Effects of the Microbiome on Xenobiotic Processing Genes

[Speaker] Curtis D. Klaassen:1
1:Pharmacology and Toxicology, University of Kansas, USA

Intestinal bacteria are known to have marked effect on development of the immune system and the synthesis of vitamins, however relatively little is known about the effect of intestinal bacteria on the expression of hepatic drug-processing genes in the host. This study characterizes the expression of drug-processing genes in liver and intestine of germ-free (GF) mice using RNA-seq. In the livers of GF mice, the mRNA of the aryl hydrocarbon receptor target gene Cyp1a2 was increased 51%, and the mRNA of the peroxisome proliferator-activated receptor alpha target gene Cyp4a14 was increased 201%. Conversely, the mRNA of the constitutive androstane receptor (CAR) target gene Cyp2b10 was decreased 57%, and the mRNA of the pregnant X receptor target gene Cyp3a11 was decreased 87% in GF mice. Although other non-Cyp phase-1 enzymes in the livers of GF mice were only moderately affected, there was a marked down-regulation in the phase-2 enzymes glutathione S-transferases p1 and p2, as well as a marked up-regulation in the major bile acid transporters Na-taurocholate cotransporting polypeptide and organic anion-transporting polypeptide 1b2, and the cholesterol transporter ATP-binding cassette transporter Abcg5/Abcg8. Lack of intestinal bacteria leads to similar alterations of some of these drug-processing genes in the intestine, especially the lower expression of Cyp3a11, but not all genes are similarly altered in the liver and intestine. In conclusion, intestinal bacteria regulate the expression of a large number of drug-processing genes, which suggests that intestinal bacteria are responsible for some individual differences in drug responses.
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