CN109069552B - 用于治疗肥胖症和相关代谢病的长双歧杆菌 - Google Patents
用于治疗肥胖症和相关代谢病的长双歧杆菌 Download PDFInfo
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Abstract
长双歧杆菌AH1362(NCIMB 41715)产生多糖并增加能量排泄。该菌株用于预防或治疗肥胖症和肥胖症相关代谢综合征。
Description
引言
本发明涉及长双歧杆菌(Bifidobacterium longum)菌株。
肥胖症是21世纪最严重的公共卫生挑战之一。全球约有13％的成年人肥胖，另有39％的人被认为超重(WHO，2015)。肥胖症是一种多因子病，其是能量摄入和支出之间长期失衡的结果，并受遗传和环境因素的影响。肥胖症的特征在于胰岛素抵抗和慢性低度炎症(Gregor和Hotamisligil，2011，Kahn等，2006)。免疫系统、代谢和肠道微生物群之间的密切相互作用可能在控制肥胖症和代谢稳态中发挥重要作用。肥胖症增加一群慢性代谢病如2型糖尿病(T2DM)、非酒精性脂肪肝疾病(NAFLD)、高血压、动脉粥样硬化、血脂异常和心血管疾病的发展和恶化的风险(Guh等，2009)，随着BMI的增加，代谢共病(comorbidity)的流行增加(Gupta等，2015)。肥胖症还增加发展严重的疾病和潜在威胁生命的疾病的风险，例如过敏和哮喘、骨关节炎、胆囊疾病和非酒精性脂肪性肝炎(NASH)(其是脂肪积聚在肝脏中的病况，并且是肝硬化的主要原因)。
代谢综合征是越来越常见的病况，是指肥胖症、高脂血症(高甘油三酯)、高血压(高的血压)和葡萄糖不耐受(高血糖)和低HDL胆固醇的组合。这些风险因素有助于确定处于发展2型糖尿病(T2D)和心血管疾病的的高风险的对象。
非酒精性脂肪肝疾病(NAFLD)是非常常见的病，指的是一组在饮酒很少或没有酒精的人的肝脏中积累过量脂肪的病况。
更严重的NAFLD形式被称为非酒精性脂肪性肝炎(NASH)。NASH引起肝脏肿胀并受损。NASH倾向于发展于超重或肥胖、或患有糖尿病、高胆固醇或高甘油三酯的人群。
大量的临床和实验数据表明，来自于增加的内脏脂肪组织的游离脂肪酸流的增加可导致与胰岛素抵抗有关的NAFLD。因此，患有肥胖症、胰岛素抵抗和血脂异常的个体处于发展NAFLD的最大风险中。
由于发现无菌小鼠比它们常规培养的对应小鼠更瘦(Backhed等，2004)，肠道微生物群对肥胖症发展的贡献越来越多地被研究(Backhed等，2007，Cani等，2008b，Ridaura等，2013，Vrieze等，2012)。肠道微生物群对肥胖症的贡献是多因子的，并涉及例如增强的能量收集和脂肪贮存(Turnbaugh等，2006)、改变的代谢途径(Kotzampassi等，2014，Turnbaugh等，2009)和细菌易位导致慢性低度炎症(Cani等，2007，Cani等，2008a)的问题。因此通过益生菌操纵肠道微生物群是一种潜在的治疗工具，以帮助改善肥胖症并提高代谢健康。乳杆菌菌株通常用作益生菌，并且具有大量的在体内以菌株特异性方式支持健康有益影响的证据(Aronsson等，2010，Lee等，2006，Naito等，2011)。
这些菌株的作用机制没有很好的表征。一组感兴趣的分子是细菌胞外多糖(EPS)。EPS是高分子量聚合物，由糖残基组成，并被细菌分泌到周围环境中。产胞外多糖(EPS)的细菌已被证明具有免疫调节影响(Fanning等，2012年，Hidalgo-Cantabrana等，2014，Vinderola等，2006，Volman等，2008，Jones等，2014)。许多乳酸菌(LAB)具有合成EPS的能力。然而，EPS是异源分子并且在组成、电荷和分子结构方面不同，这可能解释了所观察到的菌株特异性生物活性(Adams等，2008，Bland等，2004，Hidalgo-Cantabrana等，2012，Kankainen等，2009)。
与肥胖症和代谢病有关的慢性低度炎症(Gregor and Hotamisligil，2011)是一种风险因素，其可通过施用益生菌来靶向操纵以有利地影响肥胖症的发展。我们以前已经表明另一种乳酸菌，长双歧杆菌(B.longum)NCIMB41003具有抗炎效果。这种细菌具有大量的EPS外壳。如WO2010055499A所述，EPS材料也具有抗炎效果。
发明描述
本发明提供了保藏菌株NCIMB 41715。长双歧杆菌(Bifidobacterium longum)AH1362的菌株以保藏号NCIMB 41715保藏于NCIMB。
根据一个方面，本发明提供了用于预防或治疗肥胖症和肥胖症相关代谢综合征的组合物，其包含有效量的菌株。该菌株产生多糖并增加能量排泄。该菌株从安慰剂喂养的健康成年志愿者的粪便样品中分离出来。
本发明的分离的菌株可用于减少对象的身体脂肪累积。该菌株可用于阻断体重增加或用于减轻体重。该菌株可用于治疗、预防或缓解由过度身体脂肪累积引起的病况。
本发明还提供了用于预防或治疗肥胖症的方法，包括施用包含以保藏号NCIMB41715保藏于NCIMB的菌株的组合物给需要预防或治疗肥胖症的对象。
本发明进一步提供了用于预防或治疗肥胖症相关代谢综合征的方法，包括施用包含以保藏号NCIMB 41715保藏于NCIMB的菌株的组合物给需要预防或治疗肥胖症相关代谢综合征的对象。
本发明还提供了用于预防或治疗非酒精性脂肪肝疾病(NAFLD)的方法，包括施用包含以保藏号NCIMB 41715保藏于NCIMB的长双歧杆菌AH1362菌株的组合物给需要预防或治疗非酒精性脂肪肝疾病的对象。
该菌株可是活细胞的形式。该菌株可是非活细胞的形式。益生菌的一般使用是活细胞的形式。然而，也可扩展使用非活细胞，例如杀死的培养物、活的和非活的培养物的混合物或含有益生菌表达的有益因子的组合物。这可包括热杀死的微生物或暴露于改变的pH值或受到压力或γ照射而被杀死的微生物。使用非活细胞的产品制备更简单，细胞可以容易地掺入药物中，并且储存要求比活细胞的限制少得多。如美国专利号US4347240中所述，干酪乳杆菌(Lactobacillus casei)YIT 9018提供了有效使用热杀死细胞作为治疗和/或预防肿瘤生长的方法的实例。
