Novel interactions between the gut microbiome and host hepatic xenobiotic biotransformation – lessons learned from the germ-free mice

Recent studies have demonstrated the critical roles of intestinal bacteria on the host intermediary metabolism including obesity and type II diabetes. Less is known regarding the impact of intestinal bacteria on the hepatic biotransformation of various xenobiotics. The goal of this study was to utilize germ-free mice to determine the impact of alterations in gut microbiome on the hepatic drug-processing gene expression and xenobiotic metabolism. RNA-Sequencing demonstrated that in livers of germ-free mice, there was a marked decrease in the hepatic expression and enzyme activity of cytochrome P450 (Cyp) 3a, which is a major class of phase-I enzyme involved in the biotransformation of over two-thirds of the drugs prescribed in the market; in contrast, there was a marked increase in the hepatic expression and enzyme activity of Cyp4a, which is important for lipid metabolism. Chromatin immunoprecipitation and qPCR results suggested that this was due to attenuated pregnane X receptor signaling but enhanced peroxisome proliferator-activated receptor signaling. During liver development, the presence of intestinal microbiota markedly impacted the normal ontogeny of many hepatic drug-processing genes in a gender-specific manner. Introducing exogenous bacteria by probiotics or conventionalization also influenced the hepatic drug-processing capacities. Finally, the environmental chemical polybrominated diphenyl ethers (PBDEs) mediated alterations in many hepatic drug-processing genes depended on the presence of a normal configuration of the gut microbiome, and the germ-free conditions altered the amount of certain phenolic metabolites of PBDE-47. In conclusion, gut microbiome critically impacts the expression of drug-processing genes and the metabolism xenobiotics of the host liver.