CN114010665A - 罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用 - Google Patents
罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用 Download PDFInfo
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Abstract
本发明提供了罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用，属于肝病药物技术领域。本发明提供了罗伊氏乳杆菌(Lactobacillus reuteri)在制备预防和/或治疗酒精性肝病的药物中的应用。罗伊氏乳杆菌能显著缓解酒精诱导的小鼠肝脏指数增加，同时降低脂质在ALD小鼠肝脏内积聚，L.reuteri还能够显著降低ALD小鼠模型血清中的AST、ALT、TCH和TG的水平，显著缓解酒精诱导的小鼠肝脏指数增加和降低脂质在ALD小鼠肝脏内积聚。罗伊氏乳杆菌为临床常用的益生菌，与其他缓解酒精性肝病的产品相比在疗效和安全性方面有明显的优势，在防治ALD方面较高的应用潜力。
Description
技术领域
本发明属于肝病药物技术领域，具体涉及罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用。
背景技术
酒精性肝病(Alcoholic Liver Disease,ALD)是以过量饮酒为主要病因，以脂肪肝，肝炎肝硬化及肝癌等不同临床病理变化为特征的一类肝脏疾病。阐明ALD的发病机制，研发新的ALD治疗方案，制定完善的ALD防治体系，已成为亟待解决的医学问题。目前上市的缓解酒精性肝病的产品主要为水飞蓟素等保肝利胆系列产品，并未从缓解胃肠道疾病的角度开展药物研究。
罗伊氏乳杆菌(Lactobacillus reuteri)作为一种应用广泛的益生菌，能够有效调节肠道平衡，已经被广泛应用于防治胃肠道疾病，但尚未有用于防治ALD的应用研究。
发明内容
有鉴于此，本发明的目的在于提供一种罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用，在疗效方面也具有较大竞争力。
本发明提供了罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用。
优选的，所述罗伊氏乳杆菌包括罗伊氏乳杆菌菌株DSM17938。
优选的，所述药物具有显著缓解酒精诱导的小鼠肝脏指数增加作用。
优选的，所述药物具有降低肝脏内脂质积聚作用。
优选的，所述药物具有降低肝功能中转氨酶水平。
优选的，所述转氨酶包括谷草转氨酶和/或谷丙转氨酶。
优选的，所述罗伊氏乳杆菌菌株DSM17938的扩繁方法，将罗伊氏乳杆菌菌株DSM17938划线于MRS固体培养基，厌氧培养，挑取单菌落接种至MRS液体培养基中厌氧培养，取对数生长期的菌液收集菌体。
优选的，所述药物包括口服剂。
本发明提供的罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用。本发明以罗伊氏乳杆菌DSM17938菌株为代表，通过对ALD小鼠模型进行灌胃干预，8周后检测肝脏的病理变化，结果显示：L.reuteri能显著缓解酒精诱导的小鼠肝脏指数增加，同时降低脂质在ALD小鼠肝脏内积聚，L.reuteri还能够显著降低ALD小鼠血清中的AST、ALT、TG和TCH的水平。可见罗伊氏乳杆菌能有效缓解酒精性肝病，在药物疗效方面具有较大竞争力。同时罗伊氏乳杆菌作为临床常用的益生菌，其安全性已被证实，在临床上的应用极易推广，且更容易被酒精性肝病患者接受。因此，与其他缓解酒精性肝病的产品相比罗伊氏乳杆菌在治疗酒精性肝病方面具有明显的优势，在防治ALD方面有较高的应用潜力。
