| The inflammatory bowel diseases, ulcerative colitis and Crohn's disease are common ailments in found in modern society. There is currently no medical cure for inflammatory bowel diseases, and treatment is given with the goal of remission of inflammatory bowel disease symptoms and improving patient quality of life. Surgical intervention is an option for patients in severe cases of inflammatory bowel disease, and may be curative for patients with ulcerative colitis but not for patients with Crohn's disease. Current treatment options available include 5-aminosalicylic acid drugs, corticosteroids, anti-tumor necrosis factor-? biologics, and antibiotics. To improve the efficacy of therapeutic options available to patients, it is necessary to develop novel treatments for inflammatory bowel diseases with reduced toxicity. When the inflammatory sequelae associated with inflammatory bowel diseases is left untreated, patients may experience significant morbidity and may become susceptible to developing colorectal cancer. Recent work with Yersinia enterocolitica has demonstrated the efficacy of using a bacterial treatment which expresses the adhesin invasin to activate the nod-like receptor family, pyrin domain-containing 3 inflammasome. This allows for expression of the immunomodulatory cytokine interleukin-18, which has shown to be protective against colitis and development of colitis associated colorectal cancer using a murine model. We propose that by administering an invasin expressing bacterial treatment to mice, the mice will demonstrate decreased inflammatory sequelae in colitis and colitis associated colorectal cancer models. This study compares the effects of dosing schemes and experimental treatment protocols using bacteria expressing invasin in a dextran sodium sulfate induced acute and chronic colitis models, and azoxymethane/dextran sodium sulfate induced colitis associated cancer models. Treatment with bacteria expressing invasin decreased morbidity and inflammatory sequelae in wildtype mice in acute colitis and colitis associated colorectal cancer models. Mice deficient in the nod-like receptor family, pyrin domain-containing 3 inflammasome also has decreased morbidity in acute colitis and colitis associated cancer models, regardless of treatment. Whereas, mice deficient in the interleukin 18 receptor had increased morbidity in acute and colitis associated colorectal cancer models. In a chronic colitis model, no differences were observed between dosing schemes of treatment with bacteria expressing invasin in wildtype mice. The results of this study will prove useful in further understanding the effects invasion expressing bacteria has on activation of the nod-like receptor family, pyrin domain-containing 3 inflammasome and the ability of interleukin-18 expression to be beneficial in the outcome of colitis and colorectal cancer models. |
