The role of bile acids and their receptors in regulation of colonic epithelial function: novel targets for the treatment of intestinal disease

<p dir="ltr">Bile acids, classically known for their roles in facilitating lipid digestion and absorption, are now recognised as a family of hormones that are important in regulating intestinal transport and barrier function. Bile acid receptors, such as the farnesoid X receptor (FXR) and the vitamin D receptor (VDR), are important in mediating such regulatory actions, and have been shown to exert beneficial actions on intestinal epithelial function. However, before we can hope to effectively target bile acids and their receptors for therapeutic purposes, a more complete understanding of the cellular and molecular mechanisms by which they regulate colonic epithelial function in health and disease is still required. Thus, the primary objectives of this thesis were to further our understanding of how bile acids and their receptors regulate colonic epithelial transport and barrier function, and to investigate how we might target them for disease treatment. Studies were conducted primarily using polarised monolayers of T₈₄ cells as a reductionist model of the colonic epithelium. Data presented reveal, for the first time, an anti-secretory role for physiologically-relevant concentrations of the secondary bile acid, lithocholic acid, that appear to be mediated through FXR-induced downregulation of transport proteins that comprise the Cl^- secretory pathway. Additionally, we have demonstrated a new role for FXR in inhibiting cytokine-induced necroptosis, an effect that may contribute to its barrier promoting actions in conditions of intestinal inflammation. While these findings highlight the potential for targeting bile acids and their receptors in treatment of intestinal disease, further studies investigate how we might utilise bile salt hydrolase-expressing probiotics for this purpose. In summary, this thesis increases our understanding of the cellular and molecular mechanisms by which bile acids and their receptors regulate colonic epithelial transport and barrier function and how we might ultimately target such pathways in treatment and prevention of intestinal disease.</p>