# Gut-brain axis at the intersection of aging and traumatic injury

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2023 · $71,792

## Abstract

Project Summary
The proposed studies will examine mechanisms by which advanced age increases intestinal permeability and
neuroinflammation after burn injury using a clinically relevant mouse model. Regardless of age, most burn
patients do not die from primary injuries, but rather from complications, such as sepsis. Further, aged burn
patients often experience greater neurological impairments, which may stem from heightened
neuroinflammation. Clinical and experimental evidence reveal that healthy aged subjects are in an elevated
basal inflammatory state, referred to as “inflammaging,” which can contribute to deficits in tissue injury and
repair. We and others believe that inflammaging is caused by translocation of bacterial products from the
intestinal lumen and that exposure to these products triggers the production of pro-inflammatory cytokines and
chemokines, including tumor necrosis factor alpha (TNF), interleukin (IL)-1β, IL-6, and C-C Motif Chemokine
Ligand 2 (CCL2). Novel preliminary data in our clinically-relevant murine model of scald burn injury confirm that
aged mice who sustain a burn injury have heightened circulating levels of danger-associated molecular
patterns (DAMPs), and a greater breach in intestinal epithelial barrier integrity that coincides with an increase
in markers of neuroinflammation. Both neuroinflammation and burn injury in the aged population have been
correlated with breaches in the blood brain barrier, delirium, and other signs of cognitive decline. From these
observations, we hypothesize that post-burn gut leakiness seen in aged mice is driven by excessive IEC
death, ISC dysfunction, and reduced IEC proliferation. Additionally, these changes in the gut lead to
leakiness of the blood brain barrier and neuroinflammation. To test this hypothesis, in Aim 1, we will
investigate the mechanisms behind gut leakiness in young and aged sham and burn-injured mice by identifying
intestinal epithelial cell apoptosis/necroptosis, epithelial cell proliferation, and intestinal stem cell markers in
vivo and in vitro utilizing whole tissue, isolated epithelium, and intestinal organoids, along with measuring
blood-borne gut-derived bacteria and bacterial cell wall components. In Aim 2, we will examine blood brain
barrier integrity in young and aged sham and burn-injured mice using multiple measures of barrier
permeability. Further, we will examine the levels of pro-inflammatory cytokines and chemokines, and microglial
and astrocyte activation within brain regions. Finally, we will determine if limiting intestinal barrier damage after
burn injury reduces neuroinflammatory markers in the brain. These studies will expand our understanding of
how advanced age alters the gut in the context of burn injury and the impact of intestinal permeability on
neuroinflammation. It is our hope that our work will lead to the development of novel therapies to treat the
excessive inflammatory response and consequences of that inflammation in burn pati...

## Key facts

- **NIH application ID:** 10679217
- **Project number:** 1F32AG082443-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Travis Michael Walrath
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $71,792
- **Award type:** 1
- **Project period:** 2023-06-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10679217

## Citation

> US National Institutes of Health, RePORTER application 10679217, Gut-brain axis at the intersection of aging and traumatic injury (1F32AG082443-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10679217. Licensed CC0.

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