本发明还提供了一种制剂，其包含如本文所述的菌株。该制剂可以进一步包含益生菌材料。该制剂可以进一步包含益生元材料。该制剂可以进一步包含载体。该载体可以是可摄入的载体，可以是药学上可接受的载体，例如胶囊、片剂或粉末。可摄入的载体可以是食物产品，例如酸化乳、酸奶、冻酸奶、乳粉、乳浓缩物、涂抹干酪、调味品或饮料。一些实例包括发酵食物产品如发酵乳产品。该制剂还包含蛋白质和/或肽(特别是富含谷氨酰胺/谷氨酸的蛋白质和/或肽)、脂质、碳水化合物、维生素、矿物质和/或微量元素。双歧杆菌菌株可以大于106cfu每克制剂的量存在。该制剂可以进一步包含佐剂。该制剂可以进一步包含细菌组分。该制剂可以进一步包含药物实体。该制剂可以进一步包含生物化合物。在所有情况下，所述制剂包含如本文所述的菌株，并且可以包含载体或其他药剂。这种载体或其他物质在某些情况下不会发生在自然界中。该制剂在某些情况下可用于免疫和疫苗接种方案。
本发明还提供了包含本发明的菌株或本发明的制剂的冷冻干燥组合物。
本发明还提供了如本文所述的菌株或制剂用于食品中。
本发明还提供了如本文所述的菌株或制剂用作药物。
本发明还提供了如本文所述的菌株或制剂用于预防和/或治疗肥胖症和相关疾病的用途。
本发明还提供了如本文所述的菌株或制剂用于预防和/或治疗非酒精性脂肪肝疾病(NAFLD)的用途。
如本文所述的菌株可用于制备一组生物治疗剂以修饰IL-10的水平。
本发明还提供了如本文所述的菌株或制剂用于预防和/或治疗肥胖症相关炎症。
本发明还提供了如本文所述的菌株或制剂用于预防和/或治疗肥胖症相关的代谢调节异常。
应该理解，本发明的特定菌株可以以常规剂型如胶囊、微胶囊、片剂、颗粒剂、粉末、锭剂、丸剂、栓剂、混悬剂和糖浆剂以口服可摄入形式施用给动物(包括人)。合适的制剂可以通过通常采用的使用常规有机和无机添加剂的方法制备。药物组合物中活性成分的量可以处于将发挥所需治疗效果的水平。
该制剂还可以包括细菌组分、药物实体或生物化合物。
另外，包含本发明菌株的疫苗可以使用任何合适的已知方法制备，并且可以包括药学上可接受的载体或佐剂。
本发明还包括衍生自本发明菌株同时仍具有保藏菌株的活性的突变体和变体。突变体和变体包括与亲本菌株相比其遗传和/或表型特性改变的菌株。天然存在的变体包括选择性分离的靶向特性的自发改变。通过常规(体外)遗传操纵技术如基因破坏、接合转移等完成亲本菌株特性的有意改变。遗传修饰包括将外源和/或内源DNA序列引入菌株的基因组中，例如通过载体(包括质粒DNA或噬菌体)插入细菌菌株的基因组中。
天然或诱导的突变包括至少单碱基改变，例如缺失、插入、颠换或其他DNA修饰，这些修饰可能导致DNA序列编码的氨基酸序列改变。
术语突变体、变体和遗传修饰的突变体还包括已经历遗传改变的菌株，所述遗传改变在基因组中以对于所有微生物和/或遗传改变本质上一致的速率积累，所述遗传改变通过自发突变和/或基因的获得和/或基因的丢失发生，这不能通过有意(体外)操纵基因组实现，但通过自然选择提供选择性优势以支持细菌在暴露于环境压力(如抗生素)时的存活的变体和/或突变体实现。突变体可以通过将特定基因有意(体外)插入基因组而产生，其基本上不改变生物体的生物化学功能性，但其产物可用于鉴定或选择细菌，例如抗生素抗性。
本领域技术人员会理解，可以通过与亲本菌株的DNA序列同源性分析来鉴定突变体或变体菌株。与亲本菌株具有密切序列相同性但没有可证明的表型或可测量的功能差异的菌株被认为是突变体或变体菌株。与亲本DNA序列具有99.5％或更高序列相同性(同源性)的菌株可被认为是突变体或变体。可以使用在线同源性算法“BLAST”程序(可在http://www.ncbi.nlm.nih.gov/BLAST/公开获得)确定序列同源性。
亲本菌株的突变体还包括与亲本菌株的16s-23s基因间间隔多核苷酸序列具有至少95.5％序列同源性的衍生菌株。这些突变体还可在细菌基因组的其他DNA序列中包含DNA突变。
附图说明
通过以下仅以实施例的方式给出的一些实施方案的描述并参照附图，将更清楚地理解本发明，其中：
图1显示了通过EPS蓬松沉淀物高度测量的长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003的菌株蓬松度(bulkiness)；
图2是长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对十六烷的粘附的％条形图；
图3是用EPS阳性长双歧杆菌NCIMB 41003和低产EPS乳杆菌菌株刺激48小时后PBMC细胞因子诱导测定中IL-10诱导的图。相对于EPS低乳杆菌菌株，用EPS阳性长双歧杆菌NCIMB 41003刺激后，抗炎细胞因子IL-10的诱导增强；
图4是用长双歧杆菌NCIMB 41003和低产EPS乳杆菌菌株刺激48小时后PBMC细胞因子诱导测定中TNF-α诱导的图。相对于EPS低乳杆菌菌株，用EPS阳性长双歧杆菌NCIMB41003刺激后，促炎细胞因子TNF-α诱导的诱导降低；
图5是用长双歧杆菌NCIMB 41003和长双歧杆菌NCIMB 41715刺激48小时后PBMC细胞因子诱导测定中IL-10诱导的图。两种菌株都以剂量反应性方式诱导相似水平的抗炎细胞因子IL-10；
图6是用长双歧杆菌NCIMB 41003和长双歧杆菌NCIMB 41715刺激48小时后PBMC细胞因子诱导测定中TNF-α诱导的图。相对于长双歧杆菌NCIMB 41003，长双歧杆菌NCIMB41715诱导相似水平的TNF-α；
图7显示当与高脂肪饮食(HFD)对照组相比，长双歧杆菌NCIMB 41715显示第16周脂肪质量增加显著减少，而长双歧杆菌NCIMB 41003没有显著影响；
