# Metabolic Regulation of Mucosal Inflammation

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

The Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, are
among the most debilitating inflammatory disorders of the western world. It is estimated that more
than 3 million Americans suffer with IBD, with incidence rates on the rise in many populations. A
recent study of more than 100,000 military service members estimated the incidence of IBD to be
2-10 times greater than non-service members, with a striking relationship between IBD incidence
and the number of life stressors. The precise etiology of IBD is currently unknown.
 Our interest is focused on the identification of inflammation-associated changes in tissue
metabolsim during flares of active inflammation. Our ongoing studies are founded on the
observation that active intestinal inflammation is characterized by significant shifts in tissue
metabolism that can influence cell and tissue function in fundamentally important ways. Under
such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and
do so with a high degree of fidelity. The precise mechanisms by which metabolic pathways control
resolution, however, have yet to be elucidated. Our work in progress has conclusively revealed
that energy utilization becomes compromised during active inflammation and that creatine and its
associated creatine kinase (CK) family of enzymes are fundamental in shuttling of high energy
phosphates in the form of phosphocreatine between sites of ATP generation. Moreover, we have
shown that double-mutant mice lacking the brain and mitochondrial isoforms of CK (termed the
CK dKO) are significantly more susceptible to acute colitis as measured by multiple disease
parameters. In addition to impaired barrier function, CK dKO mice showed defective inflammatory
responses underscored by nearly non-existent levels of colonic IFN.
 In this proposal, we will define how creatine metabolism molds the mucosal tissue
environment during inflammation. Three synergistic specific aims are directed at testing the
hypothesis that CK expression and activity within the epithelia and immune cells are fundamental
in inflammatory resolution responses in the mucosa. Aim 1 will elucidate how creatine kinase(s)
ultimately influence tissue metabolism during active inflammation. Aim 2 will define the regulation
of IFN by CK enzymes. Specific Aim 3 will illuminate the relationship between IFN and CK
metabolism in the regulation of intestinal inflammation. It is our hope that these results will reveal
new insights into innate regulation of mucosal inflammatory resolution and that extensions of this
work will lead to targets for experimental therapeutics.

## Key facts

- **NIH application ID:** 10585958
- **Project number:** 2I01BX002182-09
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Sean P Colgan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585958

## Citation

> US National Institutes of Health, RePORTER application 10585958, Metabolic Regulation of Mucosal Inflammation (2I01BX002182-09). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10585958. Licensed CC0.

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