# Regulation of intestinal NaCl absorption

> **NIH VA I01** · HUNTINGTON VETERANS AFFAIRS MED CTR · 2022 · —

## Abstract

The most common chronic diarrheal disease in this country and in veterans is inflammatory bowel disease
(IBD; e.g. Crohn’s disease). Diarrhea is the most common and disabling morbidity of IBD. The available
treatments for diarrhea of IBD are suboptimal, non-specific and fraught with many side effects. Diarrhea in
these conditions is a result of electrolyte (e.g. Na, Cl) and fluid malabsorption by absorptive villus cells and
enhanced secretion by secretory crypt cells. Immune inflammatory mediators (e.g. prostaglandins), known to
be elevated in the mucosa of the chronically inflamed intestine, are paramount factors altering the activity of
epithelial electrolyte transporters. 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 coupled NaCl
absorption to cause diarrhea in IBD is poorly understood. The existing paradigm is that coupled NaCl
absorption occurs via the dual operation of Na:H (NHE3) and Cl:HCO3 exchange (DRA). But our studies in
multiple IBD models showing that NHE3 is unaffected, raised an important question of what other Na
absorptive pathway may be affected in tandem with DRA that results in coupled NaCl malabsorption leading to
the most common and disabling symptom of IBD, diarrhea. Of the other potential major Na absorptive
processes that may be coupled to Cl:HCO3 exchange is Na-glucose co-transport (SGLT1) on the villus cell
BBM. SGLT1 is pivotal not only for the absorption of the major nutrient glucose, but also plays a critical role in
maintaining overall fluid and electrolyte homeostasis by absorbing two Na for each glucose. Indeed,
preliminary data in two animal models of IBD and in human IBD demonstrated inhibition of SGLT1, in parallel
with DRA, albeit via different mechanisms. Further, preliminary studies showed that prostaglandins, key
immune inflammatory mediators, may be specific modulators of SGLT1 during chronic enteritis. These
observations, have led to the paradigm shifting conclusion, that in the chronically inflamed intestine it is not the
conventional coupled NaCl absorption via NHE3/DRA that is affected, but rather a novel DRA/SGLT1 coupled
absorptive pathway that may be inhibited to cause diarrhea in IBD. Given this background, the overall
hypothesis of this competing renewal proposal is that altered novel DRA/SGLT1 coupled NaCl absorption,
likely regulated by PGs, causes the diarrhea in IBD. Thus, the overall goal of this proposal is to elucidate the
molecular mechanisms of regulation of SGLT1 and DRA by immune-inflammatory mediators in the chronically
inflamed intestine. We will comprehensively and complementarily study molecular and physiological regulation
of SGLT1 in vivo in rabbits with chronic enteritis and ex vivo in human small intestinal organoid 2-D
monolayers. Outcome of the proposed studies will provide novel mechanistic insights into the cause of
impaired absorption of both electroly...

## Key facts

- **NIH application ID:** 10368181
- **Project number:** 2I01BX003443-05A1
- **Recipient organization:** HUNTINGTON VETERANS AFFAIRS MED CTR
- **Principal Investigator:** Uma Sundaram
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2017-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368181

## Citation

> US National Institutes of Health, RePORTER application 10368181, Regulation of intestinal NaCl absorption (2I01BX003443-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368181. Licensed CC0.

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