# Role of innate immunity and the microbiome in colitis-associated dysplasia

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $497,636

## Abstract

PROJECT ABSTRACT
The two greatest fears expressed by patients with ulcerative colitis (UC) are developing colon cancer and losing
their colon. Although colitis-associated cancer is less common, dysplasia is more common and often results in
colectomy. Our proposal leverages the work of the previous funding period and advances in the field to take a
translational approach to unraveling dysplasia in colitis. The focus of our studies has been the link between
innate immune signaling and intestinal bacteria leading to colitis-associated neoplasia. Our results have led us
to focus on the role of dual oxidase 2 (DUOX2) in dysplasia. DUOX2 is a NADPH oxidase that catalyzes the
conversion of oxygen into hydrogen peroxide (H2O2) upon interaction with the maturation factor DUOXA2. It is
consistently upregulated in biopsies from IBD patients and DUOX2/DUOXA2 expression is further increased in
patients who have had dysplasia. Our group has shown that both inflammatory and microbial signals induce the
expression and activity (H2O2 production) of DUOX2 in colonic epithelial cells. We have proven that chronic
activation of DUOX2 leads to the formation of tumors, which is almost totally abrogated by inactivating DUOX2
in the epithelium. In the current proposal, we hypothesize that IBD-associated dysbiosis activates Duox2 and
local production of H2O2 leading to epithelial barrier dysfunction, recruitment of tumor-promoting myeloid derived
suppressor cells (MDSCs), and generation of a tumorigenic microbiome in a feed forward loop. This is pursued
in the following specific aims: 1) Determine the dependence of inflammatory colonic dysplasia on epithelial
Duox2 signaling. Here we will investigate epithelial barrier dysfunction and DNA damage pathways caused by
epithelial Duox2 activation using colonoid models (human and murine). Using humanized germ-free mice, we
will determine if the UC-dysplasia microbiome is sufficient to cause DUOX2-mediated permeability defects and
DNA damage. 2) Dissect the role of tumor-promoting MDSCs on dysplasia development in the setting of
DUOX2-mediated oxidative stress. Our preliminary data demonstrate that TLR4-driven tumors have enhanced
recruitment of tumor supporting MDSCs. Here we will identify DUOX2-dependent epithelial factors
(chemokines/cytokines) and the transcriptional (single cell-RNA seq) and functional (T cell suppressive)
characteristics of MDSCs in our murine models of tumorigenesis and UC patients with dysplasia. 3) Identify
targetable microbial pathways linked to Duox2 activation and dysplasia. Transfer of the microbiome from
tumor-susceptible villin-TLR4 mice is sufficient to transfer CAC susceptibility. New metagenomic and
metabolomic data show clear differences between UC dysplasia and UC without dysplasia. We will use our
mouse models and UC dysplasia samples to perform deep sequencing and metabolomic characterization of the
tumor-promoting microbiome. Metabolites will be tested for their ability to induce or inhibi...

## Key facts

- **NIH application ID:** 10833632
- **Project number:** 5R01DK099076-15
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Maria Teresa Abreu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $497,636
- **Award type:** 5
- **Project period:** 2014-09-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833632

## Citation

> US National Institutes of Health, RePORTER application 10833632, Role of innate immunity and the microbiome in colitis-associated dysplasia (5R01DK099076-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10833632. Licensed CC0.

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