The delayed manifestation of the clinical symptoms related to the colonic disease indicates that loss of Hnf4a involves complex mechanistically interactions that ultimately lead to the development of the disease. The pathogenesis of IBD is complex and involves susceptibility genes, the epithelial barrier function, innate and adaptive immunity and environmental factors including Chloroxylenol bacteria. The only premature defect we were able to identify in the colon of Hnf4a null mice was a decline in ion transport. We propose that rapid down-modulation of Hnf4adependent transcriptional targets such as Cldn15 can cause defects in epithelialion transport ultimately leading to histopathological changes resembling those seen in patients with IBD. Hnf4a was recently reported to be required in colon epithelial cells to protect against dextran sodium sulphate, a commonly used model of acute intestinal injury that does not result in chronic inflammatory disease. The Muc3 gene, a transcriptional target of Hnf4a, was reported to be downmodulated in young adult Hnf4a colon null mice and was proposed to account for the Hnf4a protective effect. This specific transmembrane mucin is localized both in absorptive and goblet cells and can reduce mucosal ulceration and apoptosis in experimental acute colitis. Thus reduction in Muc3 could be partly involved in the long term spontaneous disease of Hnf4a colon null mice. However and in contrast to Ahn et al., we observed that goblet cell maturation was not significantly altered in young adult Hnf4a colon mutant mice and that the Muc2 gene transcript was only decreased in later stages, in association with the depletion of goblet cells in hyperplasic crypts. The results suggest the latter is not a primary event in the initiation of the disease but rather a consequence of progression of colonic inflammation. Colonic goblet cell maturation was reported to be altered in embryonic Hnf4a colon mutant mice with the use of another mouse conditional knockout system. The precise SR3335 window of time in which intestinal Hnf4a was altered differs in our study, as compared to what had been previously reported.