CN114381406A - 可同时降低血浆及盲肠三甲胺的短双歧杆菌ccfm1217及其应用 - Google Patents
可同时降低血浆及盲肠三甲胺的短双歧杆菌ccfm1217及其应用 Download PDFInfo
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- CN114381406A CN114381406A CN202210098006.1A CN202210098006A CN114381406A CN 114381406 A CN114381406 A CN 114381406A CN 202210098006 A CN202210098006 A CN 202210098006A CN 114381406 A CN114381406 A CN 114381406A
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- Child & Adolescent Psychology (AREA)
Abstract
本发明公开了可同时降低血浆及盲肠三甲胺的短双歧杆菌CCFM1217及其应用,属于微生物技术领域。本发明的短双歧杆菌CCFM1217能够降低血浆TMAO、血浆TMA和盲肠TMA的水平;能够改善肠道菌群的结构,恢复高胆碱造成的肠道菌群紊乱,提高有益菌的丰度(Roseburia属、Rikenellaceae RC9 gut group属),降低有害菌Anaeroplasma属的相对丰度,减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病发生的风险。因此,具有广阔的应用价值。
Description
技术领域
本发明涉及可同时降低血浆及盲肠三甲胺的短双歧杆菌CCFM1217及其应用,属于微生物技术领域。
背景技术
心血管疾病是世界范围内致病率和致死率主要的原因,动脉粥样硬化(AS)是心血管的病理基础。动脉粥样硬化是一种慢性炎症性疾病,包括病变处单核细胞及巨噬细胞聚集、平滑肌细胞增生和游移、成纤维细胞增生、胆固醇结晶及游离胆固醇和***沉积。目前,公认的AS的始动因素为动脉壁内皮损伤及脂质的沉积;危险因子为高血压,血脂升高,炎症,氧化高胆碱,肥胖,抽烟等。
人体肠道内含有超过1000多种微生物,总数约为1014~1015个,其质量可达1~1.5千克。这些肠道微生物编码基因的总数约为人类自身编码基因总数的100倍,因此肠道微生物又被认为是人体的第二基因组。肠道微生物基因组与人体基因组一起,通过与环境因素的相互作用,影响宿主的食物消化和新陈代谢、免疫反应和炎症、神经活动等多种重要的生理功能。肠道菌群及其代谢产物与宿主之间的相互作用,对于维持宿主的健康是必要的。肠道微生态的紊乱与许多疾病相关,包括糖尿病、肥胖症、炎性肠病、神经退行性疾病和肿瘤等。
有研究表明,肠道微生物主要通过细菌感染、调节胆固醇和脂质代谢、食物及微生物代谢产物三种途径对动脉粥样硬化产生影响。经膳食-肠道微生物-肝脏-氧化三甲胺(TMAO)途径产生的TMAO可以促进心血管疾病发生发展。依赖微生物的三甲胺(TMA)/TMAO途径被证明与心血管疾病的发病机制相关,是心血管疾病的重要诊断和治疗靶点。干预肠道菌群代谢,或许可以成为预防和治疗心血管疾病方法之一。
益生菌作为膳食补充剂,已被消费者广泛接受。补充益生菌能直接给人体肠道注入大量的有益菌群,帮助改善菌群的代谢功能。大量的科学研究和临床实验已经证明,益生菌对便秘、肠炎、乳糖不耐、抗感染、炎症、过敏、糖脂代谢紊乱均具有显著改善作用。
发明内容
本发明提供了一种短双歧杆菌(Bifidobacterium breve)CCFM1217,其于2021年12月31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:62176。
本发明还提供了含有所述短双歧杆菌CCFM1217的益生菌制剂。
在一种实施方式中,所述益生菌制剂中短双歧杆菌CCFM1217的含量≥1×109CFU/mL或≥1×109CFU/g。
本发明还提供了含有所述短双歧杆菌CCFM1217的组合物。
在一种实施方式中,所述组合物还含有他汀类药物。
本发明还提供一种发酵食品,所述发酵食品是使用短双歧杆菌CCFM1217发酵生产制得,所述发酵食品包括固态食品、液态食品、半固态食品。
在一种实施方式中,所述发酵食品包括乳制品、豆制品、果蔬制品,所述乳制品包括牛奶、酸奶油、干酪;所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜制品。