图8说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对脂肪垫重量的影响。长双歧杆菌NCIMB 41715脂肪垫重量(皮下脂肪和附睾脂肪)显著减少，而长双歧杆菌NCIMB 41003没有显著影响；
图9说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对肝总胆固醇和甘油三酯的影响。在DIO小鼠中，长双歧杆菌NCIMB 41715而不是长双歧杆菌NCIMB 41003减少肝总胆固醇和甘油三酯；
图10说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆总胆固醇的影响；
图11说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆LDL-胆固醇的影响；
图12说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆VLDL-胆固醇的影响；
图13说明了长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对末端血糖的影响；
图14显示在DIO小鼠模型中，相对于高脂肪饮食(HFD)对照组，在长双歧杆菌NCIMB41715和长双歧杆菌NCIMB 41003施用后，每只小鼠的累积食物摄入；和
图15显示在DIO小鼠模型中，相对于高脂肪饮食(HFD)对照组，在长双歧杆菌NCIMB41715和长双歧杆菌NCIMB 41003施用后，累积能量排泄％的估计。
发明详述
长双歧杆菌(Bifidobacterium longum)AH1362于2010年5月6日以保藏号NCIMB41715保藏于国家工业、食品和和海洋微生物保藏中心(National Collections ofIndustrial and Marine Bacteria Limited,NCIMB)Ferguson Building,CraibstoneEstate,Bucksburn,Aberdeen,AB21 9YA,苏格兰，英国。
本说明书还通过与菌株长双歧杆菌(Bifidobacterium longum)35624比较的方式进行参考，所述菌株长双歧杆菌35624于1999年1月13日以保藏号NCIMB 41003保藏于国家工业、食品和和海洋微生物保藏中心(National Collections of Industrial and MarineBacteria Limited,NCIMB)Ferguson Building,Craibstone Estate,Bucksburn,Aberdeen,AB21 9YA,苏格兰，英国。
实施例
以下实施例进一步描述和展示了本发明范围内的实施方案。这些实施例仅仅是为了说明的目的而给出的，并且不应被解释为对本发明的限制，因为在不脱离本发明的精神和范围的情况下可能有许多变化。
我们发现一种新型产EPS的双歧杆菌菌株(长双歧杆菌AH1362)减弱了与肥胖症有关和与代谢病有关的标志物。长双歧杆菌AH1362的施用与肠道微生物群的改变、降低的脂肪储存和降低的肝甘油三酯和肝总胆固醇水平和增加的脂肪排泄有关。令人惊讶的是，施用长双歧杆菌NCIMB 41003不具有相同的效果。
实施例1-长双歧杆菌NCIMB 41715的鉴定通过基因间间隔(IGS)区域的BLAST分析确认。
方法
进行16s-23s基因间间隔(IGS)测序以鉴定长双歧杆菌NCIMB 41715。简言之，使用100μl Extraction Solution和25μl Tissue Preparation solution(Sigma-Aldrich，XNAT2Kit)从菌株中分离总DNA。将样品在室温孵育5分钟，然后在95℃2小时，然后加入100μl Neutralization Solution(Sigma-Aldrich，XNAT2Kit)。使用Nanodrop分光光度计对DNA溶液进行定量并在4℃储存。使用IGS引物进行PCR。用于鉴定两个菌株的引物对是IGS R5'-CTGGTGCCAAGGCATCCA-3'和IGS L5'-GCTGGATCACCTCCTTTCT-3'。循环条件为94℃4分钟(1个循环)，94℃45秒，53℃45秒，72℃45秒(28个循环)。PCR反应物含有2μl(100ng)DNA，PCR混合物(Sigma-Aldrich，RedTaq)，0.025nM IGS L和R引物(MWG Biotech，Germany)。PCR反应在Eppendorf热循环仪上进行。PCR产物与分子量标记(100bpLadder，Roche)在TAE中的2％琼脂糖EtBr染色凝胶上一起运行以确定IGS谱。使用Promega Wizard PCR纯化试剂盒纯化双歧杆菌的PCR产物(单条带)。乳杆菌的PCR产物产生3条带。将以约280bp存在的条带(最低条带)切下，使用GenElute Agarose Spin Column(Sigma-Aldrich)纯化，并如上重新测序，使用Promega Wizard PCR纯化试剂盒纯化PCR产物。纯化的PCR产物在Beckman CoulterGenomics(UK)使用用于基因间间隔区域的引物序列(如上)进行测序。然后针对序列数据检索NCBI核苷酸数据库以通过核苷酸同源性确定该菌株的鉴定。所得的DNA序列数据经过NCBI标准核苷酸-核苷酸同源性BLAST搜索引擎(http://www.ncbi.nlm.nih.gov/BLAST/)以鉴定与该序列最接近的匹配。
结果
表1：长双歧杆菌NCIMB 41715的基因间间隔(IGS)区域的Blast结果。
表2：长双歧杆菌NCIMB 41715的基因间间隔(IGS)区域的序列。
实施例2-EPS蓬松沉淀物测试(菌株蓬松度)
方法
每种菌株在液体培养基中发酵。洗涤离心后收集的颗粒并随后冷冻干燥。
将调整总细胞数(2×10E10)的冷冻干燥粉末重悬于10ml PBS中，并以4000rpm/10分钟/4℃离心。
