肠道菌群介导溃疡性结肠炎大鼠肠CYP3A和P-糖蛋白的变化及机制

发布时间：2018-03-29 16:43

本文选题：肠道菌群失衡　切入点：粪菌移植　出处：《药学学报》2017年01期

【摘要】：肠道细胞色素P450 3A(cytochrome P450 3A,CYP3A)和P-糖蛋白(P-glycoprotein,P-gp)是肠屏障的重要组成部分。炎症性肠病中肠CYP3A和P-gp下调伴随肠道菌群紊乱。但两者是否关联?机制如何?尚不清楚。本研究采用5%葡聚糖硫酸钠诱导大鼠溃疡性结肠炎(ulcerative colitis,UC),并对正常动物分别灌胃正常及UC动物粪便,发现粪便移植改变了受体动物肠道菌组成,而移植UC粪便组肠CYP3A2和P-gp mRNA的表达显著下调。外膜囊泡(outer-membrane vesicles,OMVs)是革兰阴性菌产生、进行群体行为及与环境通信的关键结构。不同处理组的OMVs均能下调人结肠腺癌细胞Caco-2中CYP3A4和P-gp的mRNA表达,而UC组以及UC粪便处理组的OMVs的抑制作用更强,且相对分子质量3~5万的OMVs组分的作用更显著。细胞经toll样受体4(toll like receptor 4,TLR4)抑制剂瑞沙托维处理或转染TLR4 si RNA能够阻断OMVs对CYP3A4和P-gp的下调。本研究证实,UC肠道菌部分通过分泌OMVs活化TLR4受体通路下调肠道CYP3A和P-gp表达。
[Abstract]:Intestinal cytochrome P450 3A(cytochrome P450 3A (CYP3A) and P-glycoprotein P-glycoprotein (P-gp) are important components of intestinal barrier. The down-regulation of CYP3A and P-gp in the midgut of inflammatory bowel disease is associated with intestinal flora disorder. What about the mechanism? In this study, 5% sodium dextran sulfate was used to induce ulcerative colitis in rats, and normal and UC faeces were perfused to normal and UC animal faeces respectively. It was found that fecal transplantation changed the composition of intestinal bacteria in recipient animals. However, the expression of CYP3A2 and P-gp mRNA was down-regulated in UC feces transplantation group. Outer membrane vesiclesnus OMVswere produced by Gram-negative bacteria. OMVs of different treatment groups could down-regulate the mRNA expression of CYP3A4 and P-gp in Caco-2 of human colon adenocarcinoma cells, but OMVs in UC group and UC fecal treatment group had stronger inhibitory effect. The effect of OMVs components with relative molecular weight of 350-50 000 was more significant. Cells treated with toll like receptor 4(toll like receptor 4tLR4) or transfected with TLR4 si RNA could block the down-regulation of CYP3A4 and P-gp by OMVs. The expression of CYP3A and P-gp was down-regulated by secreting OMVs activated TLR4 receptor pathway.
【作者单位】：澳门大学中华医药研究院中药质量研究国家重点实验室(澳门大学);珠海澳大科技研究院;
【基金】：国家自然科学基金资助项目(81473281) 973基金资助项目(2009CB522707) 澳门大学基金资助项目(MYRG2015-00220)
【分类号】：R574.62

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