# AHR-NLRP6 interactions in gut barrier dysfunction and colitis

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2024 · $540,414

## Abstract

Abstract:
Inflammatory Bowel Diseases (IBD), which consist of ulcerative colitis and Crohn’s disease, affect as many as
1.4 million people in the USA. Intestinal barrier dysfunction is one of the hallmarks associated with IBD. Currently,
there are no treatments available to target gut barrier dysfunction in IBD pathogenesis. The aryl hydrocarbon
receptor (AHR) is a transcription factor expressed in several cell types and is activated by a variety of exogenous
and endogenous ligands, including microbial metabolites. Activation of AHR regulates many pathophysiological
functions, including inflammation and gut barrier integrity. Recently, we identified that the microbial metabolite
Urolithin A (UroA) is an AHR ligand that enhances gut barrier function. Treatment with UroA mitigated colitis in
pre-clinical models. This proposal originated from the novel observation that selective activation of AhR by UroA
in intestinal epithelial cells (IEC) is critical for the regulation of gut barrier function. This process requires
activation of the NLRP6-IL-18 pathway in IEC to induce IL-22 from type 3 innate lymphoid cells (ILC3).
Furthermore, we identified that UroA-induced genes are responsible for goblet cell differentiation, leading to
increased mucins and enhanced gut barrier function. In this proposal, we will test the hypothesis that UroA
selectively activates the AHR-NLRP6-dependent secretion of homeostatic levels of IL-18 in IEC, leading to highly
differentiated goblet cells that enhance gut barrier function, reduce unwarranted inflammation, and mitigate IBD.
We propose three specific aims to test this hypothesis. Aim 1 will determine the role of each component of the
AHR-NLRP6-IL-18/IL-22 axis in UroA-mediated protective activities against IBD pathogenesis using pre-clinical
models of colitis. We will establish the novel cross-talk mechanisms of IEC selective activation of AHR-NLRP6
pathways that regulate IL-18, and IL-18 dependent IL-22 production from ILC3. In Aim 2, we will examine the
mechanisms of UroA-mediated goblet cell differentiation and production of different types of mucus that enhance
gut barrier function. Aim 3 will establish the translational relevance of selective activation of IEC AHR-IL-18
pathway by UroA in human IBD patient samples. Upon completion of this study, the mechanisms and beneficial
effects of selective activation of the AHR-NLRP6-IL-18 axis to enhance gut barrier function and the therapeutic
implications in IBD will be established.

## Key facts

- **NIH application ID:** 10882981
- **Project number:** 1R01DK135603-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Venkatakrishna Rao Jala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,414
- **Award type:** 1
- **Project period:** 2024-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882981

## Citation

> US National Institutes of Health, RePORTER application 10882981, AHR-NLRP6 interactions in gut barrier dysfunction and colitis (1R01DK135603-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10882981. Licensed CC0.

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