附图说明
图1为本发明中构建酒精性肝病小鼠模型的示意图；
图2为益生菌(L.reuteri)降低ALD小鼠血清中的炎症因子和肝脏中脂质的积累，其中图2A和图2B分别为L.reuteri缓解ALD小鼠的肝脏损伤和脂质在肝脏中的积累，图2C和图2D分别为L.reuteri改善ALD小鼠血清中失调的谷草转氨酶和谷丙转氨酶，图2E和图2F分别为L.reuteri降低血清ALD小鼠血清中TCH和TG的水平，*p<0.05，**p<0.01；
图3L.reuteri改善ALD小鼠肠道中FXR及肝脏中CYP7A1的表达，*p<0.05，**p<0.01。
具体实施方式
本发明提供了罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用。
在本发明中，所述罗伊氏乳杆菌优选包括罗伊氏乳杆菌菌株DSM17938。罗伊氏乳杆菌菌株DSM17938的扩繁方法，优选将罗伊氏乳杆菌菌株DSM17938划线于MRS固体培养基，厌氧培养，挑取单菌落接种至MRS液体培养基中厌氧培养，取对数生长期的菌液收集菌体。所述厌氧培养的温度优选为36～38℃，更优选为37℃。所述厌氧培养的时间优选15～24h，更优选为18～20h。本发明对罗伊氏乳杆菌菌株DSM17938的来源没有特殊限制，采用本领域所熟知的罗伊氏乳杆菌菌株DSM17938的来源即可。在本发明实施例中，所述罗伊氏乳杆菌菌株DSM17938购自拜奥BioGaia(造物游传(北京)电子商务有限公司)。
在本发明中，以ALD小鼠模型为实验材料。本发明对所述ALD小鼠模型的构建方法没有特殊限制，采用本领域所熟知的ALD小鼠模型的构建方法即可。在本发明实施例中，所述ALD小鼠模型的构建方法参见现有技术完成(Bertola,A.,Mathews,S.,Ki,S.,Wang,H.,&Gao,B.J.N.p(2013).Mousemodel of chronic and binge ethanol feeding(the NIAAAmodel).Nature Protocols,8(3),627–637.https://doi.org/10.1038/nprot.2013.032)。对ALD小鼠模型计算肝脏指数和检测血清中AST、ALT、TCH和TG肝脏损伤标志物的变化，以及脂质积聚情况，观察肝脏组织的病理学变化。结果表明，酒精饲料饲喂小鼠8周后，小鼠肝脏指数显著增加，肝脏内脂质积累显著增加，肝细胞损伤显著加重；小鼠血液内AST和ALT水平显著升高。而在用酒精饲料诱导小鼠的同时，采用L.reuteri(2×107CFU)每天灌胃小鼠，8周后检测肝脏的病理变化，结果显示：L.reuteri能显著缓解酒精诱导的小鼠肝脏指数增加，同时降低脂质在ALD小鼠肝脏内积聚，L.reuteri还能够显著降低ALD小鼠血清中的AST、ALT、TCH和TG的水平。因此，本发明所述药物具有显著缓解酒精诱导的小鼠肝脏指数增加作用，具有降低肝脏内脂质积聚作用，具有降低肝功能中转氨酶水平。所述转氨酶包括谷草转氨酶和/或谷丙转氨酶。
在本发明中，药物治疗机理推测如下：L.reuteri能够调节肠道微生态，进而影响改善胆汁酸代谢，维持胆汁酸受体(FXR)的活化和肝脏中脂质代谢的平衡，缓解ALD的发生和发展。由此，本发明还优选提供了罗伊氏乳杆菌在预防和/或治疗酒精性肝病中的应用。
在本发明中，所述药物优选包括口服剂，例如，片剂、胶囊剂、口服液等。所述药物通过口服用药。所述药物的用量优选为2～10×107CFU/次，1次/天。
下面结合实施例对本发明提供的罗伊氏乳杆菌在制备预防和/或治疗酒精性肝病的药物中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
1实验材料和方法
1.1实验材料
