螺环哌嗪盐化合物DXL-A-24对肠易激综合征大鼠内脏高敏感性和肠道菌群的影响  

Effects of DXL-A-24 on visceral hypersensitivity and gut microbiota in rats of irritable bowel syndrome

作　　者：徐燕 刘冬光 赵文学 朱建国 姚方方 姚景春 张贵民 姚茹 XU Yan;LIU Dongguang;ZHAO Wenxue;ZHU Jianguo;YAO Fangfang;YAO Jingchun;ZHANG Guimin;YAO Ru(Lunan Pharmaceutical Group Corporation,Pharmacological Center for New Drugs,Shandong Linyi 276006,China;State Key Laboratory of generic technology of traditional Chinese medicine,Shandong Linyi 273400,China)

机构地区：[1]鲁南制药集团有限公司新药药理中心,山东临沂276006 [2]中药制药共性技术国家重点实验室,山东临沂273400

出　　处：《中国医院药学杂志》2023年第16期1833-1839,1865,共8页Chinese Journal of Hospital Pharmacy

摘　　要：目的:探讨螺环哌嗪盐化合物DXL-A-24对肠易激综合征(irritablebowelsyndrome,IBS)大鼠内脏高敏感性和肠道菌群的影响。方法:采用母婴分离联合束缚应激制备IBS大鼠模型,造模成功大鼠随机分为模型组、利那洛肽组(0.022mg·kg^(-1))、螺环哌嗪盐化合物DXL-A-24低、中、高剂量组(2,6,12mg·kg^(-1)),每组14只,同时设正常组,连续灌胃28d。采用腹壁回撤反射评估大鼠内脏敏感性,ELISA法检测结肠组织肿瘤坏死因子α(tumornecrosisfactor-α,TNF-α)、D-乳酸(D-lac-tate,D-LA)和二胺氧化酶(diamineoxidase,DAO)含量,免疫组化法检测结肠组织P物质(substanceP,SP)和降钙素基因肽(calcitoningene-relatedpeptide,CGRP)的表达,16SrRNA基因测序分析肠道菌群的变化。结果:与正常组相比,模型组大鼠毛发稀疏发黄,攻击性强,肛周有粪便污染,内脏敏感性明显升高(P<0.05)。与模型组相比,各给药组大鼠被毛发黄、竖毛、撕咬表现有所缓解,内脏敏感性显著降低,结肠组织TNF-α、D-LA、SP、CGRP的表达显著降低(P<0.05),肠道有益菌增加,有害菌减少。结论:DXL-A-24改善IBS大鼠内脏高敏感性和肠道屏障损伤,其机制可能与改善肠道菌群,降低SP、CGRP和TNF-α的表达有关。OBJECTIVETo investigate the effects of DXL-A-24 on visceral hypersensitivity and gut microbiota in rats of irri-table bowel syndrome(IBS).METHODS The model of IBS was established using mother-infant separation combined with binding stress.After modeling,the IBS rats were randomly divided into 5 groups:the model group,linaclotide capsules(posi-tive group,0.022 mg•kg^(-1)),and DXL-A-24 low,medium and high(2,6,12 mg·kg^(-1))dose groups,with 14 rats in each group.Normal control group were also set up.They were intragastrically administered for 28 successive days.Visceral sensa-tion was assessed by abdominal wall recovery reflex score in IBS rats.The contents of TNF-α,D-lactate(D-LA)and diamine oxidase(DAO)in colon tissue were detected by ELISA,the expressions of substance P(SP)and calcitonin gene-related peptide(CGRP)were detected by immunohistochemistry,and 16S rRNA to detect the diversity of gut microbiota.RESULTS Com-pared with normal control group,the hair of the model group was sparse,yellowed and bristled,irritable and aggressive,with loose stool pollution or deformed stool around the anus,and visceral hypersensitivity(P<0.05).Compared with model group,the visceral hypersensitivity was significantly improved in treatment groups,the content of TNF-α,D-LA and the expression of SP,CGRP in colon tissue were significantly decreased(P<0.05).Besides,there was an increase in good bacteria and a de-crease in bad bacteria in the gut after treatment.CONCLUSION DXL-A-24 has improved the visceral hypersensitivity and in-testinal barrier injure of mother-infant separation combined with binding stress induced IBS rats,which may be achieved by im-proving the intestinal microbiota and reducing the expression of CGRP,SP and TNF-α.

关 键 词：螺环哌嗪盐化合物DXL-A-24 母婴分离结合束缚应激 肠易激综合征 内脏敏感性 肠道菌群 

分 类 号：R965[医药卫生—药理学]