Experimental models of colitis have shown that the microbiota plays a crucial role in disease, in that the mice develop colitis with a conventional microbiota but fail to develop intestinal inflammation when housed under germfree conditions. However, the signaling pathways by which the microbiota promotes colitis and the commensal bacteria that elicit inflammation in the intestine remain poorly understood. A major innate signaling pathway that can be activated by bacteria is the inflammasome, a multi-protein platform that activates caspase-1 leading to the proteolytic processing of pro-IL-1? and the release of IL-1?. The cytokine IL-1? is important for the regulation of innate and adaptive immune responses in colitis models including those induced by pathogenic organisms. Furthermore, IL-1? production by intestinal cells is associated with lesional disease activity in IBD patients, suggesting an important role for this cytokine in disease pathogenesis. However, the signaling pathways by which the microbiota promotes IL-1? production and the commensal bacteria that elicit IL-1? release in the intestine remain poorly understood. We find that the indigenous microbiota triggers activation of the NLRP3 inflammasome. Remarkably, selective members of the Enterobacteriaceae family and in particular Proteus mirabilis induce rapid and robust activation of the NLRP3 inflammasome and IL-1? release in vitro and in vivo. Importantly, intestinal colonization with P. mirabillis enhanced colitis via NLRP3. Based on these preliminary studies, we propose three specific Aims to test several hypotheses to understand the role of the microbiota in the induction of IL-1? via the NLRP3 inflammasome and the role microbiota- induced IL-1? in intestinal inflammation.

Public Health Relevance

The microbiota plays a crucial role in the development of colitis in animal models disease. However, the signaling pathways by which the microbiota promotes colitis and the commensal bacteria that elicit inflammation in the intestine remain poorly understood. In this application, we propose studies to understand the link between the microbiota and the activation of the inflammasome, a major mechanism for the production of IL-1?, a cytokine implicated in colitis and host defense.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091191-14
Application #
9662813
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2005-05-15
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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