Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis
10.16438/j.0513-4870.2016-1002
- VernacularTitle: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
- Author:
Xue-jiao GAO
1
;
Ting LI
1
;
Bin WEI
1
;
Zhi-xiang YAN
1
;
Ru YAN
1
Author Information
1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
- Publication Type:SPECIAL REPORTS
- Keywords:
gut dysbiosis;
fecal microbiota transplantation;
outer membrane vesicles;
intestinal cytochrome P450 3A;
intestinal P-glycoprotein;
toll like receptor 4
- From:
Acta Pharmaceutica Sinica
2017;52(1):34-43
- CountryChina
- Language:Chinese
-
Abstract:
As important constituents of the first-line of host defense barrier, intestinal cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) play important roles in disease pathogenesis as well as drug absorption and exposure. Clinical reports and experimental data revealed diminished intestinal CYP3A and P-gp expression accompanying with gut dysbiosis in inflammatory bowel disease. Yet whether gut dysbiosis is associated with the down-regulation of CYP3A and P-gp and the underlying mechanisms are unclear. In this study, daily administration of fresh feces from normal rats and rats with ulcerative colitis (UC) induced by dextran sulfate sodium to normal rats resulted in alterations of gut bacterial compositions. Intestinal CYP3A2 and P-gp were significantly down-regulated in rats receiving UC feces. Outer-membrane vesicles (OMVs) are nano-scale special buds of the outer membrane which are produced by Gram-negative bacteria and mediate diverse functions including interactions within bacterial communities and communications with host. Expressions of CYP3A4 and P-gp mRNA were diminished in human epithelial colorectal adenocarcinoma cells (Caco-2) treated by OMVs from all different groups with OMVs from UC rats or rats receiving UC feces showing more significant effects.Moreover, the OMVs fractions within 30 000-50 000 Daltons from both normal and UC rats elicited more effects than fractions of other molecular weights. Treatment of Caco-2 cells with toll like receptor 4 (TLR4) inhibitor resatorvid (TAK-242) or TLR4 silence RNA (siRNA) blocked CYP3A4 and P-gp down-regulation induced by bacterial OMVs. Taken together, we proved in this study that gut microbiota can down-regulate intestinal CYP3A and P-gp partially through producing OMVs to activate the TLR4 signaling pathway.
