Inflammatory bowel diseases are chronic and progressive inflammatory disorders that affect more than 1.4 million Americans. There is currently no cure for IBD, and over two-thirds of IBD patients become refractory to treatment with traditional therapies at some point in their lives and require surgical bowel resection. IBD i driven by inappropriate immune responses to the intestinal microbiota, which consists of trillions of bacteria that constitutively colonize the human intestine. The human gut microbiota shows considerable interindividual complexity and diversity with each person displaying a unique consortium of hundreds of bacterial species. Studies in mouse models of IBD have shown that select members of the microbiota have dramatic effects on colitis: some species exacerbate colitis by driving chronic inflammatory responses, while others protect against colitis by inducing immunoregulatory responses. However, identifying the specific gut bacteria that influence IBD development, progression and severity in humans has remained challenging for two reasons: 1) an inability to distinguish bacterial species that influence disease susceptibility from the remaining members of the intestinal microbiota; and 2) difficulties in establishing experimental systems to directly test the effects of isolated human gut bacteria on disease. I recently conceived and developed a new approach to this problem that uses the host's own Immunoglobulin A response to the microbiota as a `tag' to identify putative immunomodulatory gut bacteria in humans. This strategy was used to identify members of the human gut microbiota from patients with IBD that could confer susceptibility to colitis when transferred into germ-free mice; thus, this approach identifies colitogenic bacteria in IBD. However, the effects of these bacteria on T helper cells, which are the major drivers of pathology in human IBD, remain untested. Therefore, in the following studies, I will use the novel and innovative systems that I have recently established in order to determine the effects of specific putative immunomodulatory human gut microbes from humans on intestinal T cell differentiation and T cell-dependent colitis. In particular, I will: 1) determine the effects of putative inflammatory gu bacteria isolated from IBD patients on intestinal T cell differentiation and colitis; and 2) test te effects of putative immunoregulatory gut bacteria isolated from healthy humans on intestinal T cell differentiation and colitis. These studies will reveal the roles of specific members of the human gut microbiota in health and disease and identify new targets for the treatment and prevention of IBD.
Inflammatory Bowel Diseases (IBDs) are chronic inflammatory diseases of the intestine that affect more than 1.4 million Americans and for which there are currently no cures. The trillions of bacteria that constitutively inhabit the human intestine play a critical role in the initiation and progression of IBD. This proposal aims to idenify the particular human gut bacteria that are responsible for driving or preventing IBD and, in so doing, identify new targets for the treatment and prevention of IBD.
