Inflammatory bowel disease is a general term used to describe a group of chronic inflammatory disorders of the gastrointestinal tract. The two major clinical entities are ulcerative colitis and Crohn's disease. The two major clinical entities are ulcerative colitis and Crohn's disease. Clinically ulcerative colitis is confined to the large intestine, whereas Crohn's disease may affect any part of the gastrointestinal tract. The Crohn'S & Colitis Foundation of America estimates that about two million Americans suffer from inflammatory bowel disease, 300,000 of them in the pediatric age group. Despite traditional medical therapy, inflammatory bowel disease in children results in significant morbidity such as chronic abdominal pain, rectal bleeding, anemia, weight loss and growth stunt. While active investigation has yet to discover what causes inflammatory bowel disease, it is believed than an inappropriate host immune response to antigens (bacteria or flood) normally found in the gastrointestinal tract results in a state of chronic inflammation. It has been difficult to investigate the relationship between luminal bacteria and immune dysregulation due to the lack of a colitis model induced by a single well-defined organism. Infection of the normally abiotic mouse stomach with Helicobacter and Lactobacillus species provides an excellent model for the investigation of bacteria-associated chronic inflammation of the gastrointestinal mucosa. We have developed several murine models in which various bacterial species, that are either normally non pathogenic or are only mildly pathogenic, can induce a state of chronic mucosal inflammation. The inflammatory response can be generated either by deleting or adding various immunoregulatory cytokines, or by systemically immunizing mice prior to infection. Of particular importance is the observation that the mucosal inflammation is maintained even when organisms are no longer detectable by microbiological and molecular techniques. Using these models we will test the central hypotheses that chronic gastrointestinal inflammation results from an aberrant immune response to antigenic stimulus, consisting of normal gastrointestinal bacteria. We propose to investigate the relationship between mucosal bacteria and immune regulation in the early, intermediate and late stages of chronic mucosal inflammation using our unique models of gastric Helicobacter and Lactobacillus infection.
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