Modification of the dextran sodium sulfate model to identify agents that induce or exacerbate inflammatory bowel disease.

Abstract

Exposure to environmental agents has been linked to inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD) in humans. In these studies, we describe a modification of an experimental model used historically in the pharmaceutical industry to help identify therapies for the treatment of IBD to facilitate its use for identification of environmental agents that have the potential to accelerate, exacerbate, and/or impair recovery from IBD. In this model, female C57BL/6 mice were exposed to low levels of dextran sodium sulfate (DSS) for 7 consecutive days in drinking water to allow for a modest level of colon inflammation and pathology as measured by a battery of clinical, pathological, toxicological endpoints (water consumption, body weights, colon length, body temperature, stool consistency, and hematochezia), and cytokine/chemokine production in the serum and colon. Treatment with DSS for 7 d showed a clear dose-response with 1% DSS producing minimal changes in the colon and 3% DSS inducing severe damage with IBD. A concentration of 2% DSS in drinking water for 7 d was selected for investigating disease recovery and exacerbation by an environmental agent as it induced mild colon inflammation that showed nearly complete resolution within 21 d following cessation of DSS exposure. Cytokine and chemokine profiles showed a Type 1 predominant immune response in the colon and serum that is consistent with inflammation observed in human IBD. The model was used to determine the impact of administration of a high salt diet (HSD) on DSS IBD progression, severity, and recovery. While administration of HSD by itself had no effect on indicators of colon damage or inflammation, co-administration of HSD with DSS, produced marked exacerbation and persistence of disease supporting the potential of the model for identifying environmental agents that can affect IBD.