可接受的辅料。优选地,所述辅料包括佐剂、稳定剂或保护剂、抑菌剂、赋形剂、助溶剂、矫味剂、稀释剂、缓冲剂中的至少一种。
本发明还保护一种药物组合物,包含上述的菌株和联用药物,所述联用药物为其他与Paraclostridium benzoelyticum起到协同作用的药物。
优选地,所述联用药物为其他降糖降脂药物活性成分,如GLP-1受体激动剂或GLP-1模拟物、GIP受体激动剂、二肽基肽酶-4抑制剂、二甲双胍等,具体选自艾塞那肽、利拉鲁肽、索马鲁肽、口服剂型索马鲁肽、贝那鲁肽、利司那肽和艾塞那肽周制剂等。
本发明所述的药物的剂型为颗粒剂、胶囊、片剂、粉末剂、口服液、混悬液或乳剂等。
本发明的有效剂量是,Paraclostridium benzoelyticum作为主要药物活性成分制成活菌制剂包含的总活菌数为106-1014CFU。
用药周期以能够实现效果为准,包括但不限于每日1-3次,每周3-7天服用等,还和具体制剂的作用浓度有关。
本发明还保护一种发酵剂/功能性菌剂/营养组合物,包含上述微生物菌株,或与上述的微生物菌株16s rRNA序列一致性达到至少98.65%、99.85%、99.93%或100%的菌株,或上述微生物菌株的培养物或加工物。
发酵剂或功能性菌剂,包括上述微生物菌株制备得到的菌液、或进一步处理得到的粉剂、或颗粒剂;所述发酵剂中还可以进一步含有一种以上互不拮抗的微生物菌剂,选自克里斯滕森菌、副拟杆菌、嗜黏蛋白阿克曼氏菌、多形拟杆菌中的一种以上制备得到复合菌剂。
有效菌剂浓度、活菌数为106-1014CFU。
发酵剂或功能性菌剂亦可用作功能性食品、营养品。
营养组合物,包括上述微生物菌株,或微生物菌株的培养物或加工物。优选地,所述营养组合物为食品、营养品、补充物、益生菌或共生菌。
所述食品,包括上述微生物菌株,或微生物菌株的培养物或加工物以及实现食品功能的辅助物质,呈现的形式包括但不限于“膳食补充剂”“发酵食品”等。
所述膳食补充剂包括上述微生物菌株的培养物或加工物,并进一步加入纤维素、维生素、矿物质等营养物质处理得到。
所述发酵食品包括乳制品、豆制品或者果蔬制品等。所述的乳制品是牛奶、酸奶油或干酪等。所述的豆制品是豆奶、豆豉或豆酱等。所述的果蔬制品是黄瓜、胡萝卜、甜菜、芹菜或圆白菜制品等。
所述益生菌是指活的微生物,当它以合适的量提供时,对于宿主有机体的健康会有益。
所述共生菌是指那些含有益生素和益生菌的混合物的食品。它们通常包含利于生长和/或代谢活性的益生组分,以及总的来说与诸如但不限于上述微生物菌株与低聚果糖或低聚半乳糖相组合的益生菌效果。
本发明的有益效果
相对于现有技术,本发明具有以下技术效果。
本发明首次提示Paraclostridium benzoelyticum能够用于预防、改善或治疗代谢性疾病,丰富了本领域的选择,具有巨大的临床应用价值。
本发明的Paraclostridium benzoelyticum可以显著激活治疗肥胖糖尿病的靶点GPR120,降低肥胖小鼠的体重、血糖、脂代谢相关指标(甘油三酯、低密度脂蛋白胆固醇),并能够改善非酒精性脂肪肝(降低肝脏中甘油三酯和总胆固醇)的症状。
生物保藏
Paraclostridium benzoelyticum ibiome015,保藏日期2023年11月17日,保藏地点为中国典型培养物保藏中心,地址为湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心,保藏号为CCTCC M 20232265。
附图说明
图1示出了多株P. benzoelyticum菌在实施例2的细胞水平实验中激活GPR120的检测结果。
图2 示出了实施例3中P. benzoelyticum菌的微观形态图。
图3 示出了实施例3中P. benzoelyticum菌的宏观形态图。
图4 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠体重的影响。
图5 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠空腹血糖的影响。
图6 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠血浆葡萄糖的影响。
