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.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…It was concluded that FXR activation in the ileum is reduced in Crohn's patients, secondary to altered enterohepatic circulation of bile acids. TGR5 and FXR agonists may have therapeutic benefit to Crohn's disease patients (Lian et al, 2011;Pols et al, 2011b;Stojancevic et al, 2012;Stepanov et al, 2013).…”

“…The therapeutic potential of bile acids and derivatives for treating hepatic and biliary diseases, NAFLD, and metabolic syndrome has been extensively reviewed Fiorucci and Baldelli, 2009;Zollner and Trauner, 2009;Lian et al, 2011;Pols et al, 2011a,b;Adorini et al, 2012;Hollman et al, 2012;Stojancevic et al, 2012;McMahan et al, 2013;Mudaliar et al, 2013;Stepanov et al, 2013;Duboc et al, 2014) and will be briefly summarized. Bile acid sequestrants have long been used for treating gallstone disease.…”

The farnesoid X receptor and colon cancer

“…[34,35] FXR activation decreases the production of pro-inflammatory cytokines, such as interleukin (IL) 1-beta, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma, thereby reducing inflammation and intestinal permeability. [36] Torres et al [37] showed that FXR expression was inversely correlated with neoplastic progression and the severity of colonic inflammation in UC. FXR expression is also reduced in colonic mucosa from patients with primary sclerosing cholangitis (PSC) and UC-associated neoplasia.…”

Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies

“…While FXR is a nuclear (hormone) receptor, TGR5 is a G-protein-coupled bile acid receptor at the plasma membrane; both receptors mediate the effects of bile acids in the regulation of glucose and lipid metabolism and inflammation [33,34]. Notably, some TGR5 polymorphisms have recently been associated with the pathogenesis of PSC and ulcerative colitis [35,36], while FXR also appears to be involved in the pathogenesis of IBD [37,38,39,40]. Selective TGR5 and FXR agonists as well as dual TGR5/FXR ligands are now available [34].…”