Bile acids as inflammatory mediators and modulators of intestinal permeability

Abstract

Bile acids are critical for the digestion and absorption of lipids and fat-soluble vitamins; however, evidence continues to emerge supporting additional roles for bile acids as signaling molecules. After they are synthesized from cholesterol in the liver, primary bile acids are modified into secondary bile acids by gut flora contributing to a diverse pool and making the composition of bile acids highly sensitive to alterations in gut microbiota. Disturbances in bile acid homeostasis have been observed in patients with Inflammatory Bowel Diseases (IBD). In fact, a decrease in secondary bile acids was shown to occur because of IBD-associated dysbiosis. Further, the increase in luminal bile acids due to malabsorption in Crohn's ileitis and ileal resection has been implicated in the induction of diarrhea and the exacerbation of inflammation. A causal link between bile acid signaling and intestinal inflammation has been recently suggested. With respect to potential mechanisms related to bile acids and IBD, several studies have provided strong evidence for direct effects of bile acids on intestinal permeability in porcine and rodent models as well as in humans. Interestingly, different bile acids were shown to exert distinct effects on the inflammatory response and intestinal permeability that require careful consideration. Such findings revealed a potential effect for changes in the relative abundance of different bile acids on the induction of inflammation by bile acids and the development of IBD. This review summarizes current knowledge about the roles for bile acids as inflammatory mediators and modulators of intestinal permeability mainly in the context of inflammatory bowel diseases.

Keywords: Crohn’s disease; bile acid receptors; bile acids; intestinal epithelial tight junction proteins; ulcerative.

Figure 1

Anti-inflammatory effects of TUDCA and UDCA in models of IBD. The enterohepatic circulation of bile acids transports bile acids synthesized and modified in the liver to the intestines through the bile duct. The rate limiting step of hepatic synthesis of bile acids is mediated by the CYP7A1 enzyme which is inhibited by bile acids and ileal FGF15/19. Gut microbes then convert primary bile acids into secondary bile acids. Gut microbial dysbiosis in IBD leads to a reduction in the secondary bile acid pool. Specifically, two key secondary bile acids have been shown to exert anti-inflammatory effects in IBD and relevant models, TUDCA and UDCA. Administration of TUDCA on cell culture and mouse models of IBD aided in bile acid homeostasis by preventing loss of OSTα expression as well as increased FXR and ASBT expression. Furthermore, TUDCA protected against colon shortening, weight loss, and led to improvements in histological score. TUDCA also led to the reduction of pro-inflammatory cytokines IL-1β, TNF, Cxcl2, and IFN-γ as well as decreased apoptotic signaling. Furthermore, TUDCA led to decrease neutrophilic infiltration and activity, as well as general decreases in leukocyte infiltration. Administration of UDCA led to less diarrhea and weight loss as well as decreases in disease activity index and histology score. UDCA also led to decreased apoptotic signaling. Furthermore, UDCA led to decreases in IL-8, TNF-α, and Mad-CAM-1 in the colon, and less IL-17 and IL-23 in the serum of subjects with UC as well as increases in the abundance of Firmicutes and decreases in Proteobacteria.