# Role of Gene-Microbial Interactions in the Development of Crohn's Disease-like Colitis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $423,729

## Abstract

ABSTRACT
Crohn’s disease (CD), one of the major forms of Inflammatory Bowel Disease (IBD), is a complex disorder
marked by chronic relapsing inflammation driven by CD4+ T helper 1 (TH1) cells that can affect any part of the
gastrointestinal tract. CD is thought to result from an inappropriate mucosal immune response to the intestinal
microbiota in genetically susceptible individuals. Consistent with this notion, CD patients harbor a dysbiotic
microbiota. However, it remains unclear if the CD-associated dysbiosis plays a casual role or is secondary to
inflammation. More than 100 loci predispose to CD of which polymorphisms in NOD2 are the strongest known
genetic risk factor for disease development in adult and pediatric onset CD. However, the great majority of
individuals homozygous for NOD2 CD-associated variants do not develop CD and no spontaneous intestinal
inflammation mimicking CD occurs in Nod2−/− mice or knockin mice homozygous for the CD-associated
L1007insC NOD2 variant. These findings suggest that additional genetic and/or environmental factors are
critical for disease development. We found that combined, but not single deficiency, of NOD2 and phagocyte
NAPDH oxidase activity triggers early-onset spontaneous TH1-type intestinal inflammation in mice with the
pathological and immune hallmarks of CD. Development of disease required the presence of Mucispirillum
schaedleri, a Gram-negative anaerobic bacterium that is an inhabitant of the colonic mucus layer of normal
mice. The absence of NOD2 and CYBB led to marked accumulation of Mucispirillum in the gut which was
associated with impaired recruitment of neutrophils and killing of the bacterium by luminal neutrophils. Mutant
mice were protected from disease by maternal immunoglobulins against Mucispirillum during breastfeeding.
These results indicate that a specific intestinal microbe can trigger CD-like disease in the presence of impaired
clearance of the bacterium by innate immunity. We hypothesize that NOD2 and the NAPDH oxidase regulate
the susceptibility to CD by controlling the abundance and local invasion of specific pathobionts such as
Mucispirillum. We further hypothesize that killing of specific microbes by neutrophils regulated via NOD2 and
NAPDH oxidase is important to prevent the development of CD-like disease. Finally, we hypothesize that
targeting colitis-causing pathobionts such as Mucispirillum using diet could be an approach to treat CD-like
colitis. In this grant application, we propose three specific Aims to understand the role of NOD2 and phagocyte
NAPDH oxidase in the regulation of the microbiota and induction of colitis using a new animal model that
exhibit pathology and immune alterations characteristic of CD.

## Key facts

- **NIH application ID:** 10426166
- **Project number:** 5R01DK121504-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gabriel Nunez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,729
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426166

## Citation

> US National Institutes of Health, RePORTER application 10426166, Role of Gene-Microbial Interactions in the Development of Crohn's Disease-like Colitis (5R01DK121504-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10426166. Licensed CC0.

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