CN114404459B - 罗伊氏乳杆菌ccfm1135在降低血浆氧化三甲胺上的应用 - Google Patents
罗伊氏乳杆菌ccfm1135在降低血浆氧化三甲胺上的应用 Download PDFInfo
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Abstract
本发明公开了罗伊氏乳杆菌CCFM1135在降低血浆氧化三甲胺上的应用，属于微生物技术领域。所述罗伊氏乳杆菌CCFM1135能够降低血浆TMAO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Roseburia属的丰度，降低有害菌Ruminococcaceae UCG‑009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、非酒精性脂肪肝、高脂血症、高血压发生的风险。因此，罗伊氏乳杆菌CCFM1135在制备预防和/或治疗心血管疾病和改善肠道菌群的产品中具有广阔的应用价值。
Description
技术领域
本发明涉及罗伊氏乳杆菌CCFM1135在降低血浆氧化三甲胺上的应用，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(Atherosclerosis，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，病理特征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；危险因素为高血压，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超过330万，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的方法之一。
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
本发明的第一个目的是提供一种罗伊氏乳杆菌(Lactobacillus reuteri)CCFM1135在制备预防和/或治疗心血管疾病和改善肠道菌群的产品中的应用。
在一种实施方式中，所述罗伊氏乳杆菌(Lactobacillus reuteri)CCFM1135，已于2020年7月24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.61102
在一种实施方式中，所述产品中，罗伊氏乳杆菌CCFM1135的数量不低于1×106CFU/mL或≥1×106CFU/g。
在一种实施方式中，所述产品具有如下至少一种作用：
(1)降低高胆碱饮食哺乳动物血浆TMAO水平；
(2)提高高胆碱饮食哺乳动物Roseburia属的丰度。
(3)降低高胆碱饮食哺乳动物Ruminococcaceae UCG-009属的丰度。
在一种实施方式中，所述哺乳动物包括但不限于人类。
在一种实施方式中，所述产品包括食品或药品。
在一种实施方式中，所述药品含有罗伊氏乳杆菌CCFM1135和/或药学上可接受的载体。
在一种实施方式中，所述载体包含微囊、微球、纳米粒和/或脂质体。
在一种实施方式中，所述药品的剂型为粉剂、颗粒剂、胶囊剂、片剂、丸剂或口服液。
在一种实施方式中，所述食品包括乳制品、豆制品、果蔬制品。
在一种实施方式中，所述乳制品包括牛奶、酸奶油、干酪。
在一种实施方式中，所述果蔬制品包括黄瓜、胡萝卜、甜菜、芹菜、圆白菜以及其他可食用的果蔬中的一种或两种以上的制品。
在一种实施方式中，所述食品还含有添加剂，所述添加剂选自香料、果蔬汁、花茶汁、着色剂、酸度调节剂、防腐剂、抗氧化剂、增稠剂、甜味剂中的一种或两种以上的组合。
在一种实施方式中，所述食品的加工形态包括固态食品、液态食品、半固态食品。
有益效果：
1、在高胆碱模型apoE-/-小鼠实验中，服用罗伊氏乳杆菌CCFM1135能够显著降低血浆TMAO水平，罗伊氏乳杆菌CCFM1135组的小鼠较模型组的血浆TMAO水平降低了29.65％。
2、在高胆碱模型apoE-/-小鼠实验中，服用罗伊氏乳杆菌CCFM1135提高了有益菌Roseburia属的丰度，罗伊氏乳杆菌CCFM1135组的小鼠较模型组的有益菌Roseburia属的相对丰度提高了8.43倍，提高有益菌Roseburia属的丰度，进一步减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病的风险。
