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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。
Intestinal cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) are important components of intestinal barrier. Inflammatory bowel disease in the intestine CYP3A and P-gp down with intestinal flora disorder. However, whether the two are related and how the mechanism is still not clear. In this study, 5% dextran sodium sulfate was used to induce ulcerative colitis (UC) in rats. Normal animals were drenched with normal and UC animal manure, and faecal transplants were found to change the composition of intestinal bacteria in recipient animals. The expression of CYP3A2 and P-gp mRNA was significantly down-regulated in UC fecal transplanted group. Outer-membrane vesicles (OMVs) are the key structures that produce gram-negative bacteria, perform group behavior and communicate with the environment. OMVs of different treatment groups could downregulate the mRNA expression of CYP3A4 and P-gp in Caco-2 cells, while OMVs in UC group and UC stool treatment group had a stronger inhibitory effect and the relative molecular mass of 3 to 50,000 The role of OMVs components is even more pronounced. Cells treated with toll-like receptor 4 (TLR4) inhibitor reatadovir or transfected with TLR4 si RNA blocked the down-regulation of CYP3A4 and P-gp by OMVs. This study confirmed that part of UC gut bacteria down-regulated the expression of CYP3A and P-gp in intestine by secreting OMVs to activate TLR4 receptor pathway.