RT Journal Article SR Electronic T1 Regulation of Hepatic Drug-metabolizing Enzymes in Germ-free mice by Conventionalization and Probiotics JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.115.067504 DO 10.1124/dmd.115.067504 A1 Felcy Pavithra Selwyn A1 Sunny Lihua Cheng A1 Curtis D. Klaassen A1 Julia Yue Cui YR 2015 UL http://dmd.aspetjournals.org/content/early/2015/11/19/dmd.115.067504.abstract 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 PPARĪ±-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.