RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice

Abstract

Intestinal bacteria can affect xenobiotic metabolism through both direct bacterial enzyme-catalyzed modification of the xenobiotics and indirect alterations of the expression of host genes. To determine how intestinal bacteria affect the expression of host xenobiotic-processing genes (XPGs), the mRNA profiles of 303 XPGs were characterized by RNA sequencing in four intestinal sections and compared with that in the liver from adult male conventional (CV) and germ-free (GF) mice. Fifty-four XPGs were not expressed in the intestine of either CV or GF mice. The GF condition altered the expression of 116 XPGs in at least one intestinal section but had no effect on 133 XPGs. Many cytochrome P450 family members such as Cyp1a, Cyp2b10, Cyp2c, and most Cyp3a members, as well as carboxylesterase (Ces) 2a were expressed lower in the intestine of GF than CV mice. In contrast, GF mice had higher intestinal expression of some phase I oxidases (alcohol dehydrogenase 1, aldehyde dehydrogenase a1l1 and 4a1, as well as flavin monooxygenase 5) and phase II conjugation enzymes (UDP-glucuronosyltransferase 1a1, and sulfotransferase 1c2, 1d1, and 2b1). Several transporters in the intestine, such as bile acid transporters (apical sodium-dependent bile acid transporter, organic solute transporter and), peptide transporter 1, and multidrug and toxin extrusion protein 1, exhibited higher expression in GF mice. In conclusion, lack of intestinal bacteria alters the expression of a large number of XPGs in the host intestine, some of which are section specific. Cyp3a is downregulated in both the liver and intestine of GF mice, which probably contributes to altered xenobiotic metabolism.

Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study

“…6 Additionally, animal and human studies suggest that microbes can alter the activities of cytochrome P450 enzymes (CYP) in the intestine leading to alterations in drug action. [7][8][9][10] A traditional approach to studying drug metabolism in humans involves investigating the pharmacokinetics (PKs) of probe compounds that serve as biomarkers for enzyme or transporter activity. A probe compound is chosen and validated based upon its high specificity for the enzyme or transporter of interest, its safety profile, and availability.…”

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

“…xenobiotic metabolism through indirect mechanisms. For example, the absence of gut microbiota in mice alters the expression of xenobiotic-processing genes, such as those for cytochrome P450 enzymes and other phase I oxidases [14]. The absence of gut microbiota in mice alters the host metabolism of polybrominated diphenyl ethers (PBDEs), and modulates the PBDE-mediated differential regulation of…”

Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

“…The relationship between the intestinal microbiome and the host metabolome is important to understand drug and xenobiotic metabolism, and mode of action [1,2]. Intestinal bacteria express enzymes, like β-glucuronidases, that may activate (and sometimes reactivate) certain drugs [3], and intestinal bacteria can alter how the host metabolizes drugs and xenobiotics [4,5]. Changes in the composition of the intestinal bacteria can influence the host due to the role intestinal microbiota play in drug metabolism [6], food metabolism [7], and gut barrier function [8].…”