# Regulation of intestinal NaCl absorption

> **NIH VA I01** · HUNTINGTON VETERANS AFFAIRS MED CTR · 2020 · —

## Abstract

Diarrheal diseases afflict U.S. Veterans both at home and abroad. While the causes may be more acute
overseas and more chronic in U.S., diarrhea in these conditions is a result of altered electrolyte (e.g. Na, Cl)
and fluid transport in the intestine. For example, alterations in epithelial electrolyte transporters (e.g. Na:H and
Cl:HCO3 exchange) is caused by immune inflammatory mediators known to be elevated in the mucosa of the
chronically inflamed intestine (e.g. Inflammatory bowel disease, IBD). Thus, while the concept of immune
regulation of electrolyte transport in IBD is fairly well accepted, specifically which of the many immune
inflammatory pathways may regulate which transport pathway to cause diarrhea is poorly understood. Given
this background, using a technique to isolate relatively pure and viable villus and crypt cells from the rabbit
intestine, we demonstrated that coupled NaCl absorption occurs via the dual operation of Na:H and Cl:HCO3
exchange in the BBM of villus cells. We also demonstrated that in the chronically inflamed intestine coupled
NaCl absorption is inhibited secondary to the inhibition of Cl:HCO3, but not Na:H exchange on the BBM of
villus cells. The mechanism of inhibition of Cl:HCO3 is secondary to diminished affinity of the transporter for Cl
and thus, it is likely a post-translational mechanism of regulation. We identified this Cl:HCO3 exchanger in the
rabbit ileal villus cell BBM to be SLC26a3 (DRA). Then we demonstrated that the inhibition can be alleviated
by a broad spectrum immune modulator (corticosteroids). Additional preliminary studies indicated a specific
and unique immune mechanism of regulation of DRA in the chronically inflamed intestine. Finally, preliminary
data from the human IBD small intestine demonstrated similar changes in coupled NaCl absorption. These
novel observations have given rise to the overall hypothesis of this proposal which is that inhibition of Cl:HCO3
exchange in villus cells is uniquely regulated by immune-inflammatory mediators produced in the chronically
inflamed intestine. Therefore, the overall aim is to determine the mechanisms of immune regulation of
Cl:HCO3 exchange in villus cells in the chronically inflamed intestine. Better understanding of the immune
regulation of NaCl absorption by the villus cells may provide the foundation to develop more novel, efficacious
and specific immune therapies for the most common morbidity of IBD, namely diarrhea.

## Key facts

- **NIH application ID:** 9989032
- **Project number:** 5I01BX003443-04
- **Recipient organization:** HUNTINGTON VETERANS AFFAIRS MED CTR
- **Principal Investigator:** Uma Sundaram
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989032

## Citation

> US National Institutes of Health, RePORTER application 9989032, Regulation of intestinal NaCl absorption (5I01BX003443-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989032. Licensed CC0.

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