L.reuteri DSM17938菌株购于拜奥BioGaia(造物游传(北京)电子商务有限公司)，95％的食用酒精购自河南鑫阳河酒业有限公司，Lieber-DeCarli液体酒精饲料和对照液体饲料购自南通特洛菲饲料科技有限公司。
谷草转氨酶(AST)、谷丙转氨酶(ALT)、总胆固醇(TCH)和甘油三酯(TG)生化检测试剂盒购自与南京建成有限责任公司。
SPF级C57BL/6小鼠，8周龄，体重(18±2)g，购于成都达硕生物技术有限公司。
1.2实验方法
1.2.1ALD小鼠模型的建立及其不同的干预处理分组
按照之前研究(Bertola,A.,Mathews,S.,Ki,S.,Wang,H.,&Gao,B.J.N.p(2013).Mousemodel of chronic and binge ethanol feeding(the NIAAA model).NatureProtocols,8(3),627–637.https://doi.org/10.1038/nprot.2013.032)中描述的方法(Gao-binge模型)，建立C57BL/6小鼠ALD模型，实验组给予L.reuteri治疗，具体方法如下。
将健康C57BL/6小鼠分组饲养在一个控制相对湿度(45％～65％)、温度(22±2℃)的环境中。
将健康C57BL/6小鼠按体重随机分为5组，每组10只：
(A)正常组：饲喂Lieber-DeCarli液体对照饲料8周；
(B)酒精组：先予以Lieber-DeCarli液体对照饲料5天以适应液体饮食，然后采用含5％酒精的Lieber-DeCarli酒精饲料8周，收集标本前8小时对小鼠进行高浓度酒精灌胃一次，浓度为5g/kg体重；
(C)益生菌组(L.reuteri干预组)：用与模型组相同的饲喂方式，同时每日灌胃2×107CFUL.reuteri，持续8周；
饲喂8周后分别进行取样(血清，血浆，肝脏，肠道，肠道内容物，粪便)，并根据不同的样本和后续的实验需求，对样本进行处理和储藏，以满足后续的检测分析。
1.2.2肝脏损伤标志物及病理性变化的检测
取出1.2.1节中收集的正常组、酒精组和L.reuteri干预组小鼠的肝脏组织和血清样本，分别计算不同处理组小鼠的肝脏指数，并通过AST、ALT、TCH和TG生化检测试剂盒分别检测血清中AST、ALT、TCH和TG肝脏损伤标志物的变化。
对液氮速冻的肝脏组织经冰冻组织包埋剂(OCT)包埋、冰冻切片机切片、油红和苏木精染色，然后中性树胶封片、镜检观察不同处理组小鼠肝脏组织内脂质积聚情况。
对福尔马林固定的肝脏组织经不同浓度的酒精梯度脱水、二甲苯透明、石蜡包埋、切片机切片、伊红和苏木精染色，然后中性树胶封片、镜检观察不同处理组小鼠肝脏组织的病理学变化。
2.实验结果
L.reuteri缓解酒精介导的肝脏损伤
与正常组小鼠相比，酒精饲料饲喂小鼠8周后，酒精组小鼠肝脏指数显著增加，肝脏内脂质积累显著增加，肝细胞损伤显著加重；小鼠血液内AST和ALT水平显著升高。这表明酒精组小鼠模型构建成功。
益生菌组小鼠在用酒精饲料诱导的同时，采用L.reuteri(2×107CFU)每天灌胃，饲喂8周后检测肝脏的病理变化，结果显示：L.reuteri能显著缓解酒精诱导的小鼠肝脏指数增加，同时降低脂质在ALD小鼠肝脏内积聚，L.reuteri还能够显著降低ALD小鼠血清中的AST、ALT、TCH和TG的水平(图2)。
实施例2
1实验材料和方法
1.1实验材料
L.reuteri DSM17938菌株购于拜奥BioGaia(造物游传(北京)电子商务有限公司)，95％的食用酒精购自河南鑫阳河酒业有限公司，Lieber-DeCarli液体酒精饲料和对照液体饲料购自南通特洛菲饲料科技有限公司。
谷草转氨酶(AST)、谷丙转氨酶(ALT)、总胆固醇(TCH)和甘油三酯(TG)生化检测试剂盒购自与南京建成有限责任公司。色谱柱(ACQUITY UPLC BEH Amide 1.7μm,2.1mm×100mm column)购自Waters公司。质谱甲醇和质谱乙腈购自赛默飞世尔科技公司。质谱级甲酸购自梯希爱(上海)化成工业发展有限公司。
