# Microbiota-sourced purines in gut health and disease

> **NIH NIH K01** · UNIVERSITY OF COLORADO DENVER · 2022 · $147,421

## Abstract

PROJECT SUMMARY
 To protect the host and perform their symbiotic role, intestinal epithelial cells secrete large amounts of
highly glycosylated mucin to physically distance yet provide bacteria habitat and fuel, while establishing apical
junction complexes that regulate nutrient and waste flux. In return, a healthy microbiota functions to provide
metabolites the epithelium relies on for function. We recently published that the purine hypoxanthine (Hpx) is a
microbiota-derived metabolite that the mucosa depends upon for energy balance, barrier function, and wound
healing, suggesting Hpx as a limiting substrate for homeostatic mucosal metabolism and function. In unbiased
extensions of that work, we demonstrated that Hpx induces TP53-inducible glycolysis and apoptosis regulator
(TIGAR) expression and activates AMP-activated kinase (AMPK) in vitro and in vivo. TIGAR increases
metabolite flux through the pentose phosphate pathway while AMPK is a master regulator of metabolism that
promotes energy balance. We hypothesize that Hpx fundamentally molds epithelial metabolism through TIGAR
and AMPK as mechanisms that support intestinal homeostasis and wound healing. In this, purine depletion
and reconstitution by colonization experiments with a developed mutant E. coli enriched in Hpx production will
be employed to determine the influence of microbiota-derived Hpx on mucosal energy metabolism, barrier
function, and wound healing.
 The applicant, Dr. Lee, has established a scientific niche in which to build a foundation for independent
research in the role of microbiota-derived purines in gut mucosal energy metabolism and function. Dr. Lee and
his mentor, Dr. Colgan, assembled an advisory committee to regularly meet as a group with Dr. Lee throughout
the duration of the award to provide feedback on the research, critique the research plans, monitor
publications, and provide career advice. Drs. Colgan and Lee also identified microbiology and immunology
courses to facilitate expansion of Dr. Lee's foundation of knowledge in fundamental intestinal processes, and
established tutelage in colonic enteroid harvesting/culturing for study and in histopathological analyses. Dr. Lee
will submit his work to present at conferences specific to his research to share his research and network with
colleagues and potential collaborators, and get valuable feedback from the scientific community. Dr. Lee's
development will benefit from continued participation in the Mucosal Inflammation Program (MIP), a multi-
disciplinary, multi-departmental program initiated to study mechanisms of mucosal inflammation and resolution.
The MIP fosters a unique lab environment for collaboration between physician scientists, clinicians, and
research scientists, and works to establish an environment for young investigators to flourish and develop. The
facilities and resources available to and development plan built for Dr. Lee provide an ideal environment and
path for his successful transition to i...

## Key facts

- **NIH application ID:** 10475271
- **Project number:** 5K01DK129410-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joseph Scott Lee
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $147,421
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475271

## Citation

> US National Institutes of Health, RePORTER application 10475271, Microbiota-sourced purines in gut health and disease (5K01DK129410-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475271. Licensed CC0.

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