溃结康调控肠道法尼醇X受体影响胆汁酸代谢治疗小鼠溃疡性结肠炎  

Kui Jie Kang regulates intestinal FXR and affects bile acidmetabolism in treatment of ulcerative colitis in mice

作　　者：徐荣漪 李小丝 马建国 杨学情 王华宁 祁燕 XU Rong-yi;LI Xiao-si;MA Jian-guo;YANG Xue-qing;WANG Hua-ning;QI Yan(School of Chinese Materia Medica,Yunnan University of Traditional Chinese Medicine,Kuiming Yunnan 650500,China;The First Affiliated Hospital,Yunnan University of Traditional Chinese Medicine/Traditional Chinese Medicine Hospital of Yunnan,Kuiming Yunnan 650021,China)

机构地区：[1]云南中医药大学中药学院,云南昆明650500 [2]云南中医药大学第一附属医院/云南省中医医院,云南昆明650021

出　　处：《中国药理学通报》2025年第2期383-391,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81960868);云南省科学基金资助项目(No 202001AZ070001-0-051,202101AZ0700001-013);云南省兴滇英才支持计划“青年人才”项目(2023.No 166);云南省高层次中医药人才(后备人才)项目(2021.No 1)。

摘　　要：目的探讨溃结康调控肠道法尼醇X受体(farnesoid X receptor/FXR)通路对溃疡性结肠炎(ulcerative colitis,UC)小鼠肠道菌群及胆汁酸代谢的影响。方法构建DSS诱导的UC小鼠模型,随机分为空白组(CON)、模型组(MOD)、溃结康12.8 g·kg^(-1)(KJK.H)、3.2 g·kg^(-1)(KJK.L)组,记录小鼠体质量并进行疾病活动指数评分,HE染色观察结肠组织病理形态学变化,糖原PAS染色及阿利新蓝染色观察结肠杯状细胞数量及黏液层修复;LC-MS/MS技术测定粪便胆汁酸含量;16S rRNA基因扩增测序分析肠道菌群组成;RT-qPCR及Western blot检测FXR靶基因和相关蛋白表达。结果溃结康明显改善UC小鼠结肠缩短,降低疾病活动及结肠病理组织评分,增加杯状细胞数量和黏液蛋白的分泌,调控粪便初级胆汁酸及次级胆汁酸含量,并增加乳酸杆菌等其他有益菌群的相对丰度。此外,明显上调结肠组织中FXR、FGF15 mRNA和蛋白变化,下调肝脏CYP7A1 mRNA表达。相关性分析显示肠道胆汁酸变化与肠道菌群种类、关键药效指标及胆汁酸代谢基因明显相关。结论溃结康激活肠道FXR-FGF15-CYP7A1通路,进而调节胆汁酸代谢,恢复肠道菌群平衡,可能为其改善UC的关键机制。Aim To explore the effects of Kui Jie Kang(KJK)on modulating the farnesoid X receptor(FXR)pathway in the gut microbiota and bile acid metabolism in mice with ulcerative colitis(UC).Methods Mice were subjected to DSS-induced UC and randomly assigned to the control(CON),model(MOD),and two KJK-dosed groups(KJK.H at 12.8 g·kg^(-1),KJK.L at 3.2 g·kg^(-1)).Mouse body weight was recorded,and disease activity index(DAI)was scored.The histopathological changes in colonic tissue were observed via HE staining,and the number of goblet cells and mucosal layer repair were assessed using PAS and Alcian blue staining.Bile acid content in feces was measured using LC-MS/MS,gut microbiota composition was analyzed by 16S rRNA gene sequencing,and the expression of FXR target genes and related proteins was detected by RT-qPCR and Western blot.Results KJK significantly ameliorated colonic shortening,decreased disease activity index in UC mice,reduced histopathological scores,increased the number of goblet cells and mucus secretion,altered the levels of primary and secondary bile acids,and increased the relative abundance of beneficial bacteria such as Lactobacillus.Additionally,it significantly upregulated the expression of FXR and FGF15 mRNA and protein in colonic tissue and downregulated the expression of hepatic CYP7A1 mRNA,and the correlation analysis in this study clearly revealed a significant correlation between bile acid metabolism disorders and gut microbiota imbalance in UC.Conclusion KJK activates the intestinal FXR-FGF15-CYP7A1 pathway,thereby regulating bile acid metabolism and restoring gut microbiota balance,which may be key to its improvement of UC.

关 键 词：溃结康 溃疡性结肠炎 胆汁酸 肠道菌群 FXR CYP7A1 

分 类 号：R-332[医药卫生] R285.5R322.45R574.62R975.5