Abstract
Intestinal bacteria have been shown to be important in regulating host intermediary metabolism and contribute to obesity. However, relatively less in known about the effect of intestinal bacteria on the expression of hepatic drug processing genes of the host. The purpose of this study was to characterize the expression of hepatic drug processing genes (DPGs) in germ-free (GF) mice using RNAseq. Total RNA was isolated from the livers of adult male conventional (CV) and GF C57BL/6J mice (n=3 per group). In livers of GF mice, the mRNA of the AhR target gene Cyp1a2 was increased 51%, and the mRNA of PPARα-target gene Cyp4a14 was increased 202%; conversely, the mRNA of the CAR target gene Cyp2b10 was decreased 57%, and the mRNA of the PXR target gene Cyp3a11 was decreased 87% in GF mice. Although other non-Cyp phase-1 enzymes in livers of GF mice are only moderately affected, there was a marked down-regulation in the phase-II enzymes glutathione S-transferases p1 and p2, as well as a marked up-regulation in the major bile acid transporters (Ntcp and Oatp1b2) and cholesterol transporters (Abcg5 and Abcg8). In summary, this study demonstrates that intestinal bacteria regulate the expression of a large number of DPGs, and suggests that intestinal bacteria are responsible for some individual differences in drug responses.
- animal models
- cytochrome P450
- distribution
- flavin-containing monooxygenase/FMO
- gene regulation/transcription
- glucuronidation/UDP-glucuronyltransferases/UGT
- glutathione conjugates/glutathione transferases/GST
- microbiome
- pregnane X receptor/PXR/SXR
- The American Society for Pharmacology and Experimental Therapeutics