# The role of IL-1?-inducing pathobionts in the pathogenesis of Crohn?s disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $376,434

## Abstract

Project Summary/Abstract:
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)-1β is an important pro-inflammatory mediator that is believed to be
associated with intestinal inflammation in CD, as the IL-1β 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-1β, is associated with increased risk for CD. Furthermore, mice deficient in Atg16l1, an
autophagy gene linked to CD, display increased NLRP3-dependent IL-1β production and sensitivity to colitis.
Thus, IL-1β appears to contribute to CD, yet the mechanisms by which IL-1β is induced in CD and how IL-1β
promotes CD pathogenesis remain uncertain. Given our recent findings that the gut microbiota is essential for
the induction of mucosal IL-1β, 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-1β. 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-1β, 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-1β is
required for the colitogenic capacity of the CD microbiota. Furthermore, We have identified candidates of IL-1β-
inducing pathobionts, which selectively accumulated in CD patients. Based on these results, our central
hypothesis is that IL-1β-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-1β. We will analyze the T cell responses downstream of IL-1β that are induced by CD-
associated pathobionts. 3. Determine the mechanism by which CD-associated pathobiont-induced IL-1β
leads to colitis. We will determine the mechanisms by which IL-1β 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-1β in the intestine and the pathogenesis of CD.

## Key facts

- **NIH application ID:** 9975824
- **Project number:** 5R01DK108901-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nobuhiko Kamada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,434
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975824

## Citation

> US National Institutes of Health, RePORTER application 9975824, The role of IL-1?-inducing pathobionts in the pathogenesis of Crohn?s disease (5R01DK108901-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975824. Licensed CC0.

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