Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Abstract

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 eight live strains of bacteria. Five groups of mice were used: 1) conventional mice (CV), 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 downregulated the cytochrome P450 (P450) 3a gene cluster, but upregulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels [reverse-transcription quantitative polymerase chain reaction (qPCR) and western blot]. Changes in the Cyp3a and 4a gene expression correlated with alterations in the pregnane X receptor and peroxisome proliferator-activated receptor a-DNA binding, respectively (chromatin immunoprecipitation-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 UDPglucuronosyltransferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients.

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