CN109666615A - 一种益生菌组合物及其应用 - Google Patents
一种益生菌组合物及其应用 Download PDFInfo
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- CN109666615A CN109666615A CN201910126879.7A CN201910126879A CN109666615A CN 109666615 A CN109666615 A CN 109666615A CN 201910126879 A CN201910126879 A CN 201910126879A CN 109666615 A CN109666615 A CN 109666615A
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
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- A23C19/00—Cheese; Cheese preparations; Making thereof
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Abstract
本发明涉及微生物技术领域,公开了一种益生菌组合物及其用途。本发明所述益生菌组合物由青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044组成,缓解代谢综合征的效果要明显优于CCFM8630或CCFM8631单独使用以及联合,尤其在降低附睾脂肪含量、降低空腹血糖水平、降低糖耐量曲线下面积以及降低血清低密度脂蛋白与总胆固醇的含量、提高肝脏抗氧化能力及降低血清IL‑1β含量等方面,其下降或上升幅度较单菌或双菌联用配方提高了9.62%‑769.62%不等,三菌联用可实现显著的协同增效。
Description
技术领域
本发明涉及微生物技术领域,具体涉及一种益生菌组合物及其应用,尤其是一种缓解代谢综合征的益生菌组合物及其应用。
背景技术
代谢综合征是一组与肥胖、糖尿病、高血压、心血管疾病密切相关的疾病,临床表现为糖耐量异常、超重或肥胖、血脂紊乱和高血压等。大量研究表明,代谢综合征是导致心血管疾病的一个主要因素,患有代谢综合征的人也更可能产生炎症,还易患其他疾病,如卵巢多囊综合症、脂肪肝、胆固醇胆石症、哮喘、睡眠不正常和某些癌症。此外,代谢综合征与冠状动脉粥样硬化性心脏病、2型糖尿病的患病率与死亡率有着显著的关系。目前,全世界代谢综合征的患病率正在迅速增加,包括发展中国家。一项在国内进行的人群调查研究发现,2016年中国大陆人群代谢综合征的患病率为24.5%,另一项研究显示,代谢综合征患病率的增长趋势,从1993年-1996年的13.6%增加到2005年-2008年的25.5%。
代谢综合征的治疗主要是控制并改善危险因素,传统的治疗方式是药物治疗如CN103977014A公开了一种应用于治疗代谢综合征的药物,包括木通皂苷和姜黄素,通过调节患者的蛋白质、脂质和碳水化合物的代谢过程,对代谢综合征起到预防和治疗作用;CN103596949A公开了一种新型化合物分子结构,其对糖尿病和代谢综合征具有治疗作用;CN103446139A公布了一种治疗代谢综合征的药物组合,包括葛根素、肉桂酸和盐酸檗碱,改善胰岛素抵抗的同时兼顾降血糖、降血压、降血脂及改善腹型肥胖的疗效。药物治疗虽然见效快,但伴有一定程度的副作用,而且需要长期服药,机体容易产生药物依赖。
有大量研究报道,肠道菌群对人体的生理代谢起着极为重要的作用,肠道菌群结构失调和多种疾病相关,包括胃肠疾病(肠易激综合征和炎症性肠病等)、代谢性疾病(肥胖、高血脂和糖尿病等)。代谢综合征的发生与肠道菌群失调也具有密切关系,常用的肠道菌群调节制剂有益生菌和益生元等。如CN107699517A公开了一株青春双歧杆菌及其用途,可以显著改善高糖高脂饮食导致的代谢综合征大鼠肝脏、十二指肠的病理损伤以及血清中甘油三酯和总胆固醇含量升高和口服糖耐量;CN107523526A公开了一种罗伊氏乳杆菌及其用途,可以降低代谢综合征大鼠血清脂质及血糖水平;CN108295098A公开了一种辅助降血糖的合生元组合物,所述的组合物包括益生元和益生菌,通过刺激肠道内免疫机能,将肠道功能恢复正常,维护人体机体微生态平衡,达到降低血糖的效果;CN103656076A公布了一种具有降血糖功能的益生菌中草药复合物制剂。但以上专利均是使用单一益生菌或是益生菌与益生元或中草药的组合物来缓解代谢综合征,而目前对多株在改善代谢综合征方面可协同增效的益生菌复配配方少有研究。
发明内容
有鉴于此,本发明的目的在于提供一种益生菌组合物,可以用来缓解代谢综合征。
为实现本发明的目的,本发明采用如下技术方案:
一种益生菌组合物,由青春双歧杆菌CCFM8630(Bifidobacteriumadolescentis)、罗伊氏乳杆菌CCFM8631(Lactobacillus reuteri)和鼠李糖乳杆菌CCFM1044(Lactobacillus rhamnosus)组成。
