The exact cause of inflammatory bowel disease is unknown, and the breakdown of the intestinal barrier causes the leaky gut syndrome. Hypoxia-inducing factors (HIF) and aryl hydrocarbon receptors (AhR) are known to be important factors in maintaining intestinal barrier homeostasis. Organoids and animal models were used to study the effects of HIF and AhR on the intestinal barrier. Stabilizing of HIF increased cell proliferation and increased junctional molecule expression. Organoid size and budding were increased. Barrier integrity in mice was no change after stabilizing of HIF. AhR deficient organoid was generated from the small intestine of AhR deficient mice. Depletion of aryl hydrocarbon receptors resulted in increased cell proliferation and altered intestinal permeability. Immunofluorescence staining showed increased size and budding. AhR deficient intestine had increased permeability, serum endotoxin, and bacterial translocation compared with wild type intestine. Stabilization of HIF in AhR deficient organoids restored intestinal permeability. AhR deficient mice treated with HIF stabilizer decreased endotoxin concentrations and bacterial translocation. Therefore, the increased intestinal permeability due to AhR deficiency can be restored by stabilization of HIF. This has the potential to contribute to the treatment of patients with inflammatory bowel disease and colorectal cancer.