结果
图1：通过EPS蓬松沉淀物高度测量的长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB41003的菌株蓬松度。
长双歧杆菌NCIMB 41003产生0.9cm蓬松沉淀物，而长双歧杆菌NCIMB 41715产生2.5cm的蓬松沉淀物
结论
长双歧杆菌NCIMB 41003被称为高EPS生产者。EPS蓬松沉淀物测试和所得的沉淀物的高度，证实长双歧杆菌NCIMB 41715产生EPS，并且比长双歧杆菌NCIMB 41003产生更多的EPS。
实施例3-微生物对十六烷的粘附(MATH)测定
疏水性是分子排斥水的物理特性。疏水材料用于从水中去除油、管理溢油和化学分离处理以从极性化合物中去除非极性物质。细菌细胞的疏水性取决于其细胞表面的组成(就存在的蛋白质、肽和多糖而言)。益生菌菌株粘附于肠粘膜的能力有助于细菌细胞在胃肠转运过程中建立自身，提供其在肠道中的竞争优势。菌株的疏水性是有助于粘附能力的一个因素。作为菌株粘附肠上皮细胞能力的指示，测定细菌对十六烷的粘附是有效的定性方法(Kiely and Olson，2000)。
方法
使用微生物对十六烷的粘附(MATH)试验测定长双歧杆菌NCIMB41715和长双歧杆菌NCIMB 41003对十六烷的黏附能力作为其疏水性的测量。根据Rosenberg等，1980的方法并进行了一些修改，测量对十六烷的粘附(Crow and Gopal，1995；Bellon-Fontaine等，1996)。通过5000g离心15分钟收获处于稳定期的细菌，用PBS洗涤两次，并重悬于0.1mol/lKNO3(pH6.2)至OD600为0.8。在600nm处测量细胞悬液的吸光度(A0)。将2ml十六烷(SigmaAldrich)加入到2ml细胞悬液中。在室温预孵育10分钟后，通过涡旋2分钟混合两相系统。在室温孵育20分钟后除去水相，测量其在600nm处的吸光度(A1)。细菌对十六烷的粘附百分比计算为(1-A1/A0)×100，其中A0和A1分别是用溶剂提取前后的吸光度。实验进行三次重复，细胞来自独立培养。
结果
图2：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对十六烷的粘附％作为其疏水性的测量。
结论
与长双歧杆菌NCIMB 41003(28.6％)相比，长双歧杆菌NCIMB41715(58.3％)对十六烷显示更高的亲和力，表明它具有更高的疏水性。
实施例4-PBMC抗炎谱
通过评估外周血单核细胞(PBMC)细胞因子诱导测定中抗炎细胞因子IL-10和促炎细胞因子TNF-α的诱导来检测长双歧杆菌NCIMB 41715、长双歧杆菌NCIMB 41003和低产EPS乳杆菌菌株的抗炎谱。
方法
外周血单核细胞(PBMC)细胞因子诱导测定
在Clinical Research Ethics Committee of the Cork Teaching Hospitals批准下，从三名健康志愿者获得血液。在献血之前，对象都是并且已经避免益生菌、抗生素或抗炎药物使用一个月或更长时间。通过使用histopaque(Sigma-Aldrich，一种亲水性多糖，其将血液层分离)密度梯度分离从全血中提取PBMC，在含有PBMC的血浆层下形成'血沉棕黄层'。对于每种菌株，称出100mg冷冻干燥粉末并重悬于无菌Dulbecos PBS(Sigma-Aldrich)中。细菌细胞通过离心(4000rpm/10min/4℃/Brake 0)洗涤两次并重悬于无菌PBS中。进行直接显微镜计数并将细胞制备物稀释至适当浓度以得到100:1；50：1；25：1的总细菌：PBMC细胞比例。技术重复进行三次重复。然后将PBMC以2×105个细胞/ml的浓度在37℃(存在青霉素和链霉素(Sigma-Aldrich))孵育48小时，使用对照培养基或使用浓度增加的细菌菌株：1×106个细胞/ml(25：1的细菌：PBMC)，1×107个细胞/ml(50：1的细菌：PBMC)和2×107个细胞/ml(100：1的细菌：PBMC)。使用MesoScale Discovery(MSD)Multiplex platformtissue culture kits(MesoScale Diagnostics，Maryland，USA)测定上清液中抗炎细胞因子IL-10和促炎细胞因子TNF-α。先前已显示具有抗炎活性的长双歧杆菌NCIMB 41003(Groeger等，2013)用作阳性对照以验证测定的准确性。
结果
图3：用EPS阳性长双歧杆菌NCIMB 41003和低产EPS的乳杆菌菌株刺激48小时后PBMC细胞因子诱导测定中的IL-10诱导。相对于EPS低乳杆菌菌株，在用EPS阳性长双歧杆菌NCIMB 41003刺激后，抗炎细胞因子IL-10的诱导增强。
图4：用长双歧杆菌NCIMB 41003和低产EPS的乳杆菌菌株刺激48小时后PBMC细胞因子诱导测定中的TNF-α诱导。相对于EPS低乳杆菌菌株，在用EPS阳性长双歧杆菌NCIMB41003刺激后，促炎细胞因子TNF-α诱导的诱导降低。
图5：用长双歧杆菌NCIMB 41003和长双歧杆菌NCIMB 41715刺激48小时后PBMC细胞因子诱导测定中的IL-10诱导。两种菌株以剂量反应性方式诱导相似水平的抗炎细胞因子IL-10。
图6：用长双歧杆菌NCIMB 41003和长双歧杆菌NCIMB 41715刺激48小时后PBMC细胞因子诱导测定中的TNF-α诱导。相对于长双歧杆菌NCIMB 41003，长双歧杆菌NCIMB 41715诱导相似水平的TNF-α。
结论
在PBMC细胞因子诱导测定中，富含EPS的长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003诱导相似的抗炎免疫谱。低产EPS菌株产生非常不同的免疫谱。
实施例5-施用长双歧杆菌NCIMB 41715、长双歧杆菌NCIMB 41003和EPS低乳杆菌菌株在饮食诱导的肥胖症(DIO)小鼠模型中对代谢结果的影响