本发明还提供短双歧杆菌CCFM1217在制备体内定植益生菌中的应用。
本发明还提供短双歧杆菌CCFM1217在制备减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病中至少一种疾病发病风险的药物或缓解肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病中至少一种疾病症状的保健品中的应用;所述心血管疾病包括但不限于动脉粥样硬化。
在一种实施方式中,所述药物还含有药学上可接受的载体;所述药学上可接受的载体包括但不限于:填充剂、润湿剂、崩解剂、粘合剂或润滑剂中的一种或多种。
在一种实施方式中,所述应用包括如下至少一种作用:
(1)降低血浆TMAO的水平;
(2)降低血浆TMA的水平;
(3)降低盲肠TMA的水平;
(4)改善肠道菌群的结构,提高有益菌的丰度。
在一种实施方式中,所述有益菌包括Roseburia属和/或Rikenellaceae RC9 gutgroup属。
本发明还提供短双歧杆菌CCFM1217在与药物联合使用时促进药物增效方面的应用。
在一种实施方式中,所述药物包括但不限于他汀类药物。
本发明的有益效果:本发明提供的短双歧杆菌CCFM1217可用于缓解动脉粥样硬化、肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病等发病风险,在制备功能的食品、保健品或药品方面具有非常广泛的应用前景。在高胆碱模型小鼠实验中,服用本发明筛选的短双歧杆菌CCFM1217能够显著降低高胆碱模型小鼠血浆TMAO、血浆TMA和盲肠TMA的水平,改善肠道菌群的结构,恢复高胆碱造成的肠道菌群紊乱,提高有益菌的丰度(Roseburia属、Rikenellaceae RC9 gut group属),降低有害菌Anaeroplasma属的相对丰度,减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病发生的风险。
生物材料保藏
短双歧杆菌(Bifidobacterium breve)CCFM1217,分类命名为Bifidobacteriumbreve,已于2021年12月31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:62176。
附图说明
图1是发酵用乳酸菌短双歧杆菌CCFM1217的菌落形态;
图2是短双歧杆菌CCFM1217对胆碱饲料饲养的小鼠的血浆TMAO的影响;其中***P<0.001,****P<0.0001。
图3是短双歧杆菌CCFM1217对胆碱饲料饲养的小鼠的血浆TMA的影响;其中**P<0.01,***P<0.001。
图4是短双歧杆菌CCFM1217对胆碱饲料饲养的小鼠的盲肠TMA的影响;其中**P<0.01,****P<0.0001。
图5是短双歧杆菌CCFM1217对胆碱饲料饲养的小鼠的盲肠Roseburia属和Rikenellaceae RC9 gut group属的影响;其中*P<0.05,***P<0.001,****P<0.0001。
图6为是短双歧杆菌CCFM1217对胆碱饲料饲养的小鼠的盲肠Anaeroplasma属的影响;其中**P<0.01。
图7是不同短双歧杆菌对胆碱饲料饲养的小鼠的血浆TMAO的影响;其中***P<0.001,****P<0.0001。
具体实施方式
实施例涉及的短双歧杆菌CCFM1217具有以下生物学特性:
(1)菌体特征:呈革兰氏染色阳性,不形成抱子,不运动的细菌。
(2)菌落特征:菌落呈乳白色,圆形,边缘整齐,微凸起,不透明,表面湿润光滑;
(3)生长特性:该菌株的最适生长温度是35-37℃,最适生长pH为6.5,培养18h后进入稳定期;
(4)在高胆碱小鼠模型中能够显著降低血浆TMAO的水平;
(5)在高胆碱小鼠模型中能够显著降低血浆TMA的水平;
(6)在高胆碱小鼠模型中能够显著降低盲肠TMA的水平;
(7)在高胆碱小鼠模型中能够显著提高Roseburia属和Rikenellaceae RC9 gutgroup属的丰度,减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病的风险;
(8)在高胆碱小鼠模型中能够显著降低Anaeroplasma属的丰度,减少肥胖、非酒精性脂肪肝、心血管疾病的风险。
