CN113509494A - 普氏菌在制备治疗胆汁淤积性疾病的药物中的应用 - Google Patents
普氏菌在制备治疗胆汁淤积性疾病的药物中的应用 Download PDFInfo
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Abstract
本发明公开了普氏菌在制备治疗胆汁淤积性疾病的药物中的应用。所述胆汁淤积性疾病包括但不限于原发性硬化性胆管炎。发明人构建PSC动物模型后，确定了小鼠中P.copri丰度同人群中一致减低，然后通过灌胃1周，每日补充1×108CFU的P.copri菌液以观察和评价P.copri对PSC模型的炎症，纤维化和胆汁淤积等各方面干预效果，并通过总胆汁酸测定和靶向的胆汁酸检测分析确定胆汁酸代谢改变，进而分析其作用机制。通过实验证明，P.copri可以明显减轻PSC小鼠的肝肠循环中的胆汁淤积，并明显改善肝脏纤维化，这对于预防或治疗胆汁淤积性疾病具有重要的意义。
Description
技术领域
本发明属于生物医药技术领域，具体涉及普氏菌在制备治疗胆汁淤积性疾病的药物中的应用。
背景技术
胆汁淤积性疾病是一类胆汁合成、代谢和排泄障碍的疾病，会造成大量胆汁酸等胆汁成分在肝内淤积，反流入血，从而引起的肝胆系统中器质性损伤，代谢紊乱和功能异常，临床上患者会伴随黄疸、瘙痒和血清碱性磷酸酶升高等特征。原发性硬化性胆管炎(Primary Sclerosing Cholangitis,PSC)是慢性胆汁淤积性疾病的一种，主要以肝内、外胆管进行性的炎症和纤维化以及多灶性胆管狭窄为特征。PSC在临床上仍然属于一种罕见的、病因未明的疾病，且预后不良，大多数患者可发展为肝硬化、门脉高压和肝功能失代偿。
目前熊去氧胆酸(ursodesoxycholic aci,UDCA)是临床上治疗该疾病的首选药物，但只针对部分早期的病人有改善胆汁淤积的作用，然而对于中后期的患者效果有限。另外，一些中药治剂，如黄芪、甘草、大枣等也被证明可改善胆汁淤积和肝损伤，但由于中药成分的讲究一人一方，因此也有一定的局限性。肝移植是临床上PSC终末治疗的一种选择，但是存在价格昂贵且配型困难等缺点。
大多数研究已经发现并证实，肠道微生物通过调节代谢和免疫反应在胆汁淤积性疾病的发病机制中发挥重要作用。研究发现，PSC患者粪便菌群与健康人群对比发现多样性明显降低，其中罗氏菌属(Rothia)、韦荣氏球菌属(Veillonella)丰度显著上升，普氏菌属(Prevotella)丰度显著下降。提示，肠道菌群可能作为调节因素在PSC的发生发展过程中发挥至关重要的作用。另外，肠道菌群会参与胆汁酸的代谢转化，将初级胆汁酸转化为次级胆汁酸，从而参与胆汁酸的肠肝循环。已有临床试验将粪菌移植(FMT)应用到PSC患者干预治疗上，结果显示部分患者ALP有超半数下降以及大多数患者ALT和AST小幅度降低，初步表明了FMT在PSC人群应用相对安全，有望通过菌群干预可以使疾病状态得到改善。普氏菌(Prevotella copri)是一种属于拟杆菌门中的Prevotella属的肠道细菌。研究发现，P.copri与抗癌药物诱导的肠道粘膜炎、化学诱导的结直肠炎以及类风湿性关节炎的发生风险相关，提示P.copri参与炎症性疾病的发生发展。但是，目前尚没有关于利用普氏菌改善胆汁淤积和肝脏纤维化方面的报道。
发明内容
本发明的目的是针对胆汁淤积性疾病的治疗药物存在的不足，提供一种利用肠道微生物来制备改善或治疗胆汁淤积性疾病的药物的方案。
为了实现上述目的，本发明提供了普氏菌(Prevotella copri)在制备治疗胆汁淤积性疾病的药物中的应用。
进一步，所述胆汁淤积性疾病，包括但不限于原发性硬化性胆管炎(PrimarySclerosing Cholangitis,PSC)。
进一步，所述治疗胆汁淤积性疾病的药物包括普氏菌，且所述普氏菌以活细胞的形式存在。
进一步，所述治疗胆汁淤积性疾病的药物还包括与普氏菌相配伍的其他药类以及药学上可接受的载体和/或辅料。
进一步，所述治疗胆汁淤积性疾病的药物的剂型为口服液、粉剂、胶囊或片剂。
