# Gut microbial metabolite-mediated neuroprotection in traumatic brain injury

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $430,375

## Abstract

The Centers for Disease Control estimates 1.7 million people suffer traumatic brain injury (TBI) in the United
States each year and 5.3 million people are living with TBI-related disability. In survivors, chronic
neuroinflammation has been linked to progressive neurologic deficits and neurodegenerative disorders. The
cause of persistent neuroinflammation, in some cases years after the primary injury, remains unknown. We
propose that chronic intestinal dysbiosis, specifically the depletion of “healthy” commensal bacteria capable of
fermenting dietary fiber to produce the short chain fatty acid (SCFA) acetate, leads to a stable maladaptive state
in the brain and neurodegeneration after TBI. Acetate, a glial specific substrate, is the most abundant SCFA in
the peripheral circulation, crosses the blood-brain barrier, and plays a critical role in development and function
of the immune system. Restoration of depleted bacteria or their metabolites has the potential to reverse
dysbiosis-associated phenotypes. Through a unique collaboration between internationally recognized centers
for TBI and microbiome research, The Safar Center for Resuscitation Research, the Center for Microbiome and
Medicine, and the Brain Care Institute at the University of Pittsburgh, we have generated exciting preliminary
data which demonstrates (1) bacterial populations in the gut that produce acetate by fermentation of dietary fiber
are depleted after severe TBI in children and controlled cortical impact (CCI) TBI in mice, (2) acetate production
is significantly reduced after CCI, and (3) surprisingly, commensal bacterial populations and acetate production
do not recover by 28 days after injury, the latest timepoint assessed in our preliminary studies. Thus, we propose
a translational study to discover if persistent inflammation-mediated neurodegeneration after TBI is fueled by
depletion of commensal bacteria and deficient microbial production of acetate. In Aim 1, we will determine
whether acetate repletion using a chow enriched with acetylated fiber or replenishing acetate-producing bacteria
in the gut prevents late neurodegeneration after TBI. Cognitive function will be assessed. Lesion volume will be
assessed by serial T2-weighted MRI. Surviving neurons will be quantified using unbiased stereology. In Aim 2,
we will determine the impact of acetate repletion on chronic microglial activation after TBI by
immunohistochemistry and use RNA-Seq to determine microglia phenotype. We hypothesize that mice
randomized to receive acetylated fiber or acetate-producing bacteria will have reduced microglial activation in
the peri-contusional cortex and assume an anti-inflammatory and tissue-supportive phenotype. In Aim 3, we will
characterize temporal changes in serum and fecal acetate levels in children admitted to the intensive care unit
with TBI. Clinical information including injury severity, antibiotic exposure, and diet will be collected for secondary
outcomes. If we identify a robu...

## Key facts

- **NIH application ID:** 9996196
- **Project number:** 1R21NS115