所述短双歧杆菌CCFM1217的提取方法为:
(一)短双歧杆菌的分离筛选:
(l)取1g健康人的新鲜粪便。梯度稀释后涂布于mMRS固体培养基,置于厌氧环境下37℃培养72小时;
(2)观察记录菌落形态,挑取菌落划线纯化;
(3)在MRS液体培养基中,37℃培养48小时,所得菌落进行革兰氏染色,记录菌落形态。
(4)弃除菌落中的革兰氏阴性菌菌株和革兰氏阳性球菌,挑选得到革兰氏阳性杆菌。
(5)过氧化氢酶分析后,弃除过氧化氢酶阳性菌株,保留过氧化氢酶阴性菌株。
(二)短双歧杆菌的分子生物学鉴定:
(l)单菌基因组抽提:将步骤(二)所筛选得到的乳酸片球菌培养过夜,取培养过夜的菌悬液lmL于1.5mL离心管,10000rpm离心2min,弃上清得菌体;用lmL无菌水吹洗菌体后,10000rpm离心2min,弃上清得菌体;加入200μL SDS裂解液,80℃水浴30min;加入酚-氯仿溶液200μL于菌体裂解液中,其中酚-氯仿溶液的组成成分及体积比为Tris饱和酚:氯仿:异戊醇=25:24:1,颠倒混匀后,12000rpm离心5-10min,取上清200μL;加入400μL冰乙醇或冰异丙醇于200uL上清中,﹣20℃静置1h,12000rpm离心5-10min,弃上清;加入500μL70%(体积百分数)冰乙醇重悬沉淀,12000rpm离心1-3min,弃上清;60℃烘箱烘干,或者自然晾干;50μLddH2O重溶沉淀以备PCR;
(2)16S rDNA PCR:
A.细菌16S rDNA 50μLPCR反应体系:
10×Taq buffer,5μL;dNTP,5μL;27F,0.5μL;1492R,0.5μL;Taq酶,0.5μL;模板,0.5μL;ddH2O,38μL。
B.PCR条件:
95℃5min;95℃10s;55℃30s;72℃30s;step2-4 30×;72℃5min;12℃2min;
C.制备1%琼脂糖凝胶,之后将PCR产物与10000×loading buffer混合,上样量2μL,120V跑30min,然后进行凝胶成像;
D.将得到PCR产物送专业测序公司,将得到的测序结果与使用BLAST在GenBank中进行搜索和相似性比对,鉴定为短双歧杆菌。
(3)全基因组测序
将提取的全基因组送专业测序公司,利用二代测序仪对菌的全基因组进行测序,将得到的序列结果使用BLAST在GenBank中进行搜索和相似性比对,测序结果鉴定为属于短双歧杆菌的一种新发现的菌株。菌株-80℃保藏备用。
实施例1:短双歧杆菌CCFM1217对模拟胃肠液的耐受性
将冷冻保存的短双歧杆菌CCFM1217接种于MRS培养基中,在温度37℃厌氧培养48h,再经MRS培养液传代培养2~3次后,取1mL短双歧杆菌CCFM1217的培养液,与9.0mLpH2.5人工模拟胃液(含1%胃蛋白酶、pH=2.5的MRS培养基)混合,并在37℃下厌氧培养,分别在0h、0.5h、1h和2h时取样,用MRS琼脂培养基浇注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。取1mL短双歧杆菌CCFM1217的培养液加入9mL人工模拟肠液(含0.3%牛胆盐、1%胰蛋白酶、pH=8.0的MRS培养基)中,在37℃下厌氧培养,分别在0h、0.5h、1h、2h、3h和4h时取样,用MRS琼脂培养基浇注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和表2所示。结果表明,短双歧杆菌CCFM1217对人工胃肠液具有较好的耐受性。
表1短双歧杆菌CCFM1217在人工模拟胃液中的耐受性
表2短双歧杆菌CCFM1217在人工模拟肠液中的耐受性
实施例2:短双歧杆菌CCFM1217用于降低血浆TMAO水平
取体重18-20g的7周龄健康雌性C57BL/6J小鼠24只,适应环境1周,随机分为4组:空白对照组(Control)、模型对照组(Choline)、短双歧杆菌CCFM1217组(CCFM1217)、短双歧杆菌FFJXM1M3对照组(按照相同方法筛选自福建省厦门市人体粪便的另一株短双歧杆菌FFJXM1M3,菌株报道于:朱如意,杭锋,张灏等.双歧杆菌生物膜形成规律及其表面性质相关性研究[J].食品与发酵工业,2020)。每组小鼠6只,每天每只小鼠灌胃0.2mL菌液。