SPF级C57BL/6小鼠，8周龄，体重(18±2)g，购于成都达硕生物技术有限公司。
1.2实验方法
1.2.1 ALD小鼠模型的建立及其不同的干预处理分组
按照之前研究(Bertola,A.,Mathews,S.,Ki,S.,Wang,H.,&Gao,B.J.N.p(2013).Mousemodel of chronic and binge ethanol feeding(the NIAAA model).NatureProtocols,8(3),627–637.https://doi.org/10.1038/nprot.2013.032)中描述的方法(Gao-binge模型)，建立C57BL/6小鼠ALD模型，实验组给予L.reuteri治疗，以健康小鼠设置为正常组对照，具体方法如下。
将健康C57BL/6小鼠分组饲养在一个控制相对湿度(45％～65％)、温度(22±2℃)的环境中。
将健康C57BL/6小鼠按体重随机分为5组，每组10只：
(A)正常组：饲喂Lieber-DeCarli液体对照饲料8周；
(B)酒精组：先予以Lieber-DeCarli液体对照饲料5天以适应液体饮食，然后采用含5％酒精的Lieber-DeCarli酒精饲料8周，收集标本前8小时对小鼠进行高浓度酒精灌胃一次，浓度为5g/kg体重；
(C)益生菌组(L.reuteri干预组)：用与模型组相同的饲喂方式，同时每日灌胃2×107CFUL.reuteri，持续8周；
饲喂8周后分别进行取样(血清，血浆，肝脏，肠道，肠道内容物，粪便)，并根据不同的样本和后续的实验需求，对样本进行处理和储藏，以满足后续的检测分析。
1.2.2肝脏组织代谢组学的检测
取出1.2.1节中收集的正常组、酒精组和L.reuteri干预组小鼠的肝脏组织，准确称取0.2g肝脏组织与2mL甲醇:水(4:1,V/V)混合，匀浆1min，冰水浴超声提取10min(80HZ)，15000RPM离心10min，取上清液冷冻干燥，冻干粉用200μL甲醇:水(4:1,V/V)复溶，0.22μm尼龙滤膜过滤，取3μL过滤液通过高效液相色谱联合质谱系统进行检测。具体的色谱和质谱检测条件如下。
A.色谱条件
样品采用Agilent 1290Infinity LC系统进行分离。流动相：A相为0.1％甲酸水溶液，B相为甲醇。样品置于8℃自动进样器中，柱温45℃，流速为250μL/min，进样量3μL。相关液相梯度如下：0-7min，B相从60％线性变化到70％；7-15min，B相从70％线性变化至85％；15-17min，B相维持在85％；17-17.1min，B相从85％线性变化至60％；17.1-20min，B相维持在60％。样本队列中每间隔一定数量的实验样本设置一个QC样本，用于检测和评价系统的稳定性及重复性。
B.质谱条件
采用5500QTRAP质谱仪(AB SCIEX)在负离子模式下进行质谱分析。5500QTRAP ESI源条件如下：source temperature：550℃；ion Source Gas1(Gas1)：55；IonSource Gas2(Gas2)：55；Curtain gas(CUR)；40；ionSapary Voltage Floating(ISVF)：-4500V；
1.2.3肝脏组织代谢组学的数据分析
质谱获取的原始数据经过格式转换，采用MSDIAL软件进行峰对齐、保留时间校正和提取峰面积。代谢物结构鉴定采用精确质量数匹配(<25ppm)和二级谱图匹配的方式，检索HMDB、MassBank等公共数据库，对提取得到的数据，删除组内缺失值>50％的离子峰，整合正负离子峰并应用软件SIMCA-P 14.1(Umetrics，Umea，Sweden)进行模式识别，数据经Unitvariance scaling(UV)预处理后，进行多维统计分析，筛选差异代谢物，并运用生物信息学对差异代谢通路进行分析。
