Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that affects 0.7 million people in the United States. Interleukin (IL)-1? is an important pro-inflammatory mediator that is believed to be associated with intestinal inflammation in CD, as the IL-1? expression is elevated in the intestinal mucosa of patients with CD. Likewise, genetic variation in NLRP3, the inflammasome protein which plays a pivotal role in the production of IL-1?, is associated with increased risk for CD. Furthermore, mice deficient in Atg16l1, an autophagy gene linked to CD, display increased NLRP3-dependent IL-1? production and sensitivity to colitis. Thus, IL-1? appears to contribute to CD, yet the mechanisms by which IL-1? is induced in CD and how IL-1? promotes CD pathogenesis remain uncertain. Given our recent findings that the gut microbiota is essential for the induction of mucosal IL-1?, the long-term objective of this study is to unravel how the gut microbiota contributes to disease pathogenesis in CD likely through the induction of IL-1?. To this end, we have generated a humanized gnotobiotic mouse (hGB) model, in which germ-free (GF) mice are colonized with human (healthy individuals and CD patients) microbiotas. Utilizing this model, we have found that GF mice colonization by the CD microbiotas induces a marked elevation of pro-inflammatory factors, including IL-1?, in colonic mucosa, while healthy microbiotas did not elicit these responses. Strikingly, colonization of CD, but not healthy, microbiotas led to the development of severe colitis in two different mouse models of colitis (dextran sulfate sodium-induced colitis and GF IL-10-deficient mice colonized with human microbiotas). Induction of IL-1? is required for the colitogenic capacity of the CD microbiota. Furthermore, We have identified candidates of IL-1?- inducing pathobionts, which selectively accumulated in CD patients. Based on these results, our central hypothesis is that IL-1?-inducing pathobionts are enriched in CD patients, which leads to the development and/or progression of intestinal inflammation.
Specific aims are: 1. Clarify the mechanism by which CD- associated pathobionts activate the inflammasome. We will identify which and how the CD-associated pathobionts activate the inflammasome. 2. Identify the immune pathways elicited by CD-associated pathobiont-induced IL-1?. We will analyze the T cell responses downstream of IL-1? that are induced by CD- associated pathobionts. 3. Determine the mechanism by which CD-associated pathobiont-induced IL-1? leads to colitis. We will determine the mechanisms by which IL-1? induced by selective members of CD- associated pathobionts leads to the development of colitis. Thus, the proposed study will shed light on the link between the microbiota-induced IL-1? in the intestine and the pathogenesis of CD.

Public Health Relevance

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. It affects 0.7 million people in the United States. Potentially pathogenic members of the intestinal bacteria, namely pathobionts, trigger inflammation in CD. We have identified 'IL-1?-inducing pathobionts', which selectively accumulated in patients with CD. Using these CD-associated pathobionts, we will investigate the mechanisms by which the pathobionts trigger intestinal inflammation, possibly through the induction of mucosal IL-1?. The proposed research is highly relevant to this serious public health problem. Unraveling the mechanism by which the microbiota promotes disease in CD will provide critical new insight into our current understanding of the pathogenesis of CD as well as aid the development of novel treatment options for CD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Perrin, Peter J
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Morhardt, Tina L; Hayashi, Atsushi; Kao, John Y et al. (2018) Regional control of regulatory immune cells in the intestine. Curr Pathobiol Rep 6:29-34
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