Multifunctional role of dextran sulfate sodium for in vivo modeling of intestinal diseases

Abstract

BackgroundInflammatory bowel diseases (IBDs) are chronic, relapsing disorders that affect the gastrointestinal tract of millions of people and continue to increase in incidence each year. While several factors have been associated with development of IBDs, the exact etiology is unknown. Research using animal models of IBDs is beginning to provide insights into how the different factors contribute to disease development. Oral administration of dextran sulfate sodium (DSS) to mice induces a reproducible experimental colitis that models several intestinal lesions associated with IBDs. The murine DSS colitis model can also be adapted to quantify intestinal repair following injury. Understanding the mechanistic basis behind intestinal repair is critical to development of new therapeutics for IBDs because of their chronic relapsing nature.ResultsThe murine DSS colitis model was adapted to provide a system enabling the quantification of severe intestinal injury with impaired wound healing or mild intestinal injury with rapid restoration of mucosal integrity, by altering DSS concentrations and including a recovery phase. We showed that through a novel format for presentation of the clinical disease data, the temporal progression of intestinal lesions can be quantified on an individual mouse basis. Additionally, parameters for quantification of DSS-induced alterations in epithelial cell populations are included to provide insights into mechanisms underlying the development of these lesions. For example, the use of the two different model systems showed that toll-like receptor 9, a nucleic acid-sensing pattern recognition receptor, is important for protection only following mild intestinal damage and suggests that this model is superior for identifying proteins necessary for intestinal repair.ConclusionsWe showed that using a murine DSS-induced experimental colitis model system, and presenting data in a longitudinal manner on a per mouse basis, enhanced the usefulness of this model, and provided novel insights into the role of an innate immune receptor in intestinal repair. By elucidating the mechanistic basis of intestinal injury and repair, we can begin to understand the etiology of IBDs, enabling development of novel therapeutics or prophylactics.

The Role of CXCR3 in DSS-Induced Colitis

“…Neovascularisation is a key pathological feature of human IBD [29], however DSS-associated neovascularisation was previously shown to be associated with repair and re-epithelialisation [30]. Consistent with this, we showed an increase in CD31 + staining in DSS challenged KO mice (Figure 1f), consistent with reduced histopathological scoring in this group.…”

Local immune compartments are related to the severity of dextran sodium sulphate induced colitis

“…These tissue changes were milder in mice treated with 1% DSS ( Figure 1C). Thus, we demonstrated that higher concentrations of DSS induced more severe and irreversible intestinal injury, which is consistent with a previous study (20). Thus, we asked whether the severity of disease related to pro-inflammatory cytokines, including IL-6, and TNF-α, which are directly involved in the pathogenesis of UC (4,5).…”

The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis

“…The mice were allowed to recover by removing DSS from their drinking water, yielding a period that bears resemblance to the remission period in IBD patients [33]. Analysis of clinical symptoms revealed that WT mice showed significantly faster decrease in faecal blood indices (figure 4a) and watery stool consistency (figure 4b) compared with ZnR/GPR39 KO mice, although both genotypes continued to lose weight even following the removal of DSS (figure 4c).…”