Bacteroides fragilis are common colonic commensals, known to occupy a mucosal niche in the colon and the leading anaerobe in human disease. One class of B. fragilis, enterotoxigenic Bacteroides fragilis (ETBF), is recently recognized as an etiology of inflammatory diarrheal disease and may incite active inflammatory bowel disease. Up to 30% of individuals, however, may be colonized, seemingly asymptomatically, with ETBF. The primary virulence factor of ETBF is a 20 kDa zinc-dependent metalloprotease toxin termed B. fragilis toxin (BFT). Our new ETBF-infected conventional C57BL/6 mouse model reveals that mice colonized with ETBF develop rapid onset symptomatic colitis (within 3 days) with marked colitis at 1 to 2 weeks. The colonic inflammatory infiltrates at 1 week are composed of increased CD4+ T cells that produce interleukin-17 (IL-17) but not ?-interferon or IL-4. Both the colonic epithelial cells and a subset of mucosal inflammatory cells display phosphorylated signal transducer and activator of transcription-3 (Stat3). Over time ETBF acute colitis subsides yielding chronic colitis that persists at least 8 months. Using matched isogenic B. fragilis strains differing only in their secretion of biologically active BFT, the colitis can be ascribed, at least in part, to BFT. In vitro BFT increases intestinal epithelial permeability at least, in part, by cleavage of the zonula adherens protein, E-cadherin, and activates Nuclear Factor-?B signaling resulting in secretion of the proinflammatory cytokine, interleukin-8. Our data support the hypothesis that ETBF colonization stimulates acute colitis mediated by induction of innate responses that direct adaptive responses along a Th17 pathway dependent on Stat3 signaling. We postulate that ETBF induce a continuum of human pathology from `asymptomatic'colonization, potentially associated with colonic hyperplasia and inflammation (precursor conditions to neoplastic transformation), to inflammatory diarrhea and colitis. The goals of this proposal are to identify the innate and adaptive host immune mechanisms associated with initiation and persistence of ETBF-induced colitis in C57BL/6 mice. We will define the contribution of Th17 effector cells and Stat signaling to the inflammatory response in ETBF-induced colitis. Our results allow us to use a common human colonic bacterium, ETBF, to begin to understand the newly recognized Th17-dependent colonic inflammation, potentially providing insights into therapeutic approaches for a common clinical problem, colitis.

Public Health Relevance

Colonic inflammation (colitis) contributes to a large burden of disease including two major public health concerns. The first is infectious diarrheal diseases, a global cause of morbidity and mortality that is associated with malnutrition and delayed cognitive development in children;and the second is colorectal cancer, the second leading cause of cancer-related mortality in the United States. Understanding colonic inflammation may also help in identifying treatments for individuals afflicted by inflammatory bowel disease (Crohn's disease and ulcerative colitis) and irritable bowel syndrome, an illness disproportionately affecting women.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Grey, Michael J
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Johns Hopkins University
Internal Medicine/Medicine
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United States
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Chung, Liam; Thiele Orberg, Erik; Geis, Abby L et al. (2018) Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells. Cell Host Microbe 23:203-214.e5
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Geis, Abby L; Housseau, Franck (2016) Procarcinogenic regulatory T cells in microbial-induced colon cancer. Oncoimmunology 5:e1118601
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Dejea, Christine; Wick, Elizabeth; Sears, Cynthia L (2013) Bacterial oncogenesis in the colon. Future Microbiol 8:445-60
Sears, Cynthia L (2012) In celebration of Sydney M. Finegold, M.D.: bacteroides fragilis in the colon: the good & the bad. Anaerobe 18:192-6
Wick, Elizabeth C; LeBlanc, Robert E; Ortega, Guillermo et al. (2012) Shift from pStat6 to pStat3 predominance is associated with inflammatory bowel disease-associated dysplasia. Inflamm Bowel Dis 18:1267-74
Goodwin, Andrew C; Destefano Shields, Christina E; Wu, Shaoguang et al. (2011) Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci U S A 108:15354-9

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