作为优选,所述青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比为1:(1-10):(1-10)。
本发明还提供了所述益生菌组合物的制备方法,分别将青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044菌液接种到改良MRS培养基中,35-37℃厌氧条件下培养18-24h,收集菌体;分别用冻干保护剂重悬使各菌体含量达到1010CFU/mL以上,然后悬浮液在37℃厌氧条件下培养40-60min,干燥制得各菌体的冻干菌粉并通过重悬稀释平板涂布后确认菌粉中的活菌数;将所述青春双歧杆菌CCFM8630冻干菌粉、罗伊氏乳杆菌CCFM8631冻干菌粉及鼠李糖乳杆菌CCFM1044冻干菌粉按一定比例进行复配混合达到需要的活菌数比例。
作为优选,所述改良MRS培养基(mMRS)为含0.05%L-半胱氨酸盐酸盐的MRS培养基;所述冻干保护剂为含有100g/L-150g/L脱脂奶粉、30g/L-100g/L蔗糖、30g/L-100g/L海藻糖的水溶液;所述干燥为在-15~-20℃预冻8-14h后进行真空冷冻干燥。
本发明还提供了所述益生菌组合物在制备缓解代谢综合征的产品中的应用。
作为优选,所述产品为保健食品或药物。
作为优选,所述保健食品为菌剂或发酵食品。
本发明还提供了含有所述益生菌组合物的菌剂。
作为优选,所述的菌剂中所述益生菌组合物的活菌数大于1×1011CFU/g。
本发明有益的技术效果在于:
本发明所述由青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044组成的益生菌组合物是一种天然、安全的,可有效缓解代谢综合征的微生态制剂,缓解代谢综合征的效果要明显优于单独使用CCFM8630或CCFM8631以及联合使用CCFM8630和CCFM8631,尤其在降低附睾脂肪含量、降低空腹血糖水平、降低糖耐量曲线下面积以及降低血清低密度脂蛋白与总胆固醇的含量、提高肝脏抗氧化能力及降低血清IL-1β含量等方面,其下降或上升幅度较CCFM8630、CCFM8631的单菌或双菌联用配方提高了9.62%-769.62%不等,青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044三菌联用可实现显著的协同增效。本发明所述的益生菌组合物可用于制备缓解代谢综合征的保健食品或药物,具有非常广泛的应用前景。
生物保藏说明
CCFM8630,分类命名:青春双歧杆菌,Bifidobacterium adolescentis,于2017年07月07日保藏在中国微生物菌种保藏管理委员会普通微生物中心,地址为北京市朝阳区北辰西路1号院3号中国科学院微生物研究所,保藏编号为CGMCC No.14395。
CCFM8631,分类命名:罗伊氏乳杆菌,Lactobacillus reuteri,于2017年07月07日保藏在中国微生物菌种保藏管理委员会普通微生物中心,地址为北京市朝阳区北辰西路1号院3号中国科学院微生物研究所,保藏编号为CGMCC No.14394。
CCFM1044,分类命名:Lactobacillus rhamnosus,于2019年01月21日保藏在广东省微生物菌种保藏中心,地址为广州市先烈中路100号大院59号楼5楼广东省微生物研究所,保藏编号为GDMCC No:60540。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示本发明实施例3中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠体内附睾脂肪含量升高的缓解作用的结果图;
图2示本发明实施例3中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠体内肾周脂肪含量升高的缓解作用的结果图;
图3示本发明实施例4中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠空腹血糖水平升高的缓解作用的结果图;
图4示本发明实施例4中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠糖耐量曲线下面积(AUC)升高的缓解作用的结果图;
图5示本发明实施例5中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠血清低密度脂蛋白(LDL-C)含量升高的缓解作用的结果图;
图6示本发明实施例6中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠血清总胆固醇(TC)含量升高的缓解作用的结果图;
图7示本发明实施例7中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠肝脏总抗氧化能力(T-AOC)降低的缓解作用的结果图;
图8示本发明实施例7中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠肝脏过氧化氢酶(CAT)含量升高的缓解作用的结果图;
