Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice

Abstract

Various disease models have been shown to alter hepatic drugmetabolizing enzyme (DME) and transporter expression and to induce cholestasis through altered enzyme and transporter expression. Previously, we detailed the regulation of hepatic DMEs during infectious colitis caused by Citrobacter rodentium infection. We hypothesized that this infection would also modulate hepatic drug transporter expression and key genes of bile acid (BA) synthesis and transport. Mice lacking Toll-like receptor 4 (TLR4), interleukin-6 (IL-6), or interferon-gamma (IFNg) and appropriate wild-type animals were orally infected with C. rodentium and sacrificed 7 days later. In two wild-type strains, drug transporter mRNA expression was significantly decreased by infection for Slc22a4, Slco1a1, Slco1a4, Slco2b1, and Abcc6, whereas the downregulation of Abcc2, Abcc3, and Abcc4 were strain-dependent. In contrast, mRNA expressions of Slco3a1 and Abcb1b were increased in a strain-dependent manner. Expression of Abcb11, Slc10a1, the two major hepatic BA transporters, and Cyp7a1, the rate-limiting enzyme of BA synthesis, was also significantly decreased in infected animals. None of the above effects were caused by bacterial lipopolysaccharide, since they still occurred in the absence of functional TLR4. The downregulation of Slc22a4 and Cyp7a1 was absent in IFNg-null mice, and the downregulation of Slco1a1 was abrogated in IL-6-null mice, indicating in vivo roles for these cytokines in transporter regulation. These data indicate that C. rodentium infection modulates hepatic drug processing through alteration of transporter expression as well as DMEs. Furthermore, this infection downregulates important genes of BA synthesis and transport and may increase the risk for cholestasis.

Characterization of Gut Microbiota Associated with Clinical Parameters in Intrahepatic Cholestasis of Pregnant Patients

“…Proportional increases of Gammaproteobacteria in IT-operated animals were a potential contributor of the observed increase in the levels of circulating bile acids (38). Another study which examined a colitis mouse model found that Citrobacterrodentium infection downregulated the genes involved in bile acid biosynthesis and transportation, and increased the risk of cholestasis (39). In our study, we also found a significantly increased levesl of Citrobacter in the ICP patient group.…”

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

“…This finding is well in line with the fact that treatment with recombinant Tnf-a, IL1-b, or IL-6 in C57BL/6 mice showed a transient or sustained down-regulation of different hepatic BA transporters such as Ntcp and Bsep 6,28 and Cyp7a1. 29 Furthermore, cytokine treatment had effects on mRNA expression of transcription factors with reduced Fxr expression after Tnf-a treatment. 30 In a recent study, Jahnel et al 23 analyzed hepatic tissue of DSS-treated mice (male BL6 mice received 3% DSS for 7 d) and did not observe any FIGURE 6.…”

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats

“…Indeed, numerous studies have demonstrated poly I:C-mediated induction of pro-inflammatory cytokines both in vivo in the liver, placenta, and brain [15,36,37] and in vitro [38][39][40]. Several studies have also demonstrated IL-6 and TNF-α-mediated downregulation of drug transporters both in vivo [41,42] and in vitro [8,43]. We recently demonstrated that IL-6 and endotoxin-mediated downregulation of transporters in the liver is mediated by NF-κB and STAT3, which are key inflammation-induced transcription factors [2,44].…”