Nutritional regulation of intestinal development, homeostasis and cancer

Abstract

The intestine functions in the absorption of nutrients and provides a first line of host-defense against pathogens. Nutritional intake has a direct influence on the intestinal epithelial layer and the function and number of different epithelial cell types; stem cells, Paneth cells, goblet cells, and enterocytes, etc. In this thesis, we investigated the influence of different nutritional components on the intestinal epithelial layer. First of all, we showed that acetate aids in intestinal maturation in fetal intestinal organoids. We showed that acetate increased differentiation and stem cell number, thereby inducing intestinal maturation. This may imply that acetate supplementation may benefit preterm infants, preventing malnutrition and the development of intestinal inflammatory diseases. Secondly, we show that the nutrient sensor Farnesoid X Receptor (FXR) inhibits colon tumor organoid proliferation in an isoform dependent manner. In addition, activation of FXR by its ligand changed the organoid morphology towards a differentiated epithelium. Both inhibition of proliferation and induction of differentiation will limit tumor growth, and targeting FXR should therefore be further exploited as therapy for colorectal cancer. Lastly, we identify that cystine restriction increases proliferation and stem cells in the small intestine as well as the number of goblet cells in the colon in mice. These data are important in the light of the current trend towards veganism, in which the diet is very restricted in the amount of cystine. To conclude, understanding nutritional regulation of the intestinal epithelial layer under normal and diseased conditions is essential to explore future treatment and prevention options.