PT - JOURNAL ARTICLE AU - Felcy Pavithra Selwyn AU - Sunny Lihua Cheng AU - Curtis D. Klaassen AU - Julia Yue Cui TI - Regulation of Hepatic Drug-metabolizing Enzymes in Germ-free mice by Conventionalization and Probiotics AID - 10.1124/dmd.115.067504 DP - 2015 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.115.067504 4099 - http://dmd.aspetjournals.org/content/early/2015/11/19/dmd.115.067504.short 4100 - http://dmd.aspetjournals.org/content/early/2015/11/19/dmd.115.067504.full AB - Little is known regarding the effect of intestinal microbiota modifiers, such as probiotics and conventionalization with exogenous bacteria, on host hepatic drug metabolism. Therefore, the goal of this study was to determine the effect of these modifiers on the expression of various drug-metabolizing enzymes of the host liver. VSL3 is a probiotic that contains 8 live strains of bacteria. Five groups of mice were used: 1) conventional mice, 2) conventional mice treated with VSL3 in drinking water, 3) germ-free (GF) mice, 4) GF mice treated with VSL3, and 5) GF mice exposed to the conventional environment for 2 months. All mice were 3-months-old at tissue collection. GF conditions markedly down-regulated the cytochrome P450 (Cyp) 3a gene cluster, but up-regulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels (RT-qPCR and western blot). Changes in the Cyp3a and 4a gene expression correlated with alterations in the PXR and PPARα-DNA binding, respectively (ChIP-qPCR). VSL3 increased each bacterial component in the large intestinal content of the CV mice, and increased these bacteria even more in GF mice, likely due to less competition for growth in the GF environment. VSL3 given to conventional mice increased the mRNAs of Cyp4v3, alcohol dehydrogenase 1, and carboxyesterase 2a, but decreased the mRNAs of multiple Phase-II glutathione-S-transferases. VSL3 given to germ-free mice decreased the mRNAs of UDP-glucuronosyl transferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many DMEs in liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients.