Compositions and Methods for the Treatment and Prevention of Ulcerative Colitis and Colon Cancer and Screening Methods to Identify Same

This invention provides methods of treating and/or preventing ulcerative colitis and colon cancer as well methods of identifying agents that treat and prevent the same.

Technology Overview

Bacteria colonize the intestinal lumen in a mutually beneficial manner, enabling digestion and extraction of energy and nutrients from food, while also suppressing pathogenic bacterial species. Mucosal inflammation is precluded in healthy individuals by the presence of an intestinal epithelial cell barrier, which protects the mucosa from bacterial and other luminal stimuli. However, this boundary is breached in certain individuals, causing persistent intestinal inflammation that results in inflammatory bowel disease, Crohn’s disease and ulcerative colitis. Hence, identifying the factors that regulate the development of colitis and the complex host-commensal relationships in the intestine is of vital importance.

Researchers in the Glimcher lab have determined that T-bet (a T-cell associated transcription factor) deficiency in the innate immune system results in or increases the susceptibility to aggressive, spontaneous and communicable ulcerative colitis. T-bet controls the response of the mucosal immune system to commensal bacteria by regulating TNF-α production which is involved in the maintenance of the colonic epithelial barrier. With the loss of T-bet, the intestinal commensal bacterial population becomes colitogenic.

This invention provides methods for evaluating the ability of a test compound to modulate spontaneous ulcerative colitis by administering the test compound to a transgenic mouse that has homozygous null mutations in T-bet and Rag2 genes. These compounds are analyzed for their ability to modulate permeability of the colonic epithelium, apoptosis in the colonic epithelium or colonic wall thickening associated with prolapsed rectal mucosa. The inventors also found that the presence of Klebsiella pneumonia and Proteus mirabilis in such mice correlates with colitis.

Potential Applications

• Treatment and/or prevention of ulcerative colitis and colon cancer
• Prevention of colonization of colitogenic bacteria
• Generation of metabolic profiles from animals that have or are at risk of developing ulcerative colitis or colorectal cancer for research purposes
• Advantages

This invention is useful for screening compounds to readily identify those that can modulate several key factors involved in the pathophysiology of intestinal inflammatory diseases.