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Inhibiting dipeptidyl peptidase activity partially ameliorates colitis in mice
Roger Yazbeck1, Gordon S Howarth, Mark S Geier
1School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia.
Abstract:
New treatment strategies are required for the debilitating inflammatory bowel diseases (IBD), Crohn's Disease and Ulcerative Colitis. DP inhibitors can prolong the bioactivity of the potent intestinotrophic growth factor glucagon-like peptide-2 (GLP-2(1-33)). We investigated whether novel inhibitors of DP activity could modify the course of disease activity in the dextran sulfate sodium (DSS) model of colitis. C57BL/6 mice consumed 2 percent DSS in drinking water for 6 days. Mice were orally gavaged twice daily with 0.9% saline, 10 mg/kg isoleucyl-cyano-pyrrolidine (P59/99) or isoleucyl-thiazolidine (P32/98). Assessment of disease severity incorporated a disease activity index (DAI), together with histological assessment of crypt area and depth in the distal colon. DP activity was significantly inhibited at all time points. The DAI was significantly lower in the P59/99 and P32/98 treatment groups compared to saline treatment in all three time courses. Crypt hyperplasia (p<0.05) was observed in the saline group compared to P32/98 treatment at day 9. This preliminary study shows that novel inhibitors of DP activity may provide a new treatment strategy for IBD.
Insights
Novel dipeptidyl peptidase (DP) inhibitors show promise for treating inflammatory bowel diseases (IBD). These DP inhibitors reduced disease activity and colonic crypt hyperplasia in a mouse model, suggesting a new therapeutic avenue for IBD.
Area of Science:
- Gastroenterology
- Pharmacology
Background:
- Inflammatory bowel diseases (IBD), including Crohn's Disease and Ulcerative Colitis, require novel therapeutic strategies.
- Dipeptidyl peptidase (DP) inhibitors can extend the biological activity of glucagon-like peptide-2 (GLP-2), a growth factor beneficial for the intestine.
Purpose of the Study:
- To investigate the efficacy of novel DP inhibitors in mitigating disease activity within the dextran sulfate sodium (DSS)-induced mouse model of colitis.
- To assess the impact of DP inhibition on colonic histology and disease severity markers.
Main Methods:
- C57BL/6 mice were administered 2% DSS in drinking water for 6 days to induce colitis.
- Mice received twice-daily oral gavage of saline, isoleucyl-cyano-pyrrolidine (P59/99), or isoleucyl-thiazolidine (P32/98).
- Disease severity was evaluated using a disease activity index (DAI) and histological analysis of distal colon crypts.
Main Results:
- DP activity was significantly inhibited by both P59/99 and P32/98 treatments across all measured time points.
- The DAI was significantly reduced in mice treated with P59/99 or P32/98 compared to the saline control group.
- Histological examination revealed reduced crypt hyperplasia in the P32/98 treatment group compared to saline controls at day 9.
Conclusions:
- Novel DP inhibitors demonstrate potential as a therapeutic approach for managing inflammatory bowel diseases.
- These findings suggest that inhibiting DP activity can ameliorate key pathological features of colitis in a preclinical model.
- Further research into DP inhibitors could lead to new treatments for IBD patients.
