# Microbial-derived purines in intestinal homeostasis

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2021 · $6,888

## Abstract

PROJECT SUMMARY/ABSTRACT
 In a healthy gastrointestinal (GI) tract, intestinal epithelial cells (IECs) form a dynamic physical and
biochemical barrier that maintains homeostasis by isolating the host immune system from an external
environment of pathogenic and commensal microorganisms. Disruption of this barrier increases bacterial
translocation, triggering inappropriate immune responses and unresolving inflammation. Dysregulation of IEC
barrier in inflammatory bowel disease (IBD) and dysbiosis of the intestinal microbiota coincides with profound
shifts in metabolic energy stores, especially in the colon, which exists in an energetically-vulnerable state of
physiologic hypoxia. Substantial interest lies in understanding immunometabolism as a window to the molecular
mechanisms of inflammatory progression or resolution, such as how metabolically active microbiota-derived
small molecules promote intestinal homeostasis. Our ongoing work has identified purines as significant products
of the intestinal microbiota. We identified a strong capacity for IECs to salvage hypoxanthine (Hpx) for ATP
production, coinciding with improved barrier and wound healing capabilities. Furthermore, an unbiased
microarray analysis of Hpx-treated T84 IECs identified TP53-inducible glycolysis and apoptosis regulator
(TIGAR) as an induced target. We postulate that TIGAR induction by Hpx is central to mediating metabolism in
response to purine availability or need for salvage due to stress-induced energetic deficits. In ongoing studies,
we found that germ-free (GF) mice monocolonized with purine-producing bacteria have significantly increased
colon tissue Hpx, with concomitant TIGAR induction. Further studies showed that the monocolonized mice were
protected from dextran sulfate sodium (DSS)-induced colitis. Based on these results, we hypothesize that
microbial-derived purines significantly contribute to intestinal homeostasis through TIGAR-mediated metabolic
shifts. Aim 1 will define the mechanism(s) of Hpx-dependent TIGAR induction and the impact of that induction
on purine metabolism. Aim 2 will elucidate the contribution of microbial-derived purines to intestinal homeostasis.
Aim 3 will utilize TIGAR knockout (-/-) mice to assess the baseline contribution of TIGAR to intestinal
homeostasis and inflammation resolution. This work lays a foundation for an IBD therapeutic in which patients
are treated with nonpathogenic microbes specifically modified to produce small molecules (e.g. purines) that
drive wound healing and inflammatory resolution.
 This proposal will provide outstanding mentorship and training under the guidance of an experienced sponsor
in the ideal environment of a rigorous basic science lab that is well-integrated clinically, while having the
necessary resources and mentorship to complete each aspect of this project, including a mentorship team within
the Mucosal Inflammation Program. This training will foster the applicant’s independent science research skil...

## Key facts

- **NIH application ID:** 10415604
- **Project number:** 3F32DK122741-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joseph Scott Lee
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $6,888
- **Award type:** 3
- **Project period:** 2019-06-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415604

## Citation

> US National Institutes of Health, RePORTER application 10415604, Microbial-derived purines in intestinal homeostasis (3F32DK122741-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10415604. Licensed CC0.

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