方法
动物
7周龄雄性C57BL/6JRccHsd小鼠(Harlan Laboratories,Netherlands)(72只小鼠，每组n＝12，基于体重随机化)维持在控制的环境中(22±3℃的温度、50±20％的湿度、每次12小时的光/暗循环和每小时15-20次新鲜空气换气)。将小鼠分组饲养(每笼4只小鼠)，并将高压灭菌的玉米芯用作铺垫材料。在5周龄时接受小鼠并隔离一周，然后在开始研究之前适应一周。从第0天起，小鼠随意取食，并且通过装有不锈钢吸管的聚碳酸酯瓶向每个笼中的小鼠提供50ml的普通无菌饮用水(第1和2组；表1)或含有冷冻干燥益生菌的饮用水(1×109cfu/剂量/天)(第3、4、5和6组；表1)。处理持续16周。
实验设计
第0天开始，第1组饲喂低脂肪饮食(LFD)D12450(10％kcal％脂肪，γ照射的；Research Diets Inc，USA)，其他五组(第2至6组)饲喂高脂肪饮食(HFD)D12451(45％kcal％脂肪，γ照射的；Research Diets Inc)16周的时间。HFD饲喂诱导的胰岛素抵抗和动物肥胖症特征在于体重和空腹血糖值增加。第1和2组提供有普通无菌饮用水，而第3、4、5和6组提供有含有1×109cfu/剂量/天的适当的益生菌的饮用水(表1)。一般健康观察在一天的相同时间每天进行。这包括警觉性、毛发质地、笼中移动以及鼻子、眼睛、嘴巴和耳朵的排泄物的出现。将预先测量的饲料保持在每个笼中，并且每隔三天测量并记录剩余饲料以获取小鼠消耗的食物量。从第一次给药日开始，每天测量动物的水消耗量。每只笼子中的小鼠(n＝4)每日提供50mL水。每24小时测量每个笼中剩余的水。
重量和组织取样
在收到所有动物并随机化的那天，在处理之前以及之后的三天内分别记录体重。根据公式(TT-TC)/TC*100计算体重变化百分比，其中TT是测试日处理的，TC是测试日对照的。在第1天和第28、56、84和112天使用Echo MRI(EchoMRI-700TM)对小鼠进行回声核磁共振成像(MRI)以评估身体脂肪和瘦肉质量组成。将动物置于塑料支架中而不镇静或麻醉。脂肪以体内所有脂肪分子的质量来测量。瘦肉是所有身体含水部分的肌肉组织质量等价物。对“自由水”的贡献主要来自膀胱。总水包括自由水和瘦肉质量中含有的水，这是身体的全部水含量。塑料支架在来自不同组的动物之间进行消毒，以避免交叉污染。在处理来自不同组的动物时遵循无菌技术。在第16周结束时，通过CO2窒息处死动物。收集肝脏、骨骼肌、内脏脂肪(附睾、肾和肠系膜)、皮下脂肪、脾脏、盲肠、褐色脂肪、脑和肠，称重并储存在-80℃以备将来生化和遗传分析。
代谢标记
在第0、30、60、90和112天的早上9点通过夹尾方法收集血液样品，用于随机血糖测量(总共5次取样)，开始/包括第一次给药日。通过Johnson and Johnson血糖仪(One touchUltra 2)进行血糖分析。在处理来自不同组的动物时遵循无菌技术。在16周结束时，将小鼠禁食6小时，并通过夹尾方法(血液采集的非麻醉模式)采集血液用于血糖估计。在轻异氟醚麻醉下通过眼眶后穿刺法采集血液，分离血浆用于通过全自动随机进入临床化学分析仪(EM-360，Erba Mannheim，Germany)估计总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)胆固醇、低密度脂蛋白(LDL)胆固醇和非酯化脂肪酸(NEFA)。通过计算方法：(VLDL＝甘油三酯(mg/dl)/5)获得血浆VLDL水平。对于肝TC和TG估计，将肝脏在异丙醇(1ml/50mg组织)中匀浆，并在4℃孵育1小时。样品在4℃以2,500rpm离心5分钟。通过全自动随机进入临床化学分析仪(EM-360，Erba Mannheim)测量上清液中的胆固醇和甘油三酯浓度。
能量排泄估计
在第6周、第10周和第15周从每只小鼠收集两个粪便颗粒，并通过弹式量热法分析它们的总热量值。对于弹式量热法分析，将样品称重并在60℃烘箱干燥48小时。使用1109半微型弹(Parr Instruments&Co.，Moline，Illinois，USA)用Parr 6100量热计评估粪便的能量含量。量热计能量当量因子使用苯甲酸标准物测定，每个样品(100mg)重复三次分析。在研究过程中益生菌饲喂小鼠的累积能量排泄估计为相对于来自高脂肪饮食对照组的小鼠排泄能量的百分比。
统计分析
使用不成对t检验对两组之间的差异进行统计分析。单因素方差分析(ANOVA)，后接Tukey’s多重比较检验用于两组以上评估。使用用于Windows的GraphPad Prism版本5.00(GraphPad Software)分析数据。当p<0.05时，结果被认为是统计学显著的。
表5：实验组和相关的饮食和处理方案。LFD＝低脂肪饮食对照；HFD＝高脂肪饮食对照。
结果
图7：当与高脂肪饮食(HFD)对照组相比，长双歧杆菌NCIMB 41715显示第16周脂肪质量增加显著减少，而长双歧杆菌NCIMB 41003没有显著影响。
图8：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对脂肪垫重量的影响。长双歧杆菌NCIMB 41715脂肪垫重量(皮下脂肪和附睾脂肪)显著减少，而长双歧杆菌NCIMB41003没有显著影响。
图9：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对肝总胆固醇和甘油三酯的影响。在DIO小鼠中，长双歧杆菌NCIMB 41715而不是长双歧杆菌NCIMB 41003减少肝总胆固醇和甘油三酯。
图10：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆总胆固醇的影响。
图11：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆LDL-胆固醇的影响。
