# Mechanisms of Regulation of Intestinal Cl Absorption in IBD Associated Diarrhea

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

Diarrhea is the hallmark symptom of inflammatory bowel diseases (IBD). Recurring diarrheal episodes not only
significantly affect treatment options, but also the quality of life of the US veteran patients with IBD. IBD
associated diarrhea results from a decrease in luminal NaCl and water absorption as well as derangements in
barrier integrity. Major route of NaCl absorption in the human intestine involves concerted operation of Na+/H+
and Cl-/HCO3- exchangers. SLC26A3 or DRA (Down-Regulated in Adenoma) is the key transporter involved in
intestinal Cl- absorption. DRA knockout mice have been shown to exhibit diarrheal phenotype resembling human
CLD (congenital chloride diarrhea) and recent genome-wide association studies (GWAS) have linked the
dysregulated DRA expression to IBD pathogenesis. Further, we have recently demonstrated that DRA deficiency
in mice enhances intestinal permeability and compromises barrier integrity. Thus, DRA has emerged as an
important novel target for intervention in diarrheal disorders and IBD. Therefore, it is vital to characterize
molecular mechanisms involved in DRA regulation in health and disease and to identify agents that can activate
DRA and/or counteract its downregulation. In this regard, glucocorticoids (GCs) are important anti-inflammatory
agents and are first line therapeutics for the induction of remission in IBD. Also, GCs have been shown to stabilize
epithelial barrier function and exert antidiarrheal effects by restoring electrolyte and water absorption in
chronically inflamed epithelium. However, to date, the direct effects of GCs on DRA expression and chloride
absorption have not been investigated. Our current preliminary data provide strong evidence that synthetic GC
such as Dexamethasone (DEX) via glucocorticoid receptor (GR) can increase DRA expression via transcriptional
activation. DEX treatment also increased DRA expression in mouse intestine. Therefore, we hypothesized that
DEX exerts antidiarrheal effects by upregulating DRA expression and chloride absorption. Also, in light
of our preliminary data demonstrating a key role of DRA in intestinal barrier integrity, we further hypothesized
that DEX mediated upregulation of DRA will not only ameliorate diarrhea but will also restore epithelial
barrier integrity. The current application is, therefore, designed to investigate the mechanisms of regulation of
DRA gene expression by DEX, role of GR receptor and the associated co-activators under normal and
inflammatory conditions utilizing both in-vitro cell culture, ex-vivo human apical-out enteroids, and in-vivo mouse
models including DRA-KO mice and mice with intestine specific deletion of GR. The Specific Aims are: 1.
Elucidate the mechanisms of DEX-induced transcriptional regulation of DRA expression and function and its role
in counteracting inhibitory effects of TNF- on DRA gene expression; 2. Elucidate the mechanisms underlying
DRA up-regulation by DEX in-vivo utilizing wild type and intestine ...

## Key facts

- **NIH application ID:** 10620145
- **Project number:** 5I01BX002011-11
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Pradeep K Dudeja
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-01-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620145

## Citation

> US National Institutes of Health, RePORTER application 10620145, Mechanisms of Regulation of Intestinal Cl Absorption in IBD Associated Diarrhea (5I01BX002011-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10620145. Licensed CC0.

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