图7 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠脂肪重量的影响。
图8 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠甘油三酯改善情况。
图9 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠低密度脂蛋白-胆固醇改善情况。
图10 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠肝脏重量的影响。
图11示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠肝脏-甘油三酯改善情况。
图12 示出了实施例4的高脂饮食诱导肥胖小鼠治疗实验中P. benzoelyticum菌对小鼠肝脏-总胆固醇改善情况。
图13示出了实施例5的高脂饮食诱导肥胖小鼠预防实验中P. benzoelyticum菌对小鼠第5周空腹血糖的影响。
图14示出了实施例5的高脂饮食诱导肥胖小鼠预防实验中P. benzoelyticum菌对小鼠第16周空腹血糖的影响。
实施方式
为更好理解本发明,下面结合实施例及附图对本发明作进一步描述,以下实施例仅是对本发明进行说明而非对其加以限定。
实施例1 菌株的分离与初步鉴定
招募一年内未使用过抗生素的健康志愿者,签订知情同意书后,志愿者自取新鲜粪便2~5 g,放入含有甘油的样本收集管中,震荡匀质后将处理好的粪便样本置于冰盒中,并于24 h内送达申请人实验室进行菌株分离。
①粪便样本前处理:从含有甘油和粪便充分混合的样本收集管中取1 mL的混合物加入到9 mL的1×无菌PBS溶液中,涡旋振荡器混匀,然后从上述混合液中取100 µL混合液进行逐级梯度稀释至10-9,用于平板涂布。
②取稀释后的样本100 μL涂布于mGAM培养基(商品化的GAM培养基(索莱宝,LA4450)中加入终浓度为1 mg/L的维生素K1、5 mg/L的氯化血红素、0.1 mg/L刃天青、1 µg/L生物素、1 µg/L钴胺素、3 µg/L对氨基苯甲酸、5 µg/L叶酸、15 µg/L吡哆胺、50 µg/L硫胺素和50 µg/L核黄素)中,等平板表面干燥后,倒置放入厌氧工作台培养(温度:37℃,湿度65%,O2:0%,),静置培养24~36 h,有单克隆菌落长出后,再将单克隆进行多次划线纯化,对纯化后的菌株进行16s rRNA测序,确定菌株分类学地位。
③16s rRNA测序:对待鉴定菌株进行16s rRNA PCR扩增,扩增体系:2 Taq MasterMix(诺唯赞;P112-01)12.5 μL、引物1(27F:AGAGTTTGATCCTGGCTCAG)1 μL、引物2(1492R:TACGGCTACCTTGTTACGACTT)1 μL、液体培养的菌液1 μL、ddH2O 9.5 μL;扩增条件:95℃ 3min;95℃ 15 s,58℃ 15 s,72℃ 30 s,35个循环;72℃ 5 min。将扩增产物送擎科生物科技有限公司测序,将测序返回的菌株16s rRNA基因序列提交到NCBI Basic LocalAlignment Search Tool,进行菌株16s rRNA基因分析。比对结果中,相似性最高的菌株对应的种作为相应菌株的种。
在分离得到的菌株中,选取鉴定为Paraclostridium benzoelyticum的菌株进行进一步筛选。
实施例2 Paraclostridium benzoelyticum在体外细胞水平激活GPR120的筛选
GPR120是长链不饱和脂肪的受体,在人体的多个组织中均有表达,尤其在结肠各脂肪组织中高表达。能够调节胃肠道肽类激素分泌从而影响食欲、调节脂肪细胞发育和分化等多种生理功能,GPR120与肥胖、糖尿病、胰岛素抵抗和脂肪肝等代谢性疾病密切相关。
综上所述,GPR120是治疗肥胖、糖尿病等代谢性疾病的重要靶点,可用于筛选能够治疗代谢性疾病的菌株。
(1)实验材料