图9示本发明实施例8中不同益生菌复配干预组对高脂饮食诱导代谢综合征小鼠血清IL-1β含量升高的缓解作用的结果图;上述各图使用Graphpad Prism5进行绘图,各实验组间采用LSD检验均数比较,与模型组相比,P<0.05标注*,P<0.01标注**,P<0.001标注***,P<0.0001标注****。
具体实施方式
本发明公开了一种益生菌组合物及其应用。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及产品已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合,来实现和应用本发明技术。
为实现本发明的目的,本发明采用如下技术方案:
一种益生菌组合物,由青春双歧杆菌CCFM8630(Bifidobacteriumadolescentis)、罗伊氏乳杆菌CCFM8631(Lactobacillus reuteri)和鼠李糖乳杆菌CCFM1044(Lactobacillus rhamnosus)组成。
本发明所述青春双歧杆菌CCFM8630(Bifidobacterium adolenscentis),于2017年07月07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CGMCC,保藏地址为北京市朝阳区北辰西路1号院3号中国科学院微生物研究所,保藏编号为CGMCC NO.14395。
本发明所述罗伊氏乳杆菌CCFM8631(Lactobacillus reuteri),于2017年07月07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CGMCC,保藏地址为北京市朝阳区北辰西路1号院3号中国科学院微生物研究所,保藏编号为CGMCC NO.14394。
本发明所述鼠李糖乳杆菌CCFM1044(Lactobacillus rhamnosus),于2019年01月21日保藏于广东省微生物菌种保藏中心,保藏地址为广州市先烈中路100号大院59号楼5楼广东省微生物研究所,保藏编号为GDMCC No:60540。
其中,作为优选,所述的益生菌组合物中所述青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比为1:(1-10):(1-10)。
在一些实施方案中,所述的益生菌组合物中所述青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比为1:1:1、1:5:5、1:2:10或1:10:2。
本发明还提供了所述益生菌组合物的制备方法,分别将青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044菌液接种到改良MRS培养基中,35-37℃厌氧条件下培养18-24h,收集菌体;分别用冻干保护剂重悬使各菌体含量达到1010CFU/mL以上,然后悬浮液在37℃厌氧条件下培养40-60min,干燥制得各菌体的冻干菌粉并通过重悬稀释平板涂布后确认菌粉中的活菌数;将所述青春双歧杆菌CCFM8630冻干菌粉、罗伊氏乳杆菌CCFM8631冻干菌粉及鼠李糖乳杆菌CCFM1044冻干菌粉按一定比例进行复配混合达到需要的活菌数比例。
本发明所述益生菌组合物的制备方法中,所述改良MRS培养基(mMRS)为含0.05%L-半胱氨酸盐酸盐的MRS培养基。具体配制方法为胰蛋白胨10g、牛肉浸膏10g、酵母粉5g、葡萄糖20g、醋酸钠5g、柠檬酸氢二铵2g、磷酸氢二钾2g、七水硫酸镁0.5g、吐温80 1mL、一水合硫酸锰0.25g、半胱氨酸盐酸盐0.5g,水定容至1000mL,调节pH至6.8,在119-123℃条件下灭菌15-25min。
本发明所述制备方法中所述冻干保护剂为含有100g/L-150g/L脱脂奶粉、30g/L-100g/L蔗糖、30g/L-100g/L海藻糖的水溶液。即所述冻干保护剂由脱脂奶粉、蔗糖、海藻糖和水组成,其中脱脂奶粉的浓度为100g/L-150g/L,蔗糖的浓度为30g/L-100g/L,海藻糖的浓度为30g/L-100g/L。
优选的,本发明所述制备方法中改良MRS培养基培养后收集的菌体采用磷酸盐缓冲液清洗2-4次,所述磷酸盐缓冲液pH为6.8-7.2。
本发明所述制备方法中所述干燥可以采用任意一种菌液干燥工艺进行干燥,如真空冷冻干燥。在一些实施例中,本发明所述制备方法中所述干燥为在-15~-20℃预冻8-14h后进行真空冷冻干燥。
在一些实施例中,本发明所述益生菌组合物的制备方法,包括如下步骤:
(1)制备改良MRS培养基(mMRS)
1L水中加入胰蛋白胨10g、牛肉浸膏10g、酵母粉5g、葡萄糖20g、醋酸钠5g、柠檬酸氢二铵2g、磷酸氢二钾2g、七水硫酸镁0.5g、吐温80 1mL、一水合硫酸锰0.25g、半胱氨酸盐酸盐0.5g,将培养基pH调至6.8-7.0。
(2)制备冻干用益生菌保护剂
1L水中加入100g-150g脱脂奶粉、30g-100g蔗糖、30g-100g海藻糖;