图12：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对血浆VLDL-胆固醇的影响。
图13：长双歧杆菌NCIMB 41715和长双歧杆菌NCIMB 41003对末端血糖的影响。
图14：在DIO小鼠模型中，相对于高脂肪饮食(HFD)对照组，在长双歧杆菌NCIMB41715和长双歧杆菌NCIMB 41003施用后，每只小鼠的累积食物摄入。
图15：在DIO小鼠模型中，相对于高脂肪饮食(HFD)对照组，在长双歧杆菌NCIMB41715和长双歧杆菌NCIMB 41003施用后，累积能量排泄％的估计。
低产EPS的乳杆菌菌株在该模型中没有任何显著影响。
结论
施用长双歧杆菌NCIMB 41715导致两种菌株在第16周时脂肪质量显著减少。这伴随着对于长双歧杆菌NCIMB 41715的皮下脂肪和附睾脂肪的统计学显着减少。与HFD对照组相比，施用长双歧杆菌NCIMB 41715导致肝总胆固醇和甘油三酯水平的显著减少。此外，与HFD对照组相比，施用长双歧杆菌NCIMB 41715也观察到总胆固醇、LDL-胆固醇和VLDL-胆固醇的显著提高。尽管在研究过程中累积食物摄入没有显著差异，但我们观察到长双歧杆菌NCIMB 41715的能量排泄增加％，这表明施用疏水长双歧杆菌NCIMB 41715菌株可以减少从摄入的食物中提取的能量的量，这可能负责在该DIO小鼠模型中观察到的代谢结果的提高。
益生元
益生菌生物体的引入是通过摄入位于适当载体中的微生物来完成的。提供能够促进大肠内菌株生长的培养基将是有利的。添加一种或多种低聚糖、多糖或其他益生元增强了乳酸菌在胃肠道中的生长。益生元是指任何非活的食物成分，其在结肠中通过被认为具有积极价值的固有细菌特别发酵，例如双歧杆菌、乳杆菌。益生元的类型可以包括含有果糖木糖、大豆、半乳糖、葡萄糖和甘露糖的那些。益生菌菌株与一种或多种益生元化合物的联合施用可以增强所施用的益生菌的体内生长，导致更显著的健康益处，并且被称为合生素。
其他活性成分
应该理解的是，该菌株可以预防性地施用，或者作为治疗方法(其本身或与如上所述的其他益生菌和/或益生元材料一起)施用。此外，菌株可以用作预防或治疗方案的一部分，使用其他活性材料，例如用于治疗炎症或其他病的那些，特别是免疫学参与的那些。这样的组合可以在单一制剂中施用，或作为分开的制剂在相同或不同时间施用并且使用相同或不同施用途径。
制剂
一种或多种本发明的菌株可以以常规剂型如胶囊、微胶囊、片剂、颗粒剂、粉末、锭剂、丸剂、栓剂、混悬剂和糖浆剂以口服可摄入形式施用给动物(包括人)。合适的制剂可以通过通常采用的常规有机和无机添加剂的方法制备。药物组合物中活性成分的量可以处于将发挥所需治疗效果的水平。
该制剂还可以包括细菌组分、药物实体或生物化合物。
另外，包含一种或多种本发明菌株的疫苗可以使用任何合适的已知方法制备，并且可以包括药学上可接受的载体或佐剂。
可配制本发明的菌株以促进控制释放，例如菌株的延迟释放。例如，该制剂可适于在胃肠道中的特定位置如小肠或结肠中释放菌株。为了实现这样的控制释放，可以将该菌株配制在具有包衣的胶囊中，该包衣适于在特定位置释放菌株。一系列包衣可用于促进这种控制释放。一种这样的包衣家族是可以在商标Eudragit下获得的那些。本文引用的所有文件的相关部分通过引用并入本文。
本发明不限于上文描述的实施方案，其可以被详细地改变。
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序列表
<110> 营养健康有限公司
<120> 用于治疗肥胖症和相关代谢病的长双歧杆菌
<130> ALIM60/C/WO
<150> EP15199660.0
<151> 2015-12-11
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 495
<212> DNA
<213> Bifidobacterium longum
<400> 1
tgctgggatc acctcctttc tacggagaat tcagtcggat gttcgtccga cggtgtgcgc 60
cccgcgcgtc gcatggtgcg atggcggcgg ggttgctggt gtggaagacg tcgttggctt 120
tgccctgccg gtcgtgcggt gggtgcgggg tggtatggat gcgcttttgg gctcccggat 180
cgccacccca ggctttttgc ctggcgcgat tcgatgcccg tcgtgcctgg gggccggccg 240
tgtgccggcg cgatggcgtg gcggtgcgtg gtggcttgag aactggatag tggacgcgag 300
caaaacaagg gtttttgaat ctttgttttg ctgttgattt cgaatcgaac tctattgttc 360
gtttcgatcg ttttgtgatc atttttagtg tgatgatttg tcgtctggga atttgctaga 420
ggaatacttg cggccatgca cttcgtggtg tgtgttgctt gcaagggcgt atggtggagg 480
ccttcgacca ccaga 495
<210> 2
<211> 18
<212> DNA
<213> Unknown
<220>
<223> synthesised sequence
<400> 2
ctggtgccaa ggcatcca 18
<210> 3
<211> 19
<212> DNA
<213> Unknown
<220>
<223> synthesised sequence
<400> 3
gctggatcac ctcctttct 19
Claims (25)
1.一种长双歧杆菌(Bifidobacterium longum) AH1362菌株，其以保藏号NCIMB 41715保藏于NCIMB。
