CN114042091A - 酪黄肠球菌在制备治疗代谢综合征产品中的应用方法 - Google Patents
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Abstract
本发明公开了酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，包括酪黄肠球菌在制备用于预防和/或治疗代谢综合征的药物、食品或保健品中的用途。本发明通过实验证实，酪黄肠球菌(Enterococcus casseliflavus)能够激活高脂饮食诱导的HFD小鼠的棕色脂肪(BAT)的产热活性来消耗机体内多余的能量，进而可以有效地改善高脂饮食诱导的HFD小鼠的肥胖症；通过对酪黄肠球菌(Enterococcus casseliflavus)进行基因改造，改善酪黄肠球菌(Enterococcus casseliflavus)的耐受和定植能力，延长酪黄肠球菌(Enterococcus casseliflavus)在体内的作用时间，增强代谢稳定性，提高生物利用度，这样的基因优化产物也应当在本发明的范围之内。
Description
技术领域
本发明涉及生物医药技术领域，尤其涉及酪黄肠球菌在制备治疗代谢综合征产品中的应用方法。
背景技术
肥胖被定义为由体内脂肪积聚过多或分布异常而造成的慢性代谢性疾病。肥胖首先引起胰岛素抵抗，进而导致糖尿病、高血压、高脂血症、动脉粥样硬化、心脑血管疾病等一系列代谢紊乱症状的发生。近年来，肥胖在世界范围内呈现出爆发增长的趋势，尽管上千亿人民币花费在饮食控制和体质改善上，但其发生率仍持续上升。据估计，全世界有4.0亿人肥胖。我国的肥胖症患病率近年来也呈上升趋势。据统计，我国目前拥有超重者至少2.7亿，肥胖者至少9.6千万。近年来，中国投入到肥胖及其相关疾病的防治费用飞速上涨。不仅如此，肥胖尤其是儿童型肥胖的迅猛发展也必然会对全民的身体素质和整个社会的和谐发展产生无法估量的不利影响，长此以往也必然会危及我国的国家安全。
目前临床上用作肥胖治疗剂的处方药主要是用来控制食欲和抑制营养吸收，但它们均具有一定的毒副作用。例如，奥利司他是获美国食品药品管理局(FDA)批准的第一个减肥处方药。它能够特异性抑制人体胃肠道中负责消化脂肪的酶，阻止脂肪在消化道的吸收，从而减少热量摄入，进而控制体重。但是，未消化的脂肪沿着胃肠道移动的同时会引发腹泻、脂肪泻等副作用。这些副作用会导致患者需穿着成人纸尿裤，难以进行正常社会生活。此外，作为GLP-1受体的激动剂，利拉鲁肽能够调节胰岛素分泌、抑制食欲、延缓胃排空、增加饱胀感。但是它同时会引发胰腺炎、恶心、呕吐等副作用，并且尤其对髓样甲状腺癌和2型多发内分泌腺瘤患者禁用。鉴于现有的肥胖治疗剂通常具有毒副作用。
发明内容
1.要解决的技术问题
本发明的目的是为了解决现有技术中临床上用作肥胖治疗剂的处方药主要是用来控制食欲和抑制营养吸收，但它们均具有一定的毒副作用的问题，而提出的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法。
2.技术方案
为了实现上述目的，本发明采用了如下技术方案：
酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，包括酪黄肠球菌在制备用于预防和/或治疗代谢综合征的药物、食品或保健品中的用途。
优选地，其中所述代谢综合征选自糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、多囊卵巢综合症、坏死性游走性红斑、高血糖素瘤等代谢性疾病、冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病、糖尿病心血管并发症、或者阿尔兹海默症或帕金森症等神经损伤性疾病；优选地，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
优选地，包括酪黄肠球菌在制备用于改善机体能量代谢的药物、食品或保健品中的用途。
优选地，其中所述药物、食品或保健品还包含除酪黄肠球菌之外的用于预防和/或治疗代谢综合征的肠球菌科的其它菌株。
优选地，其中所述药物、食品或保健品还包含除酪黄肠球菌之外的用于改善机体能量代谢的肠球菌科的其它菌株。
优选地，其中所述药物、食品或保健品包含有效量的酪黄肠球菌和可接受的辅料。
优选地，其中所述可接受的辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒。
3.有益效果
相比于现有技术，本发明的优点在于：
(1)本发明中，通过实验证实，酪黄肠球菌(Enterococcus casseliflavus)能够激活高脂饮食诱导的HFD小鼠的棕色脂肪(BAT)的产热活性来消耗机体内多余的能量，进而可以有效地改善高脂饮食诱导的HFD小鼠的肥胖症。
