The etiology of IBD is unknown, but both genetic and environmental factors are involved. In the current funding period of this grant experimentally-induced and genetically engineered rodent models have been used to provide convincing evidence that the normal endogenous enteric bacterial flora is essential to the development of chronic colitis, gastritis and arthritis in genetically susceptible rodents. Very importantly, the use of HLA-B27/beta2 transgenic (TG) rats has demonstrated that all components of the resident bacterial flora are not equal in their capacity to induce inflammation: some are aggressive (B. vulgatus), some are neutral (E. coli) and some are protective (Lactobacillus sp). B. vulgatus from several sources causes more aggressive colitis in B27 TG rats than B. distasonis isolated from normal rats. Chronic intestinal inflammation in these models is mediated by activated T lymphocytes which are induced by normal luminal bacteria. These data support the hypothesis that chronic intestinal inflammation in genetically susceptible hosts is the result of an overly aggressive cellular immune response to a subset of ubiquitous luminal bacterial constituents. Genetic susceptibility is determined by defective downregulation of inflammatory responses or defective mucosal barrier function. This clinically relevant hypothesis will be tested by the following specific aims: 1) determine mechanisms by which B. vulgatus selectively induces colitis in HLA-B27 TG rats; 2) identify the mechanisms of immunologically determined susceptibility to B. vulgatus and other resident enteric bacterial components in HLA-B27 TG rats versus nontransgenic littermates. A NIH-funded Core Center for Gastrointestinal Biology and Disease at UNC supports a barrier-intact gnotobiotic rodent facility, providing the investigators with a unique environment to selectively colonize germ-free rats with defined luminal bacterial species. These studies will generate novel insights into the pathogenesis of IBD and open new opportunities for novel therapeutic interventions to block induction of antigen-specific immune response to luminal bacteria.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Sartor, R B (2011) Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation. Mucosal Immunol 4:127-32
Packey, Christopher D; Sartor, R Balfour (2009) Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis 22:292-301
Bleich, A; Hopf, S; Hedrich, H J et al. (2009) Genetic dissection of granulomatous enterocolitis and arthritis in the intramural peptidoglycan-polysaccharide-treated rat model of IBD. Inflamm Bowel Dis 15:1794-802
Qian, Bi-Feng; Tonkonogy, Susan L; Sartor, R Balfour (2008) Reduced responsiveness of HLA-B27 transgenic rat cells to TGF-beta and IL-10-mediated regulation of IFN-gamma production. Inflamm Bowel Dis 14:921-30
Qian, Bi-Feng; Tonkonogy, Susan L; Sartor, R Balfour (2008) Aberrant innate immune responses in TLR-ligand activated HLA-B27 transgenic rat cells. Inflamm Bowel Dis 14:1358-65
Sartor, R Balfour (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134:577-94
Sartor, R Balfour; Muehlbauer, Marcus (2007) Microbial host interactions in IBD: implications for pathogenesis and therapy. Curr Gastroenterol Rep 9:497-507
Hoentjen, Frank; Tonkonogy, Susan L; Qian, Bi-Feng et al. (2007) CD4(+) T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus. Inflamm Bowel Dis 13:317-24
Balfour Sartor, R (2007) Bacteria in Crohn's disease: mechanisms of inflammation and therapeutic implications. J Clin Gastroenterol 41:S37-43
Qian, Bi-Feng; Tonkonogy, Susan L; Balfour Sartor, R (2006) Luminal bacterial antigen-specific CD4+ T-cell responses in HLA-B27 transgenic rats with chronic colitis are mediated by both major histocompatibility class II and HLA-B27 molecules. Immunology 117:319-28

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