2.一种制剂，其包含权利要求1的菌株。
3.权利要求2的制剂，其还包含益生菌材料。
4.权利要求2或3的制剂，其还包含益生元材料。
5.权利要求2或3的制剂，其还包含可摄入的载体。
6.权利要求5的制剂，其中所述可摄入的载体是药学上可接受的载体。
7.权利要求5的制剂，其中所述制剂是胶囊、片剂或粉末。
8.权利要求5的制剂，其中所述可摄入的载体是食物产品。
9.权利要求8的制剂，其中所述食物产品是酸化乳、乳浓缩物、涂抹干酪、调味品或饮料。
10.权利要求9的制剂，其中所述食物产品是酸奶。
11.权利要求10的制剂，其中所述食物产品是冻酸奶。
12.权利要求9的制剂，其中所述食物产品是乳粉。
13.权利要求2或3的制剂，其还包含蛋白质和/或肽、脂质、碳水化合物、维生素和/或矿物质。
14.权利要求13的制剂，其中所述蛋白质和/或肽是富含谷氨酰胺/谷氨酸的蛋白质和/或肽。
15.权利要求13的制剂，其中所述矿物质是微量元素。
16.权利要求2或3的制剂，其中所述菌株以大于106 cfu每克所述制剂的量存在。
17.权利要求2或3的制剂，其还包含佐剂。
18.权利要求2或3的制剂，其还包含细菌组分。
19.一种冷冻干燥组合物，其包含权利要求1的菌株或权利要求2的制剂。
20.一种食品，其包含权利要求1的菌株，权利要求2-18中任一项的制剂或权利要求19的组合物。
21.一种药物，其包含权利要求1的菌株或权利要求2-18中任一项的制剂或权利要求19的组合物。
22.一种胶囊，其包含权利要求1的菌株，权利要求2-18中任一项的制剂或权利要求19的组合物。
23.权利要求22的胶囊，其适于在胃肠道中控制释放。
24.一种包含以保藏号NCIMB 41715保藏于NCIMB的长双歧杆菌AH1362菌株的组合物在制备用于在需要预防或治疗肥胖症的对象中预防或治疗肥胖症的药物中的用途。
25.一种包含以保藏号NCIMB 41715保藏于NCIMB的长双歧杆菌AH1362菌株的组合物在制备用于在需要预防或治疗非酒精性脂肪肝疾病(NAFLD)的对象中预防或治疗非酒精性脂肪肝疾病(NAFLD)的药物中的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15199660 | 2015-12-11 | ||
| EP15199660.0 | 2015-12-11 | ||
| PCT/EP2016/080454 WO2017097987A1 (en) | 2015-12-11 | 2016-12-09 | Bifidobacterium longum for treating obesity and associated metabolic disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109069552A CN109069552A (zh) | 2018-12-21 |
| CN109069552B true CN109069552B (zh) | 2023-01-24 |
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| CN (1) | CN109069552B (zh) |
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| SG10201903823QA (en) | 2014-10-31 | 2019-05-30 | Whole Biome Inc | Methods and compositions relating to microbial treatment and diagnosis of disorders |
| EP3589726A1 (en) | 2017-02-28 | 2020-01-08 | Alimentary Health Limited | Bifidobacterium longum able to beneficially modulate immune response to respiratory virus infection |
| US11833178B2 (en) | 2017-08-25 | 2023-12-05 | University College Cork—National University of Ireland, Cork | Bifidobacterium longum for treating obesity and weight management |
| WO2019046646A1 (en) | 2017-08-30 | 2019-03-07 | Whole Biome Inc. | METHODS AND COMPOSITIONS FOR THE TREATMENT OF MICROBIOMA ASSOCIATED DISORDERS |
| CN112672749A (zh) * | 2018-04-11 | 2021-04-16 | 韩国生命工学研究院 | 具有肥胖预防或治疗效果的新的长双歧杆菌菌株或鼠李糖乳杆菌菌株及其用途 |
| KR102224072B1 (ko) * | 2019-08-19 | 2021-03-10 | 주식회사 빙그레 | 면역 조절능력과 혈중콜레스테롤 감소 능력이 모두 뛰어난 비피도박테리엄 롱검 아종 균주 및 이의 용도 |
| WO2021180973A1 (en) | 2020-03-13 | 2021-09-16 | Precisionbiotics Group Limited | Bifidobacterium longum |
| CN113564069B (zh) * | 2021-05-28 | 2023-09-29 | 中山大学 | 一种长双歧杆菌、长双歧杆菌胞外多糖及其提取方法和应用 |