菌液的制备方法为:将短双歧杆菌CCFM1217和短双歧杆菌FFJXM1M3分别划线接种至MRS固体培养基中,在37℃条件下培养72h得到单菌落,将制备得到的单菌落分别接种至MRS液体培养基中,在37℃条件下培养24h进行活化;将活化3代后的菌液分别以2%的接种量接种至1L MRS液体培养基中,振荡混匀后于厌氧培养箱中37℃培养24h。在8000g/min,4℃的条件下离心15min,去上清后,用无菌生理盐水(含0.05%-0.1%的L-半胱氨酸盐酸盐)进行清洗2次,同样以相同条件进行离心,去上清后,用30%的甘油进行重悬,获得菌浓数量级不低于1×109CFU/mL的菌液。
将菌液于-80℃冰箱冻存一周。在进行动物实验前,将冰箱中冻存的菌液取出,将菌液以6 000r/min离心5min,再用无菌生理盐水清洗两遍,用10%脱脂乳重悬菌液,震荡均匀后用平板倾注法测定初始和冻存一周后的活菌数量。实验结果:初始活菌数分别为3.6×109CFU/mL,3.0×109CFU/mL,1周后活菌数为2.6×109CFU/mL,2.3×109CFU/mL数量级并没有产生变化,说明将菌液冻存后不会对实验产生影响,可用于动物实验。
实验动物分组及处理方法见表3。
表3实验动物分组
第2-7周:正常组小鼠喂食普通饲料,其余小鼠喂食胆碱饲料。C57BL/6J小鼠(雌性,7周龄),购自于北京维通利华实验动物技术有限公司。普通饲料(LAD 3001M,胆碱含量为0.1%)和胆碱饲料(LAD 3001M,胆碱含量为1.0%),购自于南通特洛菲饲料科技有限公司。
试验结束前,小鼠禁食禁水4h,通过眼眶周围毛细管取血。血液样本4000×g、4℃条件下离心15min,取上清,冻存于-80℃冰箱,取20μL血浆样品加入80μL(V:V,1:4)乙腈沉淀血浆样品中的蛋白质,同时加入终浓度为2.0μM的d9-TMAO到血浆样品中作为内标。混匀,-80℃静置2h,在4℃条件下12000g 15分钟,吸上清至进样瓶中,保存在-80℃冰箱,通过HPLC-MS/MS测定血浆TMAO水平。
血浆TMAO实验结果如图2所示,胆碱饲料组小鼠血浆TMAO显著高于对照饲料组,大约比对照组高出5.78倍,与胆碱组小鼠相比,灌胃短双歧杆菌CCFM1217显著降低血浆TMAO的水平,与胆碱组小鼠比,灌胃短双歧杆菌CCFM1217小鼠的血浆TMAO降低了29.22%,而灌胃对照菌FFJXM1M3小鼠的血浆TMAO只降低了7.10%。
实施例3:短双歧杆菌CCFM1217用于降低血浆TMA水平
C57BL/6J小鼠分组、造模及处理方法同实施例2。
试验结束前,小鼠禁食禁水4h,通过眼眶周围毛细管取血。血液样本4000×g、4℃条件下离心15min,取上清,冻存于-80℃冰箱。取20μL血浆样品加入80μL(V:V,1:4)乙腈沉淀血浆样品中的蛋白质,同时加入终浓度为2.0μM的d9-TMAO到血浆样品中作为内标。混匀,-80℃静置2h,在4℃条件下12000g 15分钟,吸上清至进样瓶中,保存在-80℃冰箱,通过HPLC-MS/MS测定血浆TMA水平。
血浆TMA实验结果如图3所示,胆碱饲料组小鼠血浆TMA显著高于对照饲料组,与胆碱组小鼠相比,灌胃短双歧杆菌CCFM1217显著降低血浆TMA的水平,与胆碱组小鼠比,灌胃短双歧杆菌CCFM1217小鼠的血浆TMA降低了70.50%,而灌胃对照菌FFJXM1M3小鼠的血浆TMA只降低了8.05%。
实施例4:短双歧杆菌CCFM1217用于降低盲肠TMA水平
C57BL/6J小鼠分组、造模及处理方法同实施例2。
试验结束时,小鼠禁食禁水12h,腹腔注射10%的水合氯醛溶液麻醉后,取小鼠盲肠,冻存于-80℃冰箱,称取小鼠盲肠内容物,每mg盲肠内容物加入20μL的混合溶液(乙腈:甲醇:水以体积比40:40:20混合),同时加入终浓度为2.5μM的d9-TMA到盲肠样品中作为内标,振荡混匀,-80℃静置2h,在4℃条件下12000g15分钟,吸上清至进样瓶中,保存在-80℃冰箱,通过HPLC-MS/MS测定小鼠盲肠中TMA的含量。
盲肠TMA实验结果如图4所示,胆碱饲料组小鼠盲肠TMA显著高于对照饲料组,大约比对照组高出3.13倍,与胆碱组小鼠相比,灌胃短双歧杆菌CCFM1217显著降低盲肠TMA的水平,与胆碱组小鼠比,灌胃短双歧杆菌CCFM1217的小鼠盲肠TMA降低了45.14%,而灌胃对照菌FFJXM1M3的小鼠盲肠TMA不仅没有降低,反而升高了12.53%。
实施例5:短双歧杆菌CCFM1217用于提高盲肠有益微生物的丰度
C57BL/6J小鼠分组、造模及处理方法同实施例2。
试验结束时,小鼠禁食禁水12h,腹腔注射10%的水合氯醛溶液麻醉后,取盲肠,按照粪便DNA试剂盒的方法提取盲肠DNA,利用二代测序仪对盲肠的V3-V4区进行16S rDNA菌群分析。