本发明构建PSC动物模型后，确定了小鼠中P.copri丰度同人群中一致减低，然后通过灌胃1周，每日补充1×108CFU的P.copri菌液以观察和评价P.copri对PSC模型的各方面干预效果，并通过肠道菌群与胆汁酸含量的相关性分析找出P.copri的作用机制以及肠道菌群受P.copri作用后整体变化情况。通过实验证明，P.copri可以明显减轻PSC小鼠的肝肠循环中的胆汁淤积，并明显改善肝脏纤维化。
有益效果：本发明提供了普氏菌在制备治疗胆汁淤积性疾病的药物中的应用，发明人采用P.copri干预PSC小鼠后研究发现，P.copri可以显著恢复PSC小鼠的肝肠循环中的胆汁酸平衡，并明显改善肝脏纤维化，这对于预防或治疗胆汁淤积性疾病具有重要的意义。
附图说明
图1为四个处理组小鼠的粪便中P.copri丰度的变化情况；
图2为四个处理组小鼠的血清中ALP,ALT,AST和TBI的表达水平测试结果；
图3为四个处理组小鼠的肝脏和小肠中的总胆汁酸含量测试结果；
图4为结合型胆汁酸T-β-MCA，TCDCA和T-α-MCA的含量测试结果；
图5为游离型胆汁酸β-MCA，CA和LCA的含量测试结果；
图6为肝脏组织中纤维化相关基因Collagen 1a1和TIMP-1的表达水平测试结果；
图7为肝脏组织中胆汁受体FXR、PXR、LXRα、LXRβ、TGR5、RORα和RORγ的表达水平测试结果；
图8为肝脏中胆汁酸合成限速酶CYP7A1、胆汁酸合成催化酶CYP27A1、FXR下游分子配体SHP与FXR、肝脏表面胆汁酸接收蛋白Ntcp的表达水平测试结果；
图9为肝脏中5种胆汁酸转运蛋白和转出泵的表达水平测试结果；
图10为小肠中FXR相关信号通路的基因表达水平测试结果。
具体实施方式
下面结合附图和具体实施例对本发明的技术方案作进一步说明。
下述实施例中，采用的普氏菌为普氏菌DSM 18205，购于宁波明舟生物科技有限公司，普氏菌DSM 18205原始菌种在温度-80℃、20％甘油悬液形式保存。
实施例1
1、P.copri的培养
P.copri(DSM 18205)购于宁波明舟生物科技有限公司，复苏，活化和传代均在血琼脂平板(宁波明舟生物科技有限公司)上，接种后立即放置于2.5L厌氧培养罐(已放置厌氧产气袋和厌氧指示剂)中，在血琼脂培养基中37℃培养18-36h，得到菌液。
2、动物实验
实验材料说明：7周龄C57BL/6J小鼠购于江苏集萃药康生物科技有限公司，所有的实验动物处理都经过南京医科大学实验动物伦理委员会审查通过(批准编号：IACUC-2005013)；DDC(1,4-二氢-2,4,6-三甲基-3,5-吡啶二甲酸二乙酯)购自Sigma-Aldrich(CAS号：632-93-9)，由江苏省协同医药生物工程有限责任公司合成0.1％(w/w)DDC添加饲料。
实验方法：将7周龄C57BL/6J小鼠分为四个处理组，分别是对照组，P.copri单菌处理组，DDC模型组和DDC+P.copri干预组，每组6只，实验时间为2周，第1周，对照组和P.copri单菌处理组均使用正常饲料喂养，而DDC模型组和DDC+P.copri干预组都采用0.1％DDC添加饲料进行PSC样造模，其余饲养条件一致，从第8天开始，对照组和DDC模型组每天每只小鼠灌胃200微升PBS以维持对照和PSC样表型，另两组(P.copri单菌处理组和DDC+P.copri干预组)小鼠则每天每只小鼠灌胃200微升1×108CFU的P.copri菌液，进行干预，以观察其对PSC疾病症状的改善情况和作用机制，每日记录小鼠的体重，并在两周实验后收集小鼠粪便，血清，肝脏和肠道等生物材料，保存在-80℃，进行下面的测试：
(1)使用细菌基因组DNA提取试剂盒(天根生化科技有限公司)提取粪便基因组DNA后，通过qPCR，以GAPDH为内参基因表达对照，测定四个处理组小鼠的粪便中P.copri丰度变化情况，测试结果见图1；