3、在高胆碱模型apoE-/-小鼠实验中，服用罗伊氏乳杆菌CCFM1135降低了有害菌Ruminococcaceae UCG-009属的丰度，罗伊氏乳杆菌CCFM1135组的小鼠较模型组的有害菌Ruminococcaceae UCG-009属的相对丰度降低了71.33％，降低有害菌RuminococcaceaeUCG-009属的丰度，进一步减少肥胖、非酒精性脂肪肝、高脂血症、高血压的风险。
4、本发明的罗伊氏乳杆菌CCFM1135，不仅具有调节肠道菌群的功能，而且能有效地降低血浆TMAO水平，拓展了罗伊氏乳杆菌作为益生菌的应用范围，对于深入挖掘益生菌的功能，开发具有更高保健价值的益生菌具有十分重要的意义。
生物保藏材料
罗伊氏乳杆菌(Lactobacillus reuteri)CCFM1135，分类命名为Lactobacillusreuteri，已于2020年7月24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.61102。
附图说明
图1是罗伊氏乳杆菌CCFM1135的菌落形态。
图2是罗伊氏乳杆菌CCFM1135对胆碱饲料饲养的apoE-/-小鼠的血浆TMAO的影响；其中**P<0.01，****P<0.0001。
图3是罗伊氏乳杆菌CCFM1135对胆碱饲料饲养的apoE-/-小鼠的盲肠Roseburia属的影响；其中*P<0.05。
图4为是罗伊氏乳杆菌CCFM1135对胆碱饲料饲养的apoE-/-小鼠的盲肠Ruminococcaceae UCG-009属的影响；其中*P<0.05。
图5是不同罗伊氏乳杆菌对胆碱饲料饲养的apoE-/-小鼠的血浆TMAO的影响；其中**P<0.01，****P<0.0001。
具体实施方式
实施例1：罗伊氏乳杆菌CCFM1135对血浆TMAO的影响
罗伊氏乳杆菌CCFM1135的菌落形态如图1所示。
将罗伊氏乳杆菌CCFM1135和罗伊氏乳杆菌FHNXY12L1(报道于：倪彩新.乳杆菌对高尿酸血症的影响及作用途径探究[D].江南大学,2021)在MRS培养基中于37℃培养，收集菌体，将菌体重悬于生理盐水，制成浓度为1×109CFU/mL的菌悬液。
罗伊氏乳杆菌CCFM1135显著降低血浆TMAO的水平，与模型组apoE-/-小鼠比，灌胃罗伊氏乳杆菌CCFM1135菌液的apoE-/-小鼠血浆TMAO降低了29.65％；
取体重18-20g的健康雌性载脂蛋白E基因敲除小鼠(apoE-/-小鼠)24只，适应环境1周，随机分为4组，每组6只apoE-/-小鼠：对照组(Control)、模型组(胆碱，Choline)、罗伊氏乳杆菌CCFM1135组(CCFM1135)、罗伊氏乳杆菌FHNXY12L1对照组(FHNXY12L1)。实验动物分组及处理方法见表1：
表1实验动物分组
| 组别 | 只数/组 | 处理时长 | 饲料 | 处理方法 |
| Control | 6 | 2-24周 | 普通饲料 | 每天灌胃0.2mL生理盐水 |
| Choline | 6 | 2-24周 | 胆碱饲料 | 每天灌胃0.2mL生理盐水 |
| CCFM1135 | 6 | 2-24周 | 胆碱饲料 | 每天灌胃0.2mL罗伊氏乳杆菌CCFM1135菌悬液 |
| FHNXY12L1 | 6 | 2-24周 | 胆碱饲料 | 每天灌胃0.2mL罗伊氏乳杆菌FHNXY12L1菌悬液 |
第2-24周：对照组apoE-/-小鼠喂食普通饲料，其余三组apoE-/-小鼠喂食Choline饲料。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，四组apoE-/-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的氘代氧化三甲胺(d9-TMAO)到血浆样品中作为内标。混匀，-80℃静置2h，在4℃条件下12000×g 15min，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，模型组apoE-/-小鼠血浆TMAO显著高于对照组，与模型组apoE-/-小鼠相比，灌胃罗伊氏乳杆菌CCFM1135显著降低血浆TMAO的水平，与模型组apoE-/-小鼠比，灌胃罗伊氏乳杆菌CCFM1135的apoE-/-小鼠的血浆TMAO降低了29.65％。灌胃罗伊氏乳杆菌FHNXY12L1对血浆中TMAO水平无明显影响。
