# Modulation of Host-Microbe Interactions by Extracellular Purines in the Gastrointestinal Lumen

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2021 · $162,043

## Abstract

Project Summary/Abstract
Over 3 million people in the United States carry a diagnosis of inflammatory bowel disease (IBD), a chronic
and incurable condition of unknown cause that carries with it significant morbidity and healthcare costs.
Intestinal dysbiosis is a hallmark of IBD that contributes to its pathogenesis, though specific mechanisms
underlying this observation are lacking. As a gastroenterologist and physician scientist, the candidate seeks to
elucidate specific molecular mechanisms that mediate host-microbe interactions that drive IBD with the ultimate
goal of translating these findings into clinical applications. The proposed research builds on the candidate's
published observations that adenosine (Ado) regulates colonization and virulence of the Salmonella enterica
serovar Tyhpimurium and will provide the candidate with the additional training necessary to move forward as an
independent investigator. Whereas it has been shown that Ado signaling in the GI mucosa promotes resolution
of inflammation, the actions of Ado on the intestinal microbiota have not been examined. The proposed
research tests the hypothesis that extracellular Ado produced in the gastrointestinal mucosa influences the
composition and metabolism of the intestinal microbiota through inhibition of the bacterial stringent response
(SR) to inhibit dysbiosis and promote intestinal homeostasis. This hypothesis is explored through three aims: In
Aim 1, the mechanism by which Ado inhibits growth of enteric bacteria will be defined. Preliminary data show
that Ado inhibits bacterial growth by inducing amino acid auxotrophies through suppression of the SR, a global
bacterial adaptation to nutritional stress. The mechanisms underlying this observation will be determined
through metabolomic and transcriptomic analyses of bacterial mutants deficient in purine metabolism. Aim 2 will
elucidate the mechanisms by which Ado promotes intestinal homeostasis by modulating the intestinal
microbiota. A novel mouse model wherein intestinal epithelial cells lack the ability to generate extracellular Ado
(conditional knockout of ecto-5'-nucleotidase) will be used to assess how Ado shapes the intestinal microbiota.
Murine fecal microbial transfer (FMT)-IBD will be used to examine the role of Ado in promoting intestinal
homeostasis by shaping the intestinal microbiota. Finally, Aim 3 presents a translational application of the
mechanisms under study by demonstrating that exogenously administered purines can alter intestinal
homeostasis in an analogous manner to naturally-occurring purines in the intestine. The proposed work will be
performed under the mentorship of Drs. Sean Colgan and Andrés Vázquez-Torres at the University of
Colorado, who have extensive expertise in the role of adenosine in gastrointestinal inflammation and the role of
nucleotide metabolism in the pathogenesis of enteric infectious diseases, respectively. This mentoring team is
ideally suited to the proposed research, which...

## Key facts

- **NIH application ID:** 10119280
- **Project number:** 5K08DK120809-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Daniel Joseph Kao
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,043
- **Award type:** 5
- **Project period:** 2020-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119280

## Citation

> US National Institutes of Health, RePORTER application 10119280, Modulation of Host-Microbe Interactions by Extracellular Purines in the Gastrointestinal Lumen (5K08DK120809-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119280. Licensed CC0.

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