1.2.4L.reuteri对FXR及其FXR下游靶向蛋白CYP7A1的影响
取出1.2.1节中收集的正常组、酒精组和L.reuteri干预组小鼠的肠道和肝脏组织样本，通过westernblot技术测定FXR在肠道和肝脏组织样本中的表达及CYP7A1在肝脏组织样本中的表达，具体操作如下：使用组织蛋白提取试剂盒提取不同处理组小鼠肠道和肝脏样品中的蛋白质，用BCA的方法测定其蛋白浓度，十二烷基硫酸钠-聚丙烯酰氨凝胶电泳(SDS-PAGE)分离蛋白；使用PVDF膜转印分离的蛋白条带，分别用FXR和CYP7A1抗体孵育转印的蛋白条带，4℃过夜；WesternBlot洗涤液清洗3次，辣根过氧化物酶偶联的山羊抗兔IgG溶液孵育转印的蛋白条带，室温1h；ECL显色，使用凝胶图像分析系统拍照分析。
2.实验结果
L.reuteri改善ALD小鼠肝脏中的脂肪代谢异常
通过非靶向代谢组学组学的方法探究了正常组、酒精饲料组和L.reuteri干预组小鼠肝脏代谢物的差异。通过多元统计分析和生物信息学分析，涉及到脂肪酸代谢通路的棕榈酸(PA,16:0)和n-3多不饱和脂肪酸，如亚油酸(LA,18:2)、花生四烯酸(AA,20:4)和二十二碳五烯酸(DPA,22:5)等差异代谢物被发现(表1)。
表1差异代谢物结果
其中P:益生菌组；E:酒精组；Linoleic acid：亚油酸；Arachidonic acid：花生四烯酸；Docosapentaenoic acid：二十二碳五烯酸；Xanthosine：黄嘌呤核苷；Palmiticacid：棕榈酸。
进一步的分析发现：酒精饲料组小鼠肝脏内的这些差异代谢物的水平与正常组和L.reuteri干预组小鼠的显著不同。这些实验结果表明：酒精饲料能够诱导小鼠肝脏内脂肪代谢的失调，L.reuteri能够显著改善酒精诱导的小鼠肝脏中的脂肪代谢异常。
L.reuteri增强ALD小鼠肠道中FXR的表达
酒精饲料饲喂小鼠8周后，小鼠肠道内的FXR的表达显著降低。L.reuteri干预ALD小鼠后，小鼠肠道内FXR的表达显著提升。通过蛋白分子印迹技术，进一步证实了酒精饲料能够诱导FXR下游靶蛋白CYP7A1在小鼠肝脏内的高表达，L.reuteri能够显著改善酒精饲料诱导的CYP7A1在小鼠肝脏的异常表达(图3)。由此推断，L.reuteri通过维持胆汁酸受体(FXR)的活化和肝脏中脂质代谢的平衡，从而缓解ALD的发生和发展。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.罗伊氏乳杆菌(Lactobacillus reuteri)在制备预防和/或治疗酒精性肝病的药物中的应用。
2.根据权利要求1所述应用，其特征在于，所述罗伊氏乳杆菌包括罗伊氏乳杆菌菌株DSM17938。
3.根据权利要求1或2所述应用，其特征在于，所述药物具有显著缓解酒精诱导的小鼠肝脏指数增加作用。
4.根据权利要求1或2所述应用，其特征在于，所述药物具有降低肝脏内脂质积聚作用。
5.根据权利要求1或2所述应用，其特征在于，所述药物具有降低肝功能中转氨酶水平。
6.根据权利要求5所述应用，其特征在于，所述转氨酶包括谷草转氨酶和/或谷丙转氨酶。
7.根据权利要求2所述应用，其特征在于，所述罗伊氏乳杆菌菌株DSM17938的扩繁方法，将罗伊氏乳杆菌菌株DSM17938划线于MRS固体培养基，厌氧培养，挑取单菌落接种至MRS液体培养基中厌氧培养，取对数生长期的菌液收集菌体。
8.根据权利要求1、2、6和7任意一项所述应用，其特征在于，所述药物包括口服剂。
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