# Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $614,227

## Abstract

Project Summary/Abstract
This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of
serious diarrheal illness. Originally identified more than 50 years ago as a cause of severe diarrheal illness in
patients with clinical presentations indistinguishable from cholera, ETEC continue to threaten the lives of many
children in poor regions of the world where sanitation and clean water remain limited. While deaths from
diarrheal illness in low-middle income countries have declined, largely due to deployment of oral rehydration
therapy, the tremendous morbidity associated with these illnesses remains completely unchecked. ETEC are
closely linked to a condition known as environmental enteropathy or environmental enteric dysfunction (EED)
that is complicated by sequelae of malnutrition, stunted growth, and intellectual impairment, robbing poor
countries of badly needed human capital. Children with malnutrition are also at tremendously increased risk of
dying from infectious diarrhea, pneumonia, and other common infections. In addition, ETEC have been linked
to a centuries-old enigmatic disease, known as tropical sprue, that is typically diagnosed in adults with
substantial repeated exposure to these pathogens. With EED it shares features of poor nutrient absorption,
wasting, and alterations of small intestinal morphology.
Much is known about of the molecular pathogenesis of acute diarrheal disease, with heat- labile (LT) and heat-
stable (ST) toxins signaling through cAMP and cGMP second messenger pathways, respectively, to alter
enterocyte ion channels that promote the net efflux of salt and water into the intestinal lumen. However, the
biology underlying enteropathic changes to the small intestine and related sequelae are very poorly
understood. Our recent studies indicate that ETEC toxins compromise cellular messages critical to the
maintenance, biogenesis and function of small intestinal surfaces responsible for nutrient absorption.
The current project will therefore address the following questions:
· “What is the impact of ETEC and its individual toxins on the absorptive architecture of small intestine?”
· “How does repeated ETEC infection affect the overall expression of genes that direct formation of
 surfaces needed for nutrient absorption?”
· “Can we mitigate these effects by toxin-neutralizing vaccination?”
Addressing these fundamental questions will fill important gaps in our understanding of the sequelae to ETEC
infections, elucidate important features of the molecular pathogenesis of disease, and inform strategies to
prevent illnesses that threaten millions of disadvantaged children worldwide.

## Key facts

- **NIH application ID:** 10764303
- **Project number:** 5R01AI170949-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** James Michael Fleckenstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,227
- **Award type:** 5
- **Project period:** 2023-01-15 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764303

## Citation

> US National Institutes of Health, RePORTER application 10764303, Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy (5R01AI170949-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10764303. Licensed CC0.

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