(2)本发明中，通过对酪黄肠球菌(Enterococcus casseliflavus)进行基因改造，改善酪黄肠球菌(Enterococcus casseliflavus)的耐受和定植能力，延长酪黄肠球菌(Enterococcus casseliflavus)在体内的作用时间，增强代谢稳定性，提高生物利用度，这样的基因优化产物也应当在本发明的范围之内。
附图说明
其中所述的“Con”组表示灌喂等体积生理盐水的普通饲料小鼠组，“HFD”组表示灌喂等体积生理盐水的高脂诱导的HFD小鼠组，“HFD+casseliflavus”组表示以1×109CFU/只/天的剂量灌喂酪黄肠球菌(Enterococcus casseliflavus)的高脂诱导的HFD小鼠组。
图1显示Con组、HFD组和HFD+酪黄肠球菌组三组体重变化的检测结果。
图2显示Con组、HFD组和HFD+casseliflavus组三组的小鼠的一天平均摄食量的检测结果。
图3是Con组、HFD组和HFD+casseliflavus组三组小鼠各脂肪组织重量变化的结果。
图4是Con组、HFD组和HFD+casseliflavus组三组小鼠的葡萄糖耐量及胰岛素耐量的结果。
图5是Con组、HFD组和HFD+casseliflavus组三组小鼠血清中TCHO(总胆固醇)、TG(甘油三酯)和LDL(低密度脂蛋白)含量的结果。
图6是Con组、HFD组和HFD+casseliflavus组三组小鼠产热基因的mRNA相对表达量的结果。
图7是Con组、HFD组和HFD+casseliflavus组三组小鼠的UCP1蛋白及氧化磷酸化相关蛋白的表达结果。
具体实施方式
下面结合实施例和附图进一步说明本发明。应当理解，下述实施例仅是对本发明的进一步阐明，而非对本发明的限制。
除非特别指明，以下实施例中所用的C57BL/6小鼠均购自北京维通利华实验动物技术有限公司。所用的试剂均为分析纯级别的试剂，且可从正规渠道商购获得。所用的酪黄肠球菌(Enterococcus casseliflavus)购自北纳创联生物技术有限公司。
酪黄肠球菌(Enterococcus casseliflavus)溶液制作方法：将酪黄肠球菌冻干粉溶于灭菌生理盐水，最终菌落数达到5×109CFU/ml。
本发明将HFD组和HFD+酪黄肠球菌组进行统计学分析，P<0.05即表示组间差异具有统计学意义。
实施例1：
构建高脂诱导的HFD小鼠模型。
购买4周龄C57BL/6小鼠30只，随机分为Con组(10只)、HFD组(10只)和HFD+casseliflavus(10只)，高脂饮食诱导肥胖模型。
灌胃法处理上述两组小鼠。
每日用酪黄肠球菌(Enterococcus casseliflavus)溶液灌喂HFD+casseliflavus组小鼠，剂量为1×109CFU/只/天，同时灌喂Con组、HFD组小鼠等体积的生理盐水。灌胃8周，在此期间，每周称重、测摄食量，并于第8周检测葡萄糖耐量、胰岛素耐量等指标。8周后取材，进行后续分析。结果如图1-7所示。其中，“Con”组表示灌喂等体积生理盐水的普通饲料小鼠组，“HFD组”表示灌喂等体积的饮用水的高脂诱导的HFD小鼠组，“HFD+casseliflavus”表示以1×109CFU/只/天的剂量灌喂酪黄肠球菌(Enterococcus casseliflavus)的高脂诱导的HFD小鼠组。
本发明中，图1显示Con组、HFD组和HFD+casseliflavus组三组每周体重变化的检测结果。该结果表明高脂诱导的HFD小鼠每天饲喂酪黄肠球菌(Enterococcuscasseliflavus)可以有效抑制体重增加，饲喂第6周开始体重有显著差异，到第8周体重差异有2.59克(参见图1，其中第6周是“*”，第7周是“*”，第8周是“**”，分别表示p<0.05和p<0.01，“*”表示HFD组和HFD+casseliflavus组的比较)。
本发明中，图2显示HFD组和HFD+casseliflavus组两组的小鼠的一天平均摄食量结果。该结果表明饲喂酪黄肠球菌(Enterococcus casseliflavus)，小鼠的摄食量未产生差异。这一结果表明，酪黄肠球菌(Enterococcus casseliflavus)不会影响食欲，体重的降低不是因为食欲减少而导致的。
本发明中，图3是Con组、HFD组和HFD+casseliflavus组三组小鼠各脂肪组织重量变化的结果。该结果表明高脂诱导的HFD小鼠饲喂酪黄肠球菌(Enterococcuscasseliflavus)后，棕色脂肪(BAT)、皮下脂肪(sWAT)和附睾脂肪(eWAT)组织的重量显著降低(其中“***”表示p<0.001，“*”表示HFD组和HFD+casseliflavus组的比较)。
本发明中，图4是Con组、HFD组和HFD+casseliflavus组三组小鼠的葡萄糖耐量及胰岛素耐量的结果。葡萄糖耐量结果表明，高脂诱导的HFD小鼠饲喂酪黄肠球菌(Enterococcus casseliflavus)后，各个时间点的血糖较高脂饮食组相比均有所降低，且曲线下面积(AUC)也显著降低(参见图4A)。胰岛素耐量结果表明，在腹腔注射胰岛素后，HFD+casseliflavus组的血糖水平下降较快，并能较快恢复，且显著降低了AUC(参见图4B)。