(2)采集四个处理组小鼠的血清，生物化学分析碱性磷酸酶(ALP),丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转氨酶(AST)和总胆红素(TBI)的数值水平，由南京医科大学实验动物中心表性分析中心提供检测服务，测试结果见图2；
(3)使用南京建成生物工程研究所总胆汁酸(TBA)检测试剂盒测定小鼠肝脏和小肠的匀浆上清中总胆汁酸的含量，测试结果见图3；
(4)靶向胆汁酸检测
取所有小鼠的粪便样本，前处理后使用LC/MS定量分析其中目前市场上可供检测的游离型和结合型各3种胆汁酸的含量。具体的胆汁酸名称和缩写见表1：
表1定量检测的胆汁酸名称及缩写
| 胆汁酸全称 | 缩写 |
| β鼠胆酸 | β-MCA |
| 牛磺α鼠胆酸 | T-α-MCA |
| 牛磺β鼠胆酸 | T-β-MCA |
| 牛磺脱氧胆酸 | TDCA |
| 石胆酸 | LCA |
| 胆酸 | CA |
结合型胆汁酸T-β-MCA，TCDCA和T-α-MCA的含量测试结果见图4，游离型胆汁酸β-MCA，CA和LCA的含量测试结果见图5；
(5)RNA的提取和qPCR检测基因表达
将小鼠肝脏和小肠组织使用快速纯化总RNA提取试剂盒(南京诺唯赞生物科技股份有限公司)提取RNA，用NanoDrop2000测定RNA的浓度和纯度，之后使用逆转录试剂将其转为cDNA，实时荧光定量PCR使用相应的引物(表2)，SYBR Green酶和cDNA等进行各个基因表达情况的检测。
表2 qPCR所用引物序列如下
其中，肝脏组织中纤维化相关基因Collagen 1a1和TIMP-1的表达水平测试结果见图6，肝脏组织中胆汁受体FXR、PXR、LXRα、LXRβ、TGR5、RORα和RORγ的表达水平测试结果见图7，qPCR检测肝脏中FXR相关信号通路中信号分子的表达情况，其中，肝脏中胆汁酸合成限速酶CYP7A1、胆汁酸合成催化酶CYP27A1、FXR下游分子配体SHP与FGFR4、肝脏表面胆汁酸接收蛋白Ntcp的表达水平测试结果见图8，肝脏中OSTα、OSTβ、PPARα、Mrp2和Mrp3的表达水平测试结果见图9，小肠中FXR相关信号通路的基因表达水平测试结果见图10。
本研究中的图表和数据以均数±均数标准误差(SEM)表示。统计比较采用SPSS软件基于LSD检验的单因素方差分析(ANOVA)进行分析。使用GraphPad Prism 8软件(GraphPad,La Jolla,CA,USA)对数据进行分析。在每个相应的图表的图例中给出了特殊和具体的分析。P<0.05被认为有统计学意义。
检测结果如下：
图1为四个处理组小鼠的粪便中P.copri丰度的变化情况，可以看出，P.copri在正常单独灌胃P.copri处理小鼠的粪便中丰度显著上升，在DDC诱导的PSC小鼠模型粪便中丰度明显下降，通过DDC+P.copri干预后，能够显然弥补P.copri数量。
图2为四个处理组小鼠的血清中ALP,ALT,AST和TBI的表达水平测试结果，可以看出，ALP,ALT,AST和TBI在DDC诱导成模后有明显加重情况，当加入P.copri处理后有突出的改善效果，尤其对于肝功能表征指标ALT和AST。(*代表与Control组相比的统计学差异，#代表与DDC组相比的统计学差异，*P＜0.05，**P＜0.01，***P＜0.001；#P＜0.05，##P＜0.01，###P＜0.001)。
图3为四个处理组小鼠的肝脏和小肠中的总胆汁酸含量测试结果，可以看出，肝肠循环中的胆汁酸代谢在DDC模型组呈现肝内胆汁淤积和小肠中胆汁酸缺乏，然而在加入P.copri后，肝脏和小肠中的总胆汁酸得到了恢复，其水平均与对照组水平无异。(*代表与Control组相比的统计学差异，#代表与DDC组相比的统计学差异，*P＜0.05，**P＜0.01，***P＜0.001；#P＜0.05，##P＜0.01，###P＜0.001)
图4为结合型胆汁酸T-β-MCA，TCDCA和T-α-MCA的含量测试结果，图5为游离型胆汁酸β-MCA，CA和LCA的含量测试结果，可以看出，DDC刺激使得肠道中胆汁酸普遍下降，在P.copri治疗之后能有效的提升胆汁酸的水平。
