基于宏基因组测序的嘎日迪-5亚急性毒性机理初探  

Preliminary Study on Mechanism of Subacute Toxicity of Garidi-5 Based on Metagenomics

作　　者：乌日汉[1] 丽丽[1] 毕力格 陈玉花[2] 肖田梅[2] 孟香花 宝乐尔 朝鲁蒙格日勒 白梅荣[1] Wurihan;Lili;Bilige;CHEN Yuhua;XIAO Tianmei;MENG Xianghua;Bolor;Chaolumenggeril;BAI Meirong(Key Laboratory of Ministry of Education of Mongolian Medicine R&D Engineering,Inner Mongolia Minzu University,Tongliao 028000,China;Chemistry and Materials College,Inner Mongolia Minzu University,Tongliao 028000,China)

机构地区：[1]内蒙古民族大学蒙医药研发工程教育部重点实验室,内蒙古通辽028000 [2]内蒙古民族大学化学与材料学院,内蒙古通辽028000

出　　处：《中医药信息》2021年第10期37-44,共8页Information on Traditional Chinese Medicine

基　　金：国家民委-教育部蒙医药研发重点实验室开放课题(MDK2019063);蒙药安全性评价创新团队项目(MY20190003);中央支持地方建设专项资金交叉学科建设项目(JCHXKXM001);内蒙古自治区2020年博士研究生科研创新资助项目(BZ2020076)。

摘　　要：目的:初步探讨嘎日迪-5亚急性毒性作用机理,为其临床安全合理用药奠定依据。方法:以嘎日迪-5为示例药物,以大鼠为研究对象,随机分为高剂量组(GG组)、中剂量组(GZ组)、低剂量组(GD组)和正常组(Z组),除Z组外,给药组灌胃相应的药物溶液,连续灌胃28 d,末次给药后收集粪便样本,抽提粪便DNA,进行宏基因组测序分析。结果:GG组ALT、UREA、CK、CKMB含量显著升高(P<0.05)。病理学观察显示,GG组肝细胞和肾小管上皮细胞有明显水肿,GG、GZ组心肌纤维排列紊乱,胞质疏松淡染,部分细胞水肿。菌群丰度分析结果显示,嘎日迪-5使菌群组成发生一定变化,发现了35个明显差异菌种。关联性分析显示,差异菌种参与血清UREA、CK、CKMB、ALT、CREP、ALP因子的调控。KEGG富集分析显示,GG组主要涉及蛋白质输出、肽聚糖生物合成、牛磺酸和低牛磺酸代谢等通路。结论:嘎日迪-5具有一定的亚急性毒性;初步认为阿利斯佩斯菌属、Desulfovibrio fairfieldensis的显著富集是嘎日迪-5产生心脏毒性和肝肾毒性的主要机制之一;其亚急性毒性机制与蛋白质输出通路相关。Objective:To initially study the subacute toxicity and mechanism of Garidi-5,thus to lay a foundation on its safe and rational application in clinical practice.Methods:32 SD rats were randomly divided into the normal group(Z group),Garidi-5 groups of high-dose(GG group),medium-dose(GZ group)and low-dose(GD group),with 8 rats in each group.The corresponding Garidi-5 solution was intragastrically administered for 28 days in all groups except Z group.After the last administration,the fecal samples were collected and the fecal DNA was extracted for metagenomic sequencing.Results:The contents of ALT,UREA,CK and CKMB increased significantly in GG group(P<0.05).Histopathological observation showed obvious swelling of hepatocyte and renal tubular epithelial cells in GG group;in GG group and GZ group,myocardial fibers arranged disorderly and loosely with part of cells swelling.The results of flora abundance analysis showed that Garidi-5 made the flora composition change to a certain extent.There were 35 significant different microflora being found.Correlation analysis showed that different bacteria were involved in the regulation of serum factors of UREA,CK,CKMB,ALT,CREP and ALP.KEGG enrichment analysis showed that GG group was mainly involved in the pathways of protein export,Peptidoglycan biosynthesis,taurine and hypotaurine metabolism.Conclusion:The Garidi-5 had certain subacute toxicity.It is suggested that the significant enrichment of Alistipes and Desulfovibrio fairfieldensis is one of the main mechanisms for the cardiotoxicity and liver and kidney toxicity caused by Garidi-5.The mechanism of subacute toxicity is related to protein export pathway.

关 键 词：嘎日迪-5 宏基因组学 毒性 机理 

分 类 号：R285[医药卫生—中药学]