(3)冻干菌粉的制备
分别将青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631、鼠李糖乳杆菌CCFM1044从保菌管中在固体培养基平板中划线分离得到单菌落,温度35-37℃,在厌氧工作站进行培养36h-48h,分别挑取单菌落接种到改良MRS液体培养基中,在厌氧工作站34-39℃培养18h-24h,再按2%-4%(v/v)的接种量,分别接种到更大体积的液体培养基中,在厌氧工作站34-39℃培养18h-24h后,5000rpm,15min条件下离心得菌泥,用pH为6.8-7.2磷酸盐缓冲液清洗2-3次,分别用与菌泥等质量的上述冻干保护剂重悬,使得菌体含量达到1010CFU/mL以上;接着,让该悬浮液在37℃厌氧条件下预培养40-60min,再在-15~-20℃预冻8-14h,最后进行真空冷冻干燥分别得到青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044的冻干菌粉。
(4)益生菌组合物的配制
将所述青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044按一定比例进行复配混合从而实现需要的活菌数比例。
在一些实施方案中,本发明考察了由青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044组成的益生菌组合物对代谢综合征的影响。结果显示,采用两株益生菌CCFM8630及CCFM8631与鼠李糖乳杆菌CCFM1044进行复配,相比较单独使用CCFM8630或CCFM8631以及联合使用CCFM8630和CCFM8631,三菌联用组成的益生菌组合物缓解代谢综合征的效果要明显优于以上单菌及双菌等的效果,尤其在降低附睾脂肪含量、降低空腹血糖水平、降低糖耐量曲线下面积以及降低血清低密度脂蛋白与总胆固醇的含量、提高肝脏抗氧化能力及降低血清IL-1β含量等方面,其下降或上升幅度较CCFM8630、CCFM8631的单菌或双菌联用配方提高了9.62%-769.62%不等,青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044三菌联用可实现显著的协同增效。
因此本发明提供了所述益生菌组合物在制备缓解代谢综合征的产品中的应用。
其中,所述代谢综合征为肥胖,血糖、血脂异常,炎症以及氧化应激等。
本发明所述产品包括但不限于保健食品或药物。
本发明所述产品中三种菌的每日摄入总活菌数不低于2×108CFU。
其中,所述保健食品包括但不限于菌剂或发酵食品。
进一步,本发明提供了含有上述益生菌组合物的菌剂。
优选的,所述菌剂中所述益生菌组合物的活菌数不低于1×1011CFU/g。
本发明所述菌剂可以按常规方法制备。
本发明还提供了一种发酵食品,以上述益生菌组合物作为发酵剂发酵生产的食品。
所述发酵食品为发酵乳制品、发酵豆制品或发酵果蔬制品。
所述发酵乳制品包括但不限于酸奶、酸奶油、干酪。所述的发酵豆制品包括但不限于豆奶、豆豉、豆酱。所述发酵果蔬制品中果蔬包括但不限于黄瓜、胡萝卜、甜菜、芹菜、圆白菜。
本发明还提供了一种药物制剂,包括有效剂量的上述益生菌组合物和药学上可接受的辅料。
所述药学上可接受的辅料包括填充剂、粘合剂、润湿剂、崩解剂、润滑剂、矫味剂中的一种或多种。
在本发明的一些具体实施方案中,所述药物制剂的剂型为颗粒剂、胶囊剂、片剂、丸剂或口服液。
本发明有益的技术效果在于:
本发明所述由青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044组成的益生菌组合物是一种天然、安全的,可有效缓解代谢综合征的微生态制剂,缓解代谢综合征的效果要明显优于单独使用CCFM8630或CCFM8631以及联合使用CCFM8630和CCFM8631,尤其在降低附睾脂肪含量、降低空腹血糖水平、降低糖耐量曲线下面积以及降低血清低密度脂蛋白与总胆固醇的含量、提高肝脏抗氧化能力及降低血清IL-1β含量等方面,其下降或上升幅度较CCFM8630、CCFM8631的单菌或双菌联用配方提高了9.62%-769.62%不等,青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044三菌联用可实现显著的协同增效。本发明所述的益生菌组合物可用于制备缓解代谢综合征的保健食品或药物,具有非常广泛的应用前景。
为了进一步理解本发明,下面将结合本发明实施例,对本发明实施例中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前提下所获得的所有其他实施例,都属于本发明保护的范围。
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均可以通过商业渠道购买获得。
实施例1:益生菌组合物对模拟胃肠液具有良好的耐受性