实施例2：罗伊氏乳杆菌CCFM1135对小鼠肠道Roseburia属的影响
apoE-/-小鼠分组、造模及处理方法同实施例2。
试验结束时，四组apoE-/-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3所示。模型组apoE-/-小鼠盲肠Roseburia属的相对丰度显著低于对照组，与模型组apoE-/-小鼠相比，灌胃罗伊氏乳杆菌CCFM1135显著提高盲肠Roseburia属的相对丰度，与模型组apoE-/-小鼠相比，灌胃罗伊氏乳杆菌CCFM1135的盲肠Roseburia属的相对丰度提高了8.43倍，可以减少肠应激综合征、肥胖、过敏、神经性疾病、II型糖尿病的风险。
实施例3：罗伊氏乳杆菌CCFM1135对小鼠肠道Ruminococcaceae UCG-009属的影响
apoE-/-小鼠分组、造模及处理方法同实施例2。
试验结束时，四组apoE-/-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4所示。模型组apoE-/-小鼠盲肠Ruminococcaceae UCG-009属的相对丰度显著高于对照组，与模型组apoE-/-小鼠相比，灌胃罗伊氏乳杆菌CCFM1135显著降低盲肠Ruminococcaceae UCG-009属的相对丰度，与模型组apoE-/-小鼠相比，灌胃罗伊氏乳杆菌CCFM1135的盲肠Ruminococcaceae UCG-009属的相对丰度降低了71.33％，可以减少肥胖、非酒精性脂肪肝、高脂血症、高血压的风险。
实施例4：比较不同罗伊氏乳杆菌对apoE-/-小鼠血浆TMAO的影响
apoE-/-小鼠造模及处理方法同实施例1，分别用16株不同株的罗伊氏乳杆菌灌胃apoE-/-小鼠，检测血浆TMAO，如图5所示，只有CCFM1135具有显著的降低apoE-/-小鼠血浆TMAO的能力，下降了29.65％，其余罗伊氏乳杆菌均不能显著降低apoE-/-小鼠血浆的TMAO。
实施例5：利用罗伊氏乳杆菌CCFM1135制造发酵食品
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罗伊氏乳杆菌CCFM1135菌剂发酵剂，使其浓度达到108CFU/mL以上，在温度4℃下冷藏保存，于是得到含有本发明罗伊氏乳杆菌CCFM1135活菌的果蔬饮料。
利用本发明能够使用罗伊氏乳杆菌CCFM1135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。
利用本发明制备的发酵食品喂食高胆碱模型小鼠，同样能够降低血浆TMAO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Pielou均匀度指数、观测物种丰富度指数、香农多样性指数，提高有益菌Roseburia属的丰度，降低有害菌Ruminococcaceae UCG-009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、非酒精性脂肪肝、高脂血症、高血压发生的风险。
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 (5)
1.罗伊氏乳杆菌（Lactobacillus reuteri）CCFM1135在制备预防和/或治疗心血管疾病的药品中的应用；所述罗伊氏乳杆菌CCFM1135，已于2020年7月24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.61102。
2.根据权利要求1所述的应用，其特征在于，所述药品中，罗伊氏乳杆菌CCFM1135的数量不低于1×106CFU/mL或≥1×106CFU/g。
3.根据权利要求1所述的应用，其特征在于，所述药品具有如下至少一种作用：
（1）降低高胆碱饮食哺乳动物血浆TMAO水平；
（2）提高高胆碱饮食哺乳动物Roseburia属的丰度；
（3）降低高胆碱饮食哺乳动物Ruminococcaceae UCG-009属的丰度。
4.根据权利要求1所述的应用，其特征在于，所述药品含有罗伊氏乳杆菌CCFM1135和/或药学上可接受的载体。
5.根据权利要求4所述的应用，其特征在于，所述载体包含微囊、微球、纳米粒和/或脂质体。
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