An Inducible, Large-Intestine-Specific Transgenic Mouse Model for Colitis and Colitis-Induced Colon Cancer Research

Animal models are an important tool to understand intestinal biology. Our laboratory previously generated C57BL/6-Tg(Car1-cre)5Flt transgenic mice (CAC) with large-intestine-specific Cre recombinase (Cre) expression as a model to study colon health. To expand the utility of the CAC mouse model by determining the impact of chemically induced colitis on CAC transgene expression. CAC mice were crossed to Rosa reporter mice (Rosa26R (flox/flox) ) with a lox-STOP-lox signal controlling beta-galactosidase (beta gal) expression and then further crossed with Apc(CKO/CKO) mice in some experiments to delete Apc alleles (Apc (Delta 580) ). Initially, 8-week-old CAC(Tg/WT);Rosa26R (flox/WT) ;Apc (Delta 580/WT) mice were treated with dextran sulfate sodium (DSS) in drinking water (5 days, 0, 0.65, 1.35, or 2.0 %). Colon tissue damage and beta gal labeling were analyzed 10 day after stopping DSS. Next, 8-week-old CAC(Tg/WT);Rosa26R(flox/flox) mice were treated with 0 or 1.35 % DSS, and colonic beta gal labeling was assessed at 30 day post-DSS treatment. Finally, 10-week-old CAC(Tg/WT);Apc (Delta 580/WT) mice were treated with DSS (0 or 2 %) for 5 days and colonic tumors were analyzed at 20 weeks. CAC(Tg/WT);Rosa26R (flox/WT) ;Apc (Delta 580/WT) mice had a DSS dose-dependent increase in colon epithelial damage that correlated with increased epithelial beta gal labeling at 10 days (r (2) = 0.9, beta = 0.75). The beta gal labeling in CAC(Tg/WT);Rosa26R(flox/flox) mice colon remained high at 30 days, especially in the crypts of the healed ulcer. DSS also increased colon tumor incidence and multiplicity in CAC(Tg/WT);Apc (Delta 580/WT) mice. DSS-mediated epithelial damage induces a persistent, Cre-mediated recombination of floxed alleles in CAC mice. This enables the examination of gene function in colon epithelium during experimental colitis and colitis-induced colon cancer.