将保存于-80℃环境下的青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044分别接种于改良MRS培养基(mMRS)中,在厌氧工作站中37℃培养36h,再以2%-4%(v/v)的接种量传代培养2次,调整青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044培养液活菌浓度为5×108CFU/mL,取浓度为5×108CFU/mL的青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044的培养液各1mL,混合均匀,取混合培养液1mL与9.0mL pH 2.5人工模拟胃液(含1%胃蛋白酶、pH=2.5的mMRS培养基)混合,在37℃厌氧环境下培养,分别在0h、0.5h、1h和2h时取样,在mMRS固体培养基涂布培养进行平板菌落计数,测定活菌数并计算其存活率。存活率是在该培养液中在取样时的活菌数对数值与在第0h时活菌数对数值之比,以%表示。实验结果如表1所示。
取混合培养液1mL加入9mL人工模拟肠液(含0.3%牛胆盐、1%胰蛋白酶、pH=8.0的mMRS培养基)中,在37℃厌氧环境下培养,分别在0h、0.5h、1h、2h、3h和4h时取样,在mMRS固体培养基涂布培养进行平板菌落计数,测定活菌数并计算其存活率。存活率是在该培养液中在取样时的活菌数对数值与在第0h时活菌数对数值之比,以%表示。实验结果如表2所示。
表1益生菌组合物在人工模拟胃液中的耐受性
表2益生菌组合物在人工模拟肠液中的耐受性
结果表明,所述益生菌组合物对人工胃液、人工肠液具有较好的耐受性。
实施例2:益生菌组合物对C57BL/6J小鼠无毒副作用
将青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044活菌数比为1:1:1的益生菌组合物菌体重悬于3%的蔗糖溶液中,制成浓度为1.0×109CFU/mL的菌悬液。取体重20g-22g左右的健康雄性C57BL/6J小鼠8只,适应性饲养一周后,每天灌胃该浓度菌悬液一次,观察一周,记录死亡和体重情况。实验结果见表3。
表3小鼠体重的变化及死亡情况
时间(天) | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
体重(g) | 20.2±0.9 | 20.4±1.0 | 20.5±1.3 | 20.7±1.1 | 20.8±0.8 | 21.2±0.9 | 21.6±0.8 |
死亡情况 | - | - | - | - | - | - | - |
注:-:小鼠无死亡
结果显示,灌胃浓度1.0×109CFU/mL的益生菌组合物未对小鼠造成明显影响,体重增量无显著变化,无死亡现象产生。小鼠活动正常,外表无明显病状。
实施例3:益生菌组合物对高脂饮食诱导代谢综合征小鼠附睾脂肪和肾周脂肪含量的影响
实验动物选择5周龄的SPF级C57BL/6雄性小鼠48只,购自上海斯莱克实验动物中心。高脂饲料购自南通特洛菲,造模组采用TP23300高脂饲料,空白对照组采用TP23302对照饲料。将小鼠适应性喂养7天后开始正式试验,动物自由摄食、饮水,环境温度为22±2℃,湿度为55±5%,光照为12h光暗交替。
实验动物随机分为8组,空白对照组(NC)、高脂模型对照组(HF)、罗格列酮对照组(RH)、辛伐他汀对照组(SC)、青春双歧杆菌CCFM8630干预组(8630)、罗伊氏乳杆菌干预组(8631)、青春双歧杆菌CCFM8630与罗伊氏乳杆菌CCFM8631复配组(8630+8631)、青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044复配组(8630+8631+1044),每组含小鼠6只,饲养环境温度为20~26℃,湿度40%~70%,每周更换2次垫料。其中青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044复配组中青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631及鼠李糖乳杆菌CCFM1044活菌数比为1:1:1。每日每只小鼠灌胃的菌浓度为1.0×109CFU/mL,重悬于3%的蔗糖溶液中,灌胃体积为0.2mL,即每只小鼠每天的灌胃菌总量为2×108CFU。实验分组及处理方式见表4。
表4实验动物分组
第20周试验结束时,小鼠禁食不禁水12h,腹腔注射100mg/kg bw的氯胺酮麻醉后,眼球取血,然后脱臼处死。血液在4℃,3000g条件下离心10min,然后用小量程的移液枪小心吸取上层液体即为血清,-80℃冻存备用。取附睾脂肪(统一取左侧)、肾周脂肪(统一左侧)并进行称重,肝脏组织用冰冷的生理盐水漂洗后取一部分制作10%的肝匀浆,-80℃冻存。实验结果如图1和图2所示。
