Colitis/IBD

Inflammatory Bowel Disease is a group of idiopathic inflammatory diseases for which there are no cures.

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Crohn’s disease and ulcerative colitis are the main types of IBD, but there are a number of less common disorders that are part of the IBD group, including: Collagenous colitis, lymphocytic colitis, Diversion colitis, Behçet’s disease, and Indeterminate colitis. IBD is an autoimmune disease, and the differentiation between the different forms of the disease is based on the location and nature of the lesions. Although IBD is predominantly a disease of the small and large intestines, other areas of the GI tract may become involved, and even other tissues, particularly those that are involved in other autoimmune inflammatory diseases. The majority of IBD cases are classified as either Crohn’s disease, or ulcerative colitis. Crohn’s disease and ulcerative colitis (UC) are differentiated from each other by their location within the GI tract, the nature of the lesions and the histology of the lesions. Crohn’s disease lesions can occur throughout the tract, the ulcers are non-contiguous appearing as separate lesions in different parts of the GI tract, and are histologically deep, going well beyond the epithelial layer of the gut. In contrast, ulcerative colitis is usually restricted to the colon and rectum, and presents as a single large ulcer, which is histologically restricted to the epithelial cell layer.

While the exact causes of IBD are not known, it does appear that a combination of both environmental and genetic factors are involved. Among the likely environmental factors that have been implicated in the etiology of IBD, the bacteria that compose the gut microflora appear to be the most important. In particular, a decrease in the biodiversity of this gut microflora due to antibiotic treatment has been implicated in the development of IBD, suggesting that certain types of enteric bacteria may be protective against IBD. The genetic contribution to IBD has been difficult to pin down, despite clear familial patterns, particularly in Crohn’s disease. A large number of genes have been identified as being associated with IBD, but these still account for a relatively small percentage of IBD cases. Many of the genes that have been identified appear to be involved in cytokine production, which would imply that they are involved in the regulation of the immune system in the disease process. The diagnosis of IBD is almost always confirmed by colonoscopy.

Both Crohn’s disease and ulcerative colitis are often treated surgically. In the case of ulcerative colitis, the entire large intestine can be removed, thereby preventing further disease. For patients with Crohn’s disease, the worst affected regions of the small intestine can be surgically removed, but the disease will recur in the remaining tissue. Treatment with chemotherapy is highly individualized for each patient. 5-aminosalicylic acid (mesalazine, mesalamine) is useful for some patients, particularly for patients with UC. Patients with Crohn’s disease are more likely to need more immunosuppressive chemotherapy, whether in the form of steroids (prednisolone, budesonide), TNF-α inhibitors (Remicade), or cytotoxics (methotrexate, mercaptopurine).

Animal Models of Inflammatory Bowel Disease

The animal models of IBD fall into two main groups – chemically induced disease and genetically engineered mice. The genetically engineered models are typically mice that have had one or more cytokine or other immune-regulatory gene rendered inactive (“knocked-out”). In the absence of the genes involved, the mice lack adequate immune regulation and are more susceptible to IBD. The best known model in this category is the IL-10 knockout. The chemically induced models of colitis/IBD can be induced either by the direct application of a small molecule known as a hapten directly to the large intestine, or through the addition of certain compounds to the drinking water.

Once applied, the haptens elicit vigorous and rapid immune responses from the mice. The most commonly used compounds in this category are trinitrobenzoylsulfonic acid (TNBS), and oxazolone. The other commonly used model of colitis involves the addition of dextran sulfate, sodium (DSS) to the drinking water for 5 days. This model results in the inflammation of the large intestine over a period of 5-15 days, and can be extended by subsequent rounds of treatment with DSS, creating a chronic condition, which more closely resembles the clinical pattern of IBD.

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