实验结果如图5所示。胆碱饲料组小鼠盲肠Roseburia属和Rikenellaceae RC9gut group属的相对丰度显著低于对照饲料组,与胆碱组小鼠相比,灌胃短双歧杆菌CCFM1217显著提高Roseburia属和Rikenellaceae RC9 gut group属的相对丰度。
实施例6:短双歧杆菌CCFM1217用于降低盲肠Anaeroplasma属的丰度
C57BL/6J小鼠分组、造模及处理方法同实施例2。
试验结束时,小鼠禁食禁水12h,腹腔注射10%的水合氯醛溶液麻醉后,取盲肠,按照粪便DNA试剂盒的方法提取盲肠DNA,利用二代测序仪对盲肠的V3-V4区进行16S rDNA菌群分析。
实验结果如图6所示。胆碱饲料组小鼠盲肠Anaeroplasma属的相对丰度显著高于对照饲料组,与胆碱组小鼠相比,灌胃短双歧杆菌CCFM1217显著降低盲肠Anaeroplasma属的相对丰度。
实施例7:比较不同短双歧杆菌对胆碱饲料喂养的小鼠的血浆TMAO的影响
小鼠造模及处理方法同实施例2,分别用16株不同株的短双歧杆菌灌胃胆碱饲料喂养的小鼠,检测血浆TMAO,如图7所示,只有CCFM1217具有显著的降低胆碱饲料喂养的小鼠血浆TMAO的能力,下降了29.22%,其它的短双歧杆菌均未显著降低胆碱饲料喂养的小鼠血浆的TMAO。
实施例8:利用短双歧杆菌CCFM1217制造含短双歧杆菌CCFM1217的发酵食品
选用新鲜苹果洗净后榨汁,接着进行高温瞬间灭菌,在温度140℃下高温热杀菌2秒后,立即降温至37℃,再接入本发明制备的短双歧杆菌CCFM1217菌剂发酵剂,使其浓度达到108CFU/mL以上,在温度4℃下冷藏保存,得到含有本发明短双歧杆菌CCFM1217活菌的果蔬饮料。
利用短双歧杆菌CCFM1217发酵生产制备其他发酵食品,所述发酵食品包括固态食品、液态食品、半固态食品。所述发酵食品包括乳制品、豆制品、果蔬制品,所述乳制品包括牛奶、酸奶油、干酪;所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜制品。
按照实施例2的方法将制备的发酵食品用于饲喂胆碱模型小鼠,结果显示所述发酵食品能够降低血浆TMAO、血浆TMA、盲肠TMA的水平;能够改善肠道菌群的结构,恢复高胆碱造成的肠道菌群紊乱,提高有益菌的丰度(Roseburia属、Rikenellaceae RC9 gut group属),降低有害菌Anaeroplasma属的相对丰度,减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病发生的风险。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种短双歧杆菌(Bifidobacterium breve)CCFM1217,已于2021年12月31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:62176。
2.含有权利要求1所述短双歧杆菌CCFM1217的益生菌制剂。
3.根据权利要求2所述的益生菌制剂,其特征在于,所述益生菌制剂中短双歧杆菌CCFM1217的含量≥1×109CFU/mL或≥1×109CFU/g。
4.含有权利要求1所述短双歧杆菌CCFM1217的药物组合物。
5.根据权利要求4所述的药物组合物,其特征在于,所述组合物中包括但不限于他汀类药物。
6.一种发酵食品,其特征在于,所述发酵食品是使用短双歧杆菌CCFM1217发酵生产制得。
7.根据权利要求6所述的发酵食品,其特征在于,所述发酵食品包括乳制品、豆制品、或果蔬制品。
8.权利要求1所述的短双歧杆菌CCFM1217在制备减少动脉粥样硬化、肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病中至少一种疾病发病风险的药物,或缓解动脉粥样硬化、肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病、非酒精性脂肪肝、心血管疾病中至少一种疾病症状的保健品中的应用。
9.根据权利要求8所述的应用,其特征在于,所述药物还含有药学上可接受的载体。
10.权利要求1所述的短双歧杆菌CCFM1217在与药物联合使用时促进药物增效方面的应用。
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