与NC组相比,HF组代谢综合征小鼠体内的附睾脂肪含量显著增加(P<0.0001),在干预组中与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组腹部脂肪含量下降幅度分别是0.3817g、0.3925g、0.3067g、0.2125g、0.21g、0.4233g,8630+8631+1044(活菌数比为1:1:1)组的附睾脂肪含量相比于药物组和其余益生菌干预组均要低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了38.02%、99.2%、101.57%,说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠体内附睾脂肪含量具有更好的效果。
与NC组相比,HF组代谢综合征小鼠体内的肾周脂肪含量显著增加(P<0.001),在干预组中与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组肾周脂肪含量下降幅度分别是0.088g、0.102g、0.099g、0.022g、0.0665g、0.124g,8630+8631+1044(活菌数比为1:1:1)组的肾周脂肪含量相比于药物组和其余益生菌干预组均更低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了25.25%、463.64%、86.47%,说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠体内肾周脂肪含量具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠附睾脂肪和肾周脂肪含量升高的降低作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
实施例4:益生菌组合物对高脂饮食诱导代谢综合征小鼠空腹血糖水平和糖耐量曲线下面积(AUC)的影响
C57BL/6J小鼠分组、造模及处理方法同实施例3。在试验结束的前一周(第19周)进行血糖的检测,采用尾部取血的方式,用快速血糖仪和血糖试纸进行检测。空腹血糖:小鼠过夜禁食12h(不禁水)测定;糖耐量:小鼠过夜禁食12h,不禁水,检测初始血糖(0min),然后灌胃2g/kg BW葡萄糖溶液,在30、60和120min时检测血糖值。
实验结果如图3和图4所示,与NC组相比,HF组代谢综合征小鼠空腹血糖水平显著增加(P<0.0001),在干预组中与HF组相比RH、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组空腹血糖水平显著降低,下降幅度分别是1.145mmol/L、1.125mmol/L、1.205mmol/L、1.15mmol/L、1.55mmol/L,8630+8631+1044(活菌数比为1:1:1)组的空腹血糖水平相比于药物组和其余益生菌干预组均更低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了37.78%、28.63%、34.78%。说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠空腹血糖水平具有更好的效果。
与NC组相比,HF组代谢综合征小鼠的AUC显著增加(P<0.0001),在干预组中,与HF组相比RH、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组AUC均显著下降,下降幅度分别是204.6、150、213、184.8、233.5,8630+8631+1044(活菌数比为1:1:1)组的AUC相比于药物组和其余益生菌干预组均更低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了55.67%、9.62%、26.35%。说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠AUC具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠空腹血糖水平和糖耐量曲线下面积(AUC)升高的降低作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
实施例5:益生菌组合物对高脂饮食诱导代谢综合征小鼠血清低密度脂蛋白(LDL-C)的影响
C57BL/6J小鼠分组、造模及处理方法同实施例3。按照南京建成低密度脂蛋白试剂盒的检测方法测定血清中低密度脂蛋白(LDL-C)的含量。实验结果如图5所示。
与NC组相比,HF组代谢综合征小鼠血清的LDL-C含量显著增加(P<0.0001),在干预组中,与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组LDL-C均显著性下降,下降幅度分别是0.328mmol/L、0.28mmol/L、0.224mmol/L、0.184mmol/L、0.256mmol/L、0.4mmol/L,8630+8631+1044(活菌数比为1:1:1)组的LDL-C含量相比于药物组和其余益生菌干预组均更低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了78.57%、117.39%、56.25%。说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠血清LDL-C含量具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠血清低密度脂蛋白(LDL-C)升高的降低作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
