PT  - JOURNAL ARTICLE
AU  - Xuejiao Gao
AU  - Ting Li
AU  - Bin Wei
AU  - Zhixiang Yan
AU  - Nan Hu
AU  - Yanjuan Huang
AU  - Beilei Han
AU  - Tai-Seng Wai
AU  - Wei Yang
AU  - Ru Yan
TI  - Bacterial outer membrane vesicles from dextran sulfate sodium-induced colitis differentially regulate intestinal UDP-glucuronosyltransferase 1A1 partially through TLR4/MAPK/PI3K pathway
AID  - 10.1124/dmd.117.079046
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.079046
4099  - http://dmd.aspetjournals.org/content/early/2018/01/04/dmd.117.079046.short
4100  - http://dmd.aspetjournals.org/content/early/2018/01/04/dmd.117.079046.full
AB  - UDP-glucuronosyltransferase 1A1 (UGT1A1) constitutes an important part of intestinal epithelial barrier and catalyzes glucuronidation of many endogenous compounds and drugs. Down-regulation of UGT1A1 in inflammation has been reported, while the association with gut dysbiosis is poorly defined. This study verified the involvement of gut microbiota in intestinal UGT1A1 regulation using dextran sulfate sodium (DSS)-induced rat colitis model plus fecal microbiota transplantation (FMT). Generally, both DSS induction and colitis-to-normal FMT suppressed mRNA and protein expressions of UGT1A1 and nuclear xenobiotic receptors (NRs) in colon, but enhanced mRNA and decreased protein of rUGT1A1/rNRs in small intestine. Normal-to-colitis FMT alleviated DSS-induced changes. Bacterial outer membrane vesicles (OMVs) from colitis rats and rats receiving colitis feces reduced both mRNA and protein of hUGT1A1/hNRs in Caco-2 cells. Interestingly, using deoxycholate to reduce LPS, normal OMVs up-regulated hUGT1A1/hNRs, while colitis OMVs decreased, indicating the involvement of other OMVs components in UGT1A1 regulation. The 10-50 kD fractions from both normal and colitis OMVs down-regulated hUGT1A1, hPXR and hPPAR-γ, while >50 kD fractions from normal rats up-regulated hUGT1A1 and hCAR. Additionally, the conditioned medium from OMVs-stimulated rat primary macrophages also reduced hUGT1A1/hNRs expression. Both toll like receptor 2 (TLR2) and TLR4 were activated by DSS, colitis-to-normal FMT and the opposite, while only TLR4 was increased in OMVs-treated cells. TLR4 siRNA blocked hUGT1A1/hNRs down-regulation and PI3K/Akt, ERK and NF-κB phosphorylation evoked by bacterial OMVs. Taken together, this study demonstrated that gut microbiota regulate intestinal UGT1A1 partially through secreting OMVs which interact intestinal epithelial cells directly or via activating macrophage.