Bile acids regulate colonic epithelial barrier function: implications for pathogenesis and therapy of inflammatory bowel disease
Although inflammatory bowel disease (IBD) represents a significant health and economic burden to Western society, current therapeutic approaches often lack efficacy and can have severe side effects. While much progress has been made in the past 2 decades towards understanding its pathogenesis and diagnosis, there is still a significant need for new, safe and targeted therapies to treat IBD. Bile acids are classically known for their roles in digestion and absorption of dietary lipids but, more recently, they have become recognised as hormones that regulate many aspects of intestinal physiology. In particular, while secondary bile acids, such as deoxycholic acid (DCA), have been implicated in pathogenesis of IBD, the cytoprotective and anti-inflammatory effects of ursodeoxycholic acid (UDCA) suggest it may be of therapeutic benefit. Mucosal wound healing and secretion of inflammation-inducing human β-defensins (HβDs) are important aspects of intestinal barrier function that are dysregulated in IBD. This thesis set out to investigate the effects of DCA and UDCA on these processes. Our studies show that DCA stimulates HβD release from colonic epithelial cells and human colonic tissues in vitro. Moreover, we found DCA to inhibit restitution in a model of wounded colonic epithelial cells. In contrast, UDCA attenuates DCA-induced effects on HβDs and restitution and exerts protective effects in a chemically-induced model of mucosal inflammation. Taken together, these data suggest that high concentrations of colonic DCA are likely to dysregulate barrier function and contribute to disease progression in IBD, while UDCA appears to have therapeutic properties. Data presented in this thesis contribute to our understanding of the importance of bile acids in regulating intestinal barrier function, provide new insights into the molecular pathways involved, and may lead to the identification of new therapeutic targets for effective treatment of patients suffering from IBD.