Regulation of colonic epithelial function by the nuclear bile acid receptor, farnesoid X receptor

Bile acids, classically known for their role in lipid digestion, are now recognised as important signalling hormones that influence many aspects of intestinal epithelial function. The nuclear bile acid receptor, farnesoid X receptor (FXR), is now appreciated not only as a master regulator of bile acid homeostasis, but also as a ligand-activated transcription factor with a wide range of biological effects. Since its discovery, our understanding of the role that FXR plays in preventing the onset and progression of intestinal disease has grown exponentially. Despite this, there are still no FXR-targeted therapeutics approved for use in these conditions. Interestingly, dietary phytochemicals, including pentacyclic triterpenes (PCTs) and polyunsaturated fatty acids (PUFAs), have been reported to modulate FXR signalling, which may be of therapeutic relevance. The primary goal of this thesis was to investigate the role of FXR in regulating colonic epithelial function and the potential for targeting the receptor with dietary phytochemicals. These studies show that FXR regulates the expression of the cystic fibrosis transmembrane conductance regulator (CFTR), a transmembrane Cl- channel important in regulating fluid and electrolyte secretion, through mechanisms that may involve transcription factors such as NF-κB and direct binding of FXR to the CFTR promoter. Moreover, we found that dietary phytochemicals, acting via peroxisome proliferator-activated receptors (PPARs), can upregulate FXR expression and enhance its activation, with potential implications for diarrhoeal disease. Furthermore, we report a possible role for FXR in protecting against COVID-19 associated intestinal inflammation through its effects in inhibiting pro-inflammatory cytokine release and modulating ACE2 expression. Data presented in this thesis contributes to our understanding of the importance of FXR in regulating colonic epithelial function and suggests that by virtue of their ability to modulate FXR expression, dietary phytochemicals have potential to be developed as FXR-targeted nutraceuticals for the treatment and prevention of intestinal disease.