Importantly, given that we did not observe spontaneous colitis following acute CLDN23 downregulation in vivo, it is possible that the lack of IEC CLDN23 expression may come into play in the presence of a “second hit.” Previous studies have shown that unchallenged mice harboring IEC-specific Cldn2 overexpression as well as knockout of Desmocollin-2, Junctional Adhesion Molecule-A, or non-muscle myosin IIA displayed increased mucosal permeability without the development of colitis due to adaptive protective mechanisms77,89–91. The gene discussed is CLDN2; the disease is colitis.