图6为肝脏组织中纤维化相关基因Collagen 1a1和TIMP-1的表达水平测试结果，图中，*代表与Control组相比的统计学差异，#代表与DDC组相比的统计学差异，*P＜0.05，**P＜0.01，***P＜0.001；#P＜0.05，##P＜0.01，###P＜0.001，可以看出，在P.copri干预后，胶原蛋白I a1(Collagen 1a1)和金属肽酶抑制因子1(TIMP-1)的表达水平下降，肝脏纤维化明显减轻。
图7为肝脏组织中胆汁受体FXR、PXR、LXRα、LXRβ、TGR5、RORα和RORγ的表达水平测试结果，可以看出，FXR是其中唯一非常符合肝肠循环中总胆汁酸变化的受体。
图8为肝脏中胆汁酸合成限速酶CYP7A1、胆汁酸合成催化酶CYP27A1、FXR下游分子配体SHP与FXR、肝脏表面胆汁酸接收蛋白Ntcp的表达水平测试结果，其中，图8A为CYP7A1和CYP27A1的表达水平测试结果，显示P.copri对胆汁酸合成有显著抑制作用，图8B为FXR下游分子配体SHP与FGFR4的表达水平测试结果，可以看出SHP与FXR变化情况一致，表明其受到了响应，FGFR4在P.copri干预DDC后显著升高，图8C为Ntcp的表达水平测试结果，可以看出，肝脏表面胆汁酸接收蛋白Ntcp表达在P.copri作用之后没有变化，显示肝脏并未从血清中重吸收更多的胆汁酸。
图9为肝脏中5种胆汁酸转运蛋白和转出泵(OSTα、OSTβ、PPARα、Mrp2和Mrp3)的表达水平测试结果，可以看出，这5种种胆汁酸转运蛋白和转出泵在DDC+P.copri组中都显著上升，说明了肝内的大量胆汁酸转运泵出到了胆道系统中，从而缓解了肝内淤积症状。
图10为小肠中FXR相关信号通路的基因表达水平测试结果，可以看出，小肠胆汁酸由ASBT接收进入，与IBABP结合，最终通过表面转运蛋白OSTα，OSTβ和Mrp2泵出回到肝肠循环中；小肠中FXR的表达在DDC背景下加了P.copri的小鼠中明显升高，使得IBABP结合由ASBT接收进肠的胆汁酸增多，回补了肠道中胆汁酸的不足。FGF15受到响应大量在DDC+P.copri组中汇聚，进一步刺激了肝脏中FGFR4受体的表达，使得肝肠循环中胆汁酸代谢达到平衡。
Claims (5)
1.普氏菌在制备治疗胆汁淤积性疾病的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述胆汁淤积性疾病为原发性硬化性胆管炎。
3.如权利要求1所述的应用，其特征在于，所述治疗胆汁淤积性疾病的药物包括普氏菌，且所述普氏菌以活细胞的形式存在。
4.如权利要求1所述的应用，其特征在于，所述治疗胆汁淤积性疾病的药物还包括与普氏菌相配伍的其他药类以及药学上可接受的载体和/或辅料。
5.如权利要求1或2或3或4所述的应用，其特征在于，所述治疗胆汁淤积性疾病的药物的剂型为口服液、粉剂、胶囊或片剂。
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| WO2024061169A1 (zh) * | 2022-09-19 | 2024-03-28 | 重庆医科大学 | 普雷沃氏菌在防治注意缺陷多动障碍中的应用 |
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| CN114438236A (zh) * | 2021-12-07 | 2022-05-06 | 南京医科大学 | 肠道脱硫弧菌在筛选胆囊胆固醇结石病高危人群及防治药物中的应用 |
| CN114438236B (zh) * | 2021-12-07 | 2023-04-11 | 南京医科大学 | 肠道脱硫弧菌在筛选胆囊胆固醇结石病高危人群及防治药物中的应用 |
| WO2024061169A1 (zh) * | 2022-09-19 | 2024-03-28 | 重庆医科大学 | 普雷沃氏菌在防治注意缺陷多动障碍中的应用 |
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