# Mechanisms of aryl hydrocarbon receptor control of eosinophilic esophagitis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $623,589

## Abstract

PROJECT SUMMRAY
Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus partially mediated by epithelial barrier
breach, resulting in harmless antigens penetrating the underlying tissues, encountering immune cells, and
triggering allergic responses. The surge in allergy prevalence is often attributed to shifts in environmental
conditions and western life style. The molecular mechanisms involved in how the environment elicits allergic
diseases is an area of active research that is yet to be fully understood. The aryl hydrocarbon receptor (AHR) is
an intracellular receptor responsive to various external stimuli, including dietary compounds, air toxicants,
pharmacologic agents, microbiota metabolites and tryptophan metabolites. Our research has uncovered that
AHR acts as a sensor molecule, capable of either maintaining epithelial homeostasis and barrier integrity, or
initiating an innate immune response when exposed to diverse AHR ligands from different environmental
sources. As a result, AHR can play a dual role in EoE, both protecting against and exacerbating EoE. We have
shown that select AHR ligands induced protective transcriptional responses in esophageal epithelial cells. These
responses counteract pathways involved in the development of type 2 immunity, including restoring barrier
function and the deficiency of SPINK7, a crucial endogenous protease inhibitor, normally essential for averting
EoE. These anti-inflammatory reactions rely on the activation of the transcription factor Ovo Like Zinc (OVOL1).
Conversely, environmental factors such as enriched tryptophan diets can stimulate AHR, exacerbating
esophageal inflammation in mice.
In this study we aim to elucidate the mechanism through which AHR mediates its protective and detrimental
reactions in response to divergent AHR ligands. We have established experimental platforms including the
generation of AHR and OVOL1 deficient esophageal epithelial cell lines, mice with conditional depletion of Ahr
and Ovol1 in the esophageal epithelium, experimental EoE murine models and three-dimensional human
organotypic esophageal raft cultures to test the hypothesis that AHR drives differential esophageal epithelial
responses, and the nature of the AHR ligands dictates the AHR dependent protective (barrier function)
and detrimental (innate inflammation) outcomes. Successful completion of this study holds immediate
translational significance, as it could pave the way for dietary adjustments, probiotics, and newly-approved AHR
agonists which will offer potential avenues for interventions against EoE.

## Key facts

- **NIH application ID:** 10938426
- **Project number:** 1R01DK140127-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Nurit P AZOUZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,589
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938426

## Citation

> US National Institutes of Health, RePORTER application 10938426, Mechanisms of aryl hydrocarbon receptor control of eosinophilic esophagitis (1R01DK140127-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10938426. Licensed CC0.

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