白皮杉醇调控肠道菌群减轻慢性肾病模型小鼠并发系统性炎症  

Piceatannol alleviates host inflammation in chronic kidney disease model mice through regulating gut microbiota

作　　者：李成曦 王颖异 王雨萌 尹佳婷 杨淑惠 刘云[1] 段金廒[1] 郭建明[1] LI Cheng-xi;WANG Ying-yi;WANG Yu-meng;YIN Jia-ting;YANG Shu-hui;LIU Yun;DUAN Jin-ao;GUO Jian-ming(Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources,Nanjing University of Chinese Medicine,Nanjing 210023,China)

机构地区：[1]南京中医药大学,江苏省中药资源产业化过程协同创新中心,江苏南京210023

出　　处：《药学学报》2022年第2期364-374,共11页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81773983)。

摘　　要：本研究探讨天然小分子化合物白皮杉醇(PIC)对腺嘌呤诱导的慢性肾病(CKD)模型小鼠体内炎症水平的影响,并基于肠道菌群探讨其作用机制。动物实验遵循南京中医药大学动物伦理委员会规定。采用酶联免疫吸附法(ELISA)检测小鼠体内炎症因子白介素6(IL-6)及肿瘤坏死因子α(TNF-α)水平;液质联用法检测促炎尿毒素分子硫酸吲哚酚(IS)、硫酸对甲酚(PCS)水平;蛋白印迹方法检测肠道紧密连接蛋白occludin表达;肠道细菌体外厌氧培养技术检测IS的前体分子吲哚在肠道细菌中的合成;采用16S rDNA测序检测肠道菌群丰度。结果发现,PIC对CKD模型小鼠肾脏组织炎性浸润无改善作用,但可降低模型小鼠血液中IL-6以及结肠组织中IL-6及TNF-α水平。PIC对CKD模型小鼠肠道中缺失的occludin蛋白无改善作用;但可显著降低模型小鼠血液以及肝脏中IS、PCS水平。进一步研究表明,PIC可抑制尿毒素IS前体吲哚在肠道细菌中的合成;降低肠道中吲哚合成细菌的丰度水平。综上所述,PIC可调控肠道菌群,抑制尿毒素前体的合成,进而减轻尿毒素IS、PCS在体内的蓄积,改善CKD小鼠并发的体内炎症。The purpose of this research is to study the effect of small molecule compound piceatannol(PIC)on host inflammation in adenine induced chronic kidney disease(CKD)mice,and then to explore its mechanism based on the regulation of gut microbiota.All procedures were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine.The level of interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)was detected by enzyme linked immunosorbent assay(ELISA);UPLC-TQ/MS technology was used to monitor the level of proinflammatory uremic toxin indoxyl sulfate(IS)and p-cresol sulfate(PCS);the expression of occludin was tested by Western blot;in vitro anaerobic culture of gut bacteria was used to produce indole;the abundance of gut microbiota was evaluated by 16S rDNA sequencing.The results showed that PIC had no effect on inflammatory infiltration in kidney tissue of CKD mice,but could decrease IL-6 level in blood and IL-6/TNF-α level in colon tissue.PIC did not improve intestinal occludin protein expression in CKD mice;while it could significantly reduce the levels of IS and PCS in blood and liver of CKD mice.Further mechanism studies showed that PIC could inhibit the synthesis of IS precursor indole in gut bacteria.Moreover,PIC could decrease the abundance of gut bacteria which producing uremic toxin,such as reducing the abundance of indole and p-cresol producing gut bacteria.In conclusion,PIC could regulate gut microbiota and inhibit the synthesis of uremic toxin precursor,thereafter reducing the accumulation of IS and PCS in vivo,ultimately relieving the inflammation of CKD mice.

关 键 词：慢性肾病 系统性炎症 白皮杉醇 肠道菌群 尿毒素 

分 类 号：R966[医药卫生—药理学]