实施例6:益生菌组合物对高脂饮食诱导代谢综合征小鼠血清总胆固醇(TC)的影响
C57BL/6J小鼠分组、造模及处理方法同实施例3。按照南京建成总胆固醇试剂盒的检测方法测定血清中总胆固醇(TC)的含量,实验结果如图6所示。
与NC组相比,HF组体内的TC显著增加(P<0.0001),在干预组中,与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:1:1)各组TC含量均显著性下降,下降幅度分别是0.996mmol/L、0.912mmol/L、0.696mmol/L、0.706mmol/L、0.872mmol/L、1.16mmol/L,8630+8631+1044(活菌数比为1:1:1)组的TC含量相比于药物组和其余益生菌干预组均更低,与8630组、8631组及8630+8631组相比,下降幅度分别增加了66.67%、64.31%、33.03%。说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠血清TC含量具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠血清总胆固醇(TC)升高的降低作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
实施例7:益生菌组合物对高脂饮食诱导代谢综合征小鼠肝脏总抗氧化能力(T-AOC)和过氧化氢酶(CAT)的影响
C57BL/6J小鼠造模方式同实施例3,青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比例由原来的1:1:1变更为1:5:5,1:10:2和1:2:10,总活菌数仍保持为1.0×109CFU/mL。按照南京建成T-AOC试剂盒、CAT试剂盒、总蛋白试剂盒的检测方法测定小鼠肝匀浆中T-AOC含量、CAT含量及总蛋白含量。实验结果如图7和图8所示。
与NC组相比,HF组代谢综合征小鼠总抗氧化能力显著下降(P<0.001),在干预组中与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:5:5)、8630+8631+1044(活菌数比为1:10:2)、8630+8631+1044(活菌数比为1:2:10)各组总抗氧化能力均增加,增加幅度分别是0.0075mmol/g prot、0.012mmol/g prot、0.016mmol/g prot、0.0166mmol/g prot、0.0256mmol/g prot、0.0316mmol/g prot、0.0360mmol/g prot、0.0292mmol/g prot,8630+8631+1044各配比组的总抗氧化能力相比于药物组和其余益生菌干预组均更高,8630+8631+1044(活菌数比为1:5:5)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了97.33%、90.19%、23.33%,8630+8631+1044(活菌数比为1:10:2)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了125.25%、117.11%、40.78%,8630+8631+1044(活菌数比为1:2:10)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了82.50%、75.90%、14.06%,说明CCFM8630+CCFM8631+CCFM1044对于增加代谢综合征小鼠肝脏抗氧化能力具有更好的效果。
与NC组相比,HF组代谢综合征小鼠的过氧化氢酶含量显著下降(P<0.001),在干预组中,与HF组相比RH、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:5:5)、8630+8631+1044(活菌数比为1:10:2)、8630+8631+1044(活菌数比为1:2:10)各组过氧化氢酶含量均有所上升,上升幅度分别是3.48U/mg prot、5.30U/mg prot、1.26U/mg prot、7.12U/mgprot、10.02U/mg prot、10.99U/mg prot、9.31U/mg prot,8630+8631+1044各配比组的过氧化氢酶含量相比于药物组和其余益生菌干预组均更高,8630+8631+1044(活菌数比为1:5:5)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了89.17%、692.59%、40.62%,8630+8631+1044(活菌数比为1:10:2)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了107.55%、769.62%、54.29%,8630+8631+1044(活菌数比为1:2:10)组与8630组、8631组及8630+8631组相比,上升幅度分别增加了75.89%、636.95%、30.75%。