Colonic Gene Expression Patterns of Mucin Muc2 Knockout Mice Reveal Various Phases in Colitis Development

Background: Mucin Muc2 knockout (Muc2(-/-)) mice spontaneously develop colitis. Methods: To identify genes and biological responses which play a pivotal role during colitis development in Muc2(-/-) mice, gene expression profiles of colonic tissues from 2-and 4-week-old Muc2(-/-) and wildtype mice were determined using microarrays. Results: The majority of highly upregulated genes in 2-week-old as well as 4-week-old Muc2(-/-) mice were primarily involved in immune responses related to antigen processing/presentation, B-cell and T-cell receptor signaling, leukocyte transendothelial migration, and Jak-STAT signaling. Specifically, Muc2(-/-) mice expressed high levels of immunoglobulins, murine histocompatibility-2, proinflammatory cytokines, chemokines, and antimicrobial proteins. Additionally, in 4-week-old Muc2(-/-) mice, expression of genes involved in cell structure related pathways was significantly altered. Particularly, the tight junction-associated gene claudin-10 was upregulated, whereas claudin-1 and claudin-5 were down-regulated. Furthermore, 4-week-old Muc2(-/-) mice showed increased expression of genes regulating cell growth in conjunction with increased crypt length and increased epithelial proliferation. Conclusions: Muc2-deficiency leads to an active inflammatory response in 2-and 4-week-old Muc2(-/-) mice as demonstrated by the altered expression in immune response related genes. In addition, 4-week-old Muc2(-/-) mice also showed a decrease in epithelial barrier function and an increase in epithelial proliferation as indicated by, respectively, the altered expression in tight junction-related genes and upregulation of genes stimulating cell growth. Remarkably, upregulation of genes stimulating cell growth correlated with increased crypt length and increased epithelial proliferation in 4-week-old Muc2(-/-) mice. Together, these data demonstrate that there are distinct phases in colitis development in 2-4-week-old Muc2(-/-) mice.