本发明中，图5是Con组、HFD组和HFD+casseliflavus组三组小鼠血清中TCHO(总胆固醇)、TG(甘油三酯)和LDL(低密度脂蛋白)含量的结果。该结果表明酪黄肠球菌(Enterococcus casseliflavus)饲喂后，高脂诱导的HFD小鼠的TCHO、TG和LDL的表达水平明显降低(其中“*”表示p<0.05，“*”表示HFD组和HFD+casseliflavus组的比较)。
本发明中，图6是Con组、HFD组和HFD+casseliflavus组三组小鼠产热基因的mRNA相对表达量的结果。该结果表明酪黄肠球菌(Enterococcus casseliflavus)饲喂后，高脂诱导的HFD小鼠的UCP1、Prdm16、C/EBPβ、Dio2、PPARα、PGC1α的mRNA相对表达水平显著增加(其中“***”表示p<0.001，“*”表示HFD组和HFD+casseliflavus组的比较)。
本发明中，图7是Con组、HFD组和HFD+casseliflavus组三组小鼠的UCP1蛋白及氧化磷酸化相关蛋白的表达结果。该结果表明酪黄肠球菌(Enterococcus casseliflavus)饲喂后，高脂诱导的HFD小鼠的UCP1、氧化磷酸化相关蛋白(ATP5A、UQCRC2、SDHB、NDUFB8)的蛋白表达水平显著增加。
本发明中，综上所述，图1-7表明肠道微生物-酪黄肠球菌(Enterococcuscasseliflavus)有效的提高机体的能量代谢，进而改善高脂诱导的HFD小鼠的肥胖。
本发明中，通过实验证实，酪黄肠球菌(Enterococcus casseliflavus)能够激活高脂饮食诱导的HFD小鼠的棕色脂肪(BAT)的产热活性来消耗机体内多余的能量，进而可以有效地改善高脂饮食诱导的HFD小鼠的肥胖症。
本发明中，通过对酪黄肠球菌(Enterococcus casseliflavus)进行基因改造，改善酪黄肠球菌(Enterococcus casseliflavus)的耐受和定植能力，延长酪黄肠球菌(Enterococcus casseliflavus)在体内的作用时间，增强代谢稳定性，提高生物利用度，这样的基因优化产物也应当在本发明的范围之内。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
Claims (7)
1.酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，包括酪黄肠球菌在制备用于预防和/或治疗代谢综合征的药物、食品或保健品中的用途。
2.根据权利要求1所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，其中所述代谢综合征选自糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、多囊卵巢综合症、坏死性游走性红斑、高血糖素瘤等代谢性疾病、冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病、糖尿病心血管并发症、或者阿尔兹海默症或帕金森症等神经损伤性疾病；优选地，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
3.根据权利要求1所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，包括酪黄肠球菌在制备用于改善机体能量代谢的药物、食品或保健品中的用途。
4.根据权利要求1或2所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，其中所述药物、食品或保健品还包含除酪黄肠球菌之外的用于预防和/或治疗代谢综合征的肠球菌科的其它菌株。
5.根据权利要求3所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，其中所述药物、食品或保健品还包含除酪黄肠球菌之外的用于改善机体能量代谢的肠球菌科的其它菌株。
6.根据权利要求1至5任一所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，其中所述药物、食品或保健品包含有效量的酪黄肠球菌和可接受的辅料。
7.根据权利要求6所述的酪黄肠球菌在制备治疗代谢综合征产品中的应用方法，其特征在于，其中所述可接受的辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒。
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