| CN115466689B (zh) * | 2022-02-09 | 2023-06-16 | 中国科学技术大学 | 用于预防和/或治疗代谢类疾病的益生菌组合物及其应用 |
| BG113505A (bg) * | 2022-03-18 | 2023-09-29 | Ел Би Булгарикум ЕАД | ЩАМ Bifidobacterium longum ssp. longum И БИФИДОБАКТЕРИАЛЕН ПРЕПАРАТ С ХИПОЛИПИДЕМИЧЕН ЕФЕКТ, ПРОТИВОВЪЗПАЛИТЕЛЕН ИМУНОМОДУЛИРАЩ ЕФЕКТ И С НАМАЛЯВАЩ ИНСУЛИНОВАТА РЕЗИСТЕНТНОСТ ЕФЕКТ |
| CN115637237A (zh) * | 2022-09-07 | 2023-01-24 | 辽宁贝克瑞生物科技有限公司 | 一株长双歧杆菌及其应用 |
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| CN101646445A (zh) * | 2007-03-28 | 2010-02-10 | 雀巢产品技术援助有限公司 | 用于减少肥胖风险的益生菌 |
| CN102665737A (zh) * | 2009-09-30 | 2012-09-12 | 雀巢产品技术援助有限公司 | 长双歧杆菌atcc baa-999(bl999)和体重控制 |
| US20120276143A1 (en) * | 2009-11-11 | 2012-11-01 | O'mahony Liam | Probiotic bifidobacterium strain |
| CN104968780A (zh) * | 2012-09-20 | 2015-10-07 | 普洛特拉有限公司 | 用于治疗肥胖和肥胖相关病症的益生菌组合物和方法 |
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| MY146590A (en) | 2007-03-28 | 2012-08-30 | Alimentary Health Ltd | Probiotic bifidobacterium strains |
| BRPI0811451A2 (pt) | 2007-05-04 | 2014-11-04 | Alimentary Health Ltd | Exopolissacarídeo |
| RU2570557C2 (ru) | 2008-11-11 | 2015-12-10 | Алиментари Хелс Лимитед | ПРОБИОТИЧЕСКАЯ БИФИДОБАКТЕРИЯ Bifidobacterium Longum |
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Patent Citations (4)
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| CN101646445A (zh) * | 2007-03-28 | 2010-02-10 | 雀巢产品技术援助有限公司 | 用于减少肥胖风险的益生菌 |
| CN102665737A (zh) * | 2009-09-30 | 2012-09-12 | 雀巢产品技术援助有限公司 | 长双歧杆菌atcc baa-999(bl999)和体重控制 |
| US20120276143A1 (en) * | 2009-11-11 | 2012-11-01 | O'mahony Liam | Probiotic bifidobacterium strain |
| CN104968780A (zh) * | 2012-09-20 | 2015-10-07 | 普洛特拉有限公司 | 用于治疗肥胖和肥胖相关病症的益生菌组合物和方法 |
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| RU2018119287A3 (zh) | 2020-06-30 |
| KR20180083352A (ko) | 2018-07-20 |
| DK3386523T3 (da) | 2020-01-06 |
| ES2760076T3 (es) | 2020-05-13 |
| AU2016368527B2 (en) | 2023-01-12 |
| JP2018536427A (ja) | 2018-12-13 |
| CN109069552A (zh) | 2018-12-21 |
| EP3386523A1 (en) | 2018-10-17 |
| PL3386523T3 (pl) | 2020-03-31 |
| AU2016368527A1 (en) | 2018-07-12 |
| CA3006176A1 (en) | 2017-06-15 |
| JP6843140B2 (ja) | 2021-03-17 |
| BR112018011665A2 (pt) | 2018-12-04 |
| US20190111090A1 (en) | 2019-04-18 |
| MX2018006905A (es) | 2018-08-24 |
| CA3006176C (en) | 2023-10-31 |
| RU2740096C2 (ru) | 2021-01-11 |
| EP3386523B1 (en) | 2019-10-09 |
| RU2018119287A (ru) | 2020-01-13 |
| WO2017097987A1 (en) | 2017-06-15 |
| US10973862B2 (en) | 2021-04-13 |
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