说明CCFM8630+CCFM8631+CCFM1044对于增加代谢综合征小鼠肝脏过氧化氢酶含量具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠肝脏总抗氧化能力(T-AOC)和过氧化氢酶(CAT)降低的升高作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
实施例8:益生菌组合物对高脂饮食诱导代谢综合征小鼠血清IL-1β的影响
C57BL/6J小鼠造模方式同实施例3,青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比例由原来的1:1:1变更为1:5:5,1:10:2和1:2:10,总活菌数仍保持为1.0×109CFU/mL。按照南京森倍伽小鼠IL-1βELISA试剂盒方法测定小鼠血清中IL-1β。实验结果如图9所示。
与NC组相比,HF组血清中IL-1β含量显著增加(P<0.001),在干预组中,与HF组相比RH、SC、8630、8631、8630+8631、8630+8631+1044(活菌数比为1:5:5)、8630+8631+1044(活菌数比为1:10:2)、8630+8631+1044(活菌数比为1:2:10)各组IL-1β含量均显著性下降,下降幅度分别是12.26ng/L、8.88ng/L、8.79ng/L、9.11ng/L、11.09ng/L、13.85ng/L、14.63ng/L、12.80ng/L,8630+8631+1044各配比组的IL-1β含量相比于药物组和其余益生菌干预组均更低,8630+8631+1044(活菌数比为1:5:5)组与8630组、8631组及8630+8631组相比,下降幅度分别增加了57.53%、52.03%、24.89%,8630+8631+1044(活菌数比为1:10:2)组与8630组、8631组及8630+8631组相比,下降幅度分别增加了66.41%、60.60%、31.93%,8630+8631+1044(活菌数比为1:2:10)组与8630组、8631组及8630+8631组相比,下降幅度分别增加了45.63%、40.55%、15.46%。说明CCFM8630+CCFM8631+CCFM1044对于降低代谢综合征小鼠体内的炎症反应具有更好的效果。
由此可见,对高脂饮食诱导代谢综合征小鼠血清IL-1β升高的降低作用,CCFM8630、CCFM8631和CCFM1044三株菌复配表现出显著的协同增效。
Claims (9)
1.一种益生菌组合物,由青春双歧杆菌CCFM8630(Bifidobacterium adolescentis)、罗伊氏乳杆菌CCFM8631(Lactobacillus reuteri)和鼠李糖乳杆菌CCFM1044(Lactobacillus rhamnosus)组成。
2.根据权利要求2所述的益生菌组合物,所述青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044的活菌数比为1:(1-10):(1-10)。
3.权利要求1所述益生菌组合物的制备方法,分别将青春双歧杆菌CCFM8630、罗伊氏乳杆菌CCFM8631与鼠李糖乳杆菌CCFM1044菌液接种到改良MRS培养基中,35-37℃厌氧条件下培养18-24h,收集菌体;分别用冻干保护剂重悬使各菌体含量达到1010CFU/mL以上,然后悬浮液在37℃厌氧条件下培养40-60min,干燥制得各菌体的冻干菌粉并通过重悬稀释平板涂布后确认菌粉中的活菌数;将所述青春双歧杆菌CCFM8630冻干菌粉、罗伊氏乳杆菌CCFM8631冻干菌粉及鼠李糖乳杆菌CCFM1044冻干菌粉按一定比例进行复配混合达到需要的活菌数比例。
4.根据权利要求3所述的制备方法,所述改良MRS培养基(mMRS)为含0.05%L-半胱氨酸盐酸盐的MRS培养基;所述冻干保护剂为含有100g/L-150g/L脱脂奶粉、30g/L-100g/L蔗糖、30g/L-100g/L海藻糖的水溶液;所述干燥为在-15~-20℃预冻8-14h后进行真空冷冻干燥。
5.权利要求1-2任意一项所述益生菌组合物在制备缓解代谢综合征的产品中的应用。
6.根据权利要求5所述的应用,所述产品为保健食品或药物。
7.根据权利要求6所述的应用,其特征在于,所述保健食品为菌剂或发酵食品。
8.含有权利要求1-2任意一项所述益生菌组合物的菌剂。
9.根据权利要求8所述的菌剂,所述益生菌组合物的活菌数大于1×1011CFU/g。
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