The impact of farnesoid X receptor activation on intestinal permeability in inflammatory bowel disease

Abstract

The most important function of the intestinal mucosa is to form a barrier that separates luminal contents from the intestine. Defects in the intestinal epithelial barrier have been observed in several intestinal disorders such as inflammatory bowel disease (IBD). Recent studies have identified a number of factors that contribute to development of IBD including environmental triggers, genetic factors, immunoregulatory defects and microbial exposure. The current review focuses on the influence of the farnesoid X receptor (FXR) on the inhibition of intestinal inflammation in patients with IBD. The development and investigation of FXR agonists provide strong support for the regulatory role of FXR in mucosal innate immunity. Activation of FXR in the intestinal tract decreases the production of proinflammatory cytokines such as interleukin (IL) 1-beta, IL-2, IL-6, tumour necrosis factor-alpha and interferon-gamma, thus contributing to a reduction in inflammation and epithelial permeability. In addition, intestinal FXR activation induces the transcription of multiple genes involved in enteroprotection and the prevention of bacterial translocation in the intestinal tract. These data suggest that FXR agonists are potential candidates for exploration as a novel therapeutic strategy for IBD in humans.

Figure 1)

A General structure of nuclear receptors. A typical nuclear receptor contains several domains: the N-terminal region (A/B), which contains the ligand-independent AF1 transactivation domain; the DNA binding domain (C) contains the conserved DNA binding domain; a flexible hinge region (D) that connects the DNA- and ligand-binding domain and the C-terminal ligand-binding domain (E/F) containing the ligand-dependent AF2 activation domain. B Mechanisms of farnesoid X receptor (FXR)-mediated transcriptional regulation. On ligand binding, FXR alters the transcription of target genes by interacting with FXR response elements (FXRE) as a heterodimer with the retinoid X receptor (RXR, 9-cis-retinoic acid receptor). Examples of consensus sequences are shown. After recruiting the coregulators and the RNA polymerase machinery, gene transcription is induced. BSEP Bile salt export pump; IBABP Intestinal bile acid binding protein; IR Inverted repeat; L Ligand; MRP 2 Multidrug resistance protein 2; SHP Small heterodimer partner

Figure 2)

Mechanisms of farnesoid X receptor (FXR) regulation of bile acids homeostasis. FXR negatively regulates bile acid production by repressing CYP7A1. FXR modulates CYP7A1 expression by induction of fibroblast growth factor (FGF)-19 expression. On its secretion, FGF19 activates the hepatic FGF receptor FGFR-4, which in turn downregulates CYP7A1. FXR induces the expression of a small heterodimer partner (SHP), which in turn interacts with two other receptors that decrease the transcription of CYP7A1. FXR activates the expression of the bile acid export transporters multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP), and simultaneously represses bile acid import by downregulation of the sodium-dependent cotransporting polypeptide (NTCP). At the intestinal level, FXR induces the expression of intestinal bile acid binding protein (IBABP) and organic solute transporter (OST)α–OSTβ, and influences the import of bile acids by interfering with the transcription factor network controlling the apical sodium-dependent bile acid transporter (ASBT)