P. benzoelyticum细菌培养上清的制备:取100 μL的甘油菌(保存在甘油中的P. benzoelyticum细菌)加入2 mL mGAM培养基(配制方法同实施例1)中,在37℃培养箱培养48h,将培养物在12000 rpm,4 ℃,离心10 min,取上清用于细胞筛选。
其中,P. benzoelyticum标准株为LMG 28745,购于LMG比利时细菌菌种保藏中心。
阳性药:GSK-137647A(厂家:Selleck)。
mGAM培养基对照:没有培养细菌的mGAM培养基(配制方法同实施例1)
空白对照:转染了GPCR-tango质粒的HTLA细胞不加任何处理。
(2)实验方法
A.将稳定表达β-arrestintev和tTA-luciferase的HEK293细胞株(厂家:HTLA;中国科学技术大学免疫学研究所提供)放到含有10%胎牛血清(厂家:Viva cell;货号:C04001-500)和1%青霉素/链霉素(厂家:Viva cell;货号:C3420-0100)的DMEM培养基(厂家:Gibco;货号:C11995500BT)中培养;
B.转染混合物制备:200 ng/孔GPCR-tango质粒(中国科学技术大学免疫学研究所提供)在20 μL opti-MEM(厂家:Gibco;货号:31985070)中与400 ng polyethylenimine(厂家:翌圣生物;货号:40816ES03)(溶于20 μL的opti-MEM中)混合,室温孵育20分钟;
C.将步骤A的细胞培养达到大约90%融合后,将步骤B的转染混合物加入该细胞中;
D.转染16~24小时后,离心收集细胞,弃上清,用180 μL含1%青霉素/链霉素和10mM HEPES(厂家:普诺赛;货号:PB180325)的DMEM培养基(厂家:Gibco;货号:C11995500BT)进行重悬后加入20 μL的i) P. benzoelyticum细菌培养上清液,或ii)阳性药,或iii)DMEM培养基空白对照;
E.步骤D的P. benzoelyticum细菌培养上清液(或阳性药或空白对照)刺激16~24h后,1500 g离心6 min,弃上清,每孔加入50 μL用含20 mM HEPES的PBS稀释20倍的Bright-Glo溶液(厂家:Promega;货号:E2610);
F. 室温孵育20分钟后,进行荧光定量。
(3)实验结果:
菌株激活率以该菌株荧光定量值与培养基荧光定量值之比来计算。实验中,有超过40株P. benzoelyticum菌株均能显著激活GPR120,挑取其中10株,结果如图1所示,P. benzoelyticum菌株对GPR120的激活水平均显著高于空白组,提示可能在代谢性疾病中存在治疗作用,因而进行进一步实验。
实施例 3 Paraclostridium benzoelyticum菌株特征
对实施例2筛选出来的P. benzoelyticum PB1进行进一步鉴定。
菌体特征:P. benzoelyticum PB1菌株经过染色后在光学显微镜40倍镜下的形态如图2所示。显微镜下,在mGAM培养基中37℃厌氧培养24 h,革兰氏染色呈阳性,菌体呈杆状,平均长度2 μm左右。
菌落特征:P. benzoelyticum PB1菌株在平板上的生长状况如图3所示,在mGAM培养基中37℃厌氧培养24 h,菌落呈圆形,表面湿润,不透明,呈淡黄色,边缘整齐。
生长特征:分离到的菌株在无氧条件下生长,最适生长温度为37℃。
16s rRNA测序:测序返回的16s rRNA基因序列如SEQ ID NO.1所示,提交到NCBIBasic Local Alignment Search Tool,进行菌株16s rRNA基因分析。比对结果表明,与其相似性最高的菌株是Paraclostridium benzoelyticum strainJC272,相似度为100%。
将Paraclostridium benzoelyticum PB1菌株命名为Paraclostridium benzoelyticum ibiome015,保藏至中国典型培养物保藏中心,保藏地址为:湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心;保藏日期为:2023年11月17日;保藏编号为:CCTCC M 20232265。
