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Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis
Gao X.-J.2; Li T.2; Wei B.2; Yan Z.-X.2; Yan R.2
2017-01-12
Source PublicationYaoxue Xuebao
ISSN05134870
Volume52Issue:1Pages:34-43
AbstractAs important constituents of the first-line of host defense barrier, intestinal cytochrome P450 3 A (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.
KeywordFecal microbiota transplantation Gut dysbiosis Intestinal cytochrome P450 3A Intestinal P-glycoprotein Outer membrane vesicles Toll like receptor 4
DOI10.16438/j.0513-4870.2016-1002
URLView the original
Language英語
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Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.UM Zhuhai Research Institute
2.Universidade de Macau
Recommended Citation
GB/T 7714
Gao X.-J.,Li T.,Wei B.,et al. Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis[J]. Yaoxue Xuebao,2017,52(1):34-43.
APA Gao X.-J.,Li T.,Wei B.,Yan Z.-X.,&Yan R..(2017).Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis.Yaoxue Xuebao,52(1),34-43.
MLA Gao X.-J.,et al."Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis".Yaoxue Xuebao 52.1(2017):34-43.
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