Functional roles of the AhR in the intestine
In recent years studies of AhR deficient mice have revealed a range of physiological AhR functions, mainly in barrier organs such as the skin, lung and intestine.
The role of the AhR in the intestine is complex, affecting haematopoietic cells as well as epithelium and involving interactions with the microbiota as well as dietary components both of which are sources for AhR ligands, which are essential to maintain intestinal homeostasis. AhR deficient mice lack important immune cells that support barrier protection in the intestine and are vulnerable to intestinal infections as well as prone to develop caecal and colonic tumours. It appears that chronic underlying inflammation in AhR deficient mice facilitates tumour development, particularly under conventional housing conditions, but baseline susceptibility is present even under SPF conditions.
Our aim is to dissect the pathways of AhR interactions in the intestine using the Cre lox system to restrict AhR deficiency to particular cell types that express AhR. We will particularly focus on mice in which AhR is deleted selectively in intestinal cells in steady state as well as during infection with Citrobacter rodentium, an infection that targets the colon and is known to promote tumour formation in genetically susceptible mice. We are culturing organoids to study epithelial cell development in the absence or presence of AhR and modulate the AhR pathway with ligands such as dietary components (eg. I3C) or tryptophan metabolites and with antagonists such as CH223181 aim to identify the molecular pathways that are influenced by AhR in epithelial cells and could be linked to promotion or prevention of tumorigenesis.