使用同样的方法对PB2~PB10进行16s rRNA测序,结果表明:PB3~PB5的16s rRNA基因序列同PB1;PB2、PB6和PB10的16s rRNA基因序列如SEQ ID NO.2所示,与Paraclostridium benzoelyticum strainJC272的相似度为99.93%;PB7~PB9的16s rRNA基因序列如SEQ ID NO.3~NO.5所示,与Paraclostridium benzoelyticum strainJC272的相似度分别为99.85%、99.93%、99.93%。
实施例 4 Paraclostridium benzoelyticum改善高脂饲料诱导的肥胖及相关症状
以P. benzoelyticum PB1为例,考察P. benzoelyticum菌种对代谢性疾病的作用。
(1)实验方法
C57BL/6J小鼠(购自江苏集萃药康生物科技股份有限公司)高脂饲料喂养20周,根据体重进行筛选,入选小鼠平均体重50 g,入选小鼠随机分为对照组、实验组,每组10只小鼠。各组小鼠给药同时继续进行高脂饲料喂养,持续到实验结束。
对照组灌胃0.4 mL 0.9%生理盐水/只/天;
实验组灌胃P. benzoelyticum PB1,根据各批次冻干菌粉的活菌数,计算每次灌胃109CFU/只所需的菌粉克数,再重悬于0.4mL 0.9%生理盐水,每天一次;
分别进行如下实验:
a. 每周监测体重;
b. 给药第4周检测空腹血糖(禁食6小时);
c. 给药13周后,小鼠禁食12小时,取小鼠脂肪组织(肠系膜白色脂肪、附睾白色脂肪、皮下白色脂肪),并对脂肪组织分别称重;
d. 给药13周后,小鼠禁食12 h,摘眼球取血放入肝素管,4000 rpm,室温离心10min,取上清血浆至新的离心管,-80℃保存备用,利用试剂盒检测血液中葡萄糖(索莱宝;BC2505)、甘油三酯(南京建成;A110-1-1)和低密度脂蛋白-胆固醇(南京建成;A111-1-1)水平;
e. 给药13周后,小鼠禁食12h,取小鼠肝脏并称重,然后取肝脏100 mg,加入900 μL PBS,匀浆,4000 rpm室温离心10 min,取上清至新的离心管,-80℃保存备用;利用试剂盒检测肝脏中总胆固醇(南京建成;A111-1-1)、甘油三酯(南京建成;A110-1-1)水平。
(2)实验结果
① 给药期间体重变化
如图4所示,与对照组相比,灌胃P. benzoelyticum菌株从第10周开始体重有明显下降,并可以显著抑制小鼠体重的增长。
② 给药对小鼠血糖的影响
如图5所示,灌胃P. benzoelyticum菌株能够显著降低小鼠的空腹血糖。
如图6所示,灌胃P. benzoelyticum菌株能够显著降低小鼠血液中葡萄糖含量。
以上结果表明P. benzoelyticum能够调节小鼠血糖水平。
③ 给药对小鼠脂肪重量的影响
如图7所示,与对照组相比,灌胃P. benzoelyticum菌株能够降低小鼠脂肪组织重量,尤其是显著降低了小鼠皮下白色脂肪重量。
④ 给药对小鼠脂代谢的影响
如图8所示,与对照组相比,灌胃P. benzoelyticum菌株能够显著降低小鼠甘油三酯水平。
如图9所示,与对照组相比,灌胃P. benzoelyticum菌株能够显著降低小鼠低密度脂蛋白-胆固醇水平。
以上结果表明,P. benzoelyticum菌株可以改善脂代谢水平。
⑤ 给药对小鼠非酒精性脂肪肝的影响
如图10所示,与对照组相比,灌胃P. benzoelyticum菌株能够显著降低小鼠肝脏重量。
如图11所示,与对照组相比,灌胃P. benzoelyticum能够显著降低小鼠肝脏甘油三酯水平。
如图12所示,与对照组相比,灌胃P. benzoelyticum能够显著降低小鼠肝脏总胆固醇水平。
以上结果表明,P. benzoelyticum可以改善小鼠非酒精性脂肪肝症状。
实施例5 Paraclostridium benzoelyticum预防小鼠的肥胖及相关症状
(1)实验方法:
C57BL/6J小鼠(购自江苏集萃药康生物科技股份有限公司)36只,根据体重进行筛选,入选小鼠平均体重26g,入选小鼠随机分为对照组、实验组和阳性药组。各组小鼠给药同时进行高脂饲料喂养,持续到实验结束。
对照组灌胃0.2 mL 0.9%生理盐水/只/天;
实验组灌胃Paraclostridium benzoelyticum PB1,根据各批次冻干菌粉的活菌数,计算每次灌胃109 CFU/只所需的菌粉克数,再重悬于0.2mL 0.9%生理盐水,每天一次;
阳性药组皮下注射索马鲁肽(诺和诺德),每只小鼠按体重给予12.8μg/kg的索玛鲁肽,用生理盐水进行稀释,每只小鼠皮下注射0.1mL,每周一次。
给药第5周和第16周分别检测各组小鼠的空腹血糖(禁食6小时)。
(2)实验结果:
如图13所示,灌胃P. benzoelyticum菌株在第5周就能够显著降低小鼠的空腹血糖,且效果强于阳性药。
如图14所示,灌胃P. benzoelyticum菌株在第16周仍能够显著降低小鼠的空腹血糖。
以上结果表明,P. benzoelyticum可以用于预防高脂饮食导致的肥胖和糖尿病等相关症状。
以上所述实施方式仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明的权利要求书确定的保护范围内。
Claims (10)
1.微生物菌株、或所述微生物菌株的培养物或加工物在制备用于预防、改善或治疗代谢性疾病的药物中的应用,其特征在于:所述微生物菌株属于Paraclostridium benzoelyticum种,所述代谢性疾病为糖尿病、肥胖及肥胖相关疾病和/或代谢综合征;所述肥胖相关疾病包括如下疾病中的至少一种:心血管疾病、高脂血症、胰岛素抵抗综合征和脂肪性肝炎。
2.根据权利要求1所述的应用,其特征在于,所述药物用于如下至少一种用途:
预防或治疗肥胖引起的糖尿病;
预防或治疗Ⅱ型糖尿病;
减轻超重哺乳动物的体重或抑制体重增长速度;
减轻哺乳动物脂肪组织重量;
降低哺乳动物的空腹血糖;
降低哺乳动物血液中甘油三酯和/或低密度脂蛋白-胆固醇水平;
降低哺乳动物肝脏中总胆固醇和/或甘油三酯水平。
3.根据权利要求1所述的应用,其特征在于:所述微生物菌株具有与SEQ ID NO:1~NO:5中任一条至少98.65%、至少99.85%、至少99.93%或100%一致性的16s rRNA序列。
4.根据权利要求1所述的应用,其特征在于:所述药物还包括药学上可接受的辅料,所述辅料包括佐剂、稳定剂或保护剂、抑菌剂、赋形剂、助溶剂、矫味剂、稀释剂、缓冲剂中的至少一种。
5.根据权利要求1~4任一所述的应用,其特征在于:所述微生物菌株能够激活GPR120。
6.根据权利要求1所述的应用,其特征在于:所述微生物菌株是以保藏号CCTCC M20232265保藏的Paraclostridium benzoelyticum ibiome015菌株,所述Paraclostridium benzoelyticum ibiome015菌株在中国典型培养物保藏中心保藏,地址为湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心,保藏日期2023年11月17日。
7.一种微生物菌株,其特征在于,所述微生物菌株是以保藏号CCTCC M 20232265保藏的Paraclostridium benzoelyticum ibiome015菌株,所述Paraclostridium benzoelyticum ibiome015菌株在中国典型培养物保藏中心保藏,地址为湖北省武汉市武昌区八一路武汉大学中国典型培养物保藏中心,保藏日期2023年11月17日。
8.权利要求7所述的微生物菌株的培养物或加工物。
9.一种药物,其特征在于:包含Paraclostridium benzoelyticum种微生物菌株,或其培养物或加工物,和药学上可接受的辅料,优选地,所述辅料包括佐剂、稳定剂或保护剂、抑菌剂、赋形剂、助溶剂、矫味剂、稀释剂、缓冲剂中的至少一种。
10.一种发酵剂/功能性菌剂/营养组合物,包含Paraclostridium benzoelyticum种微生物菌株,或其培养物或加工物;优选地,所述营养组合物为食品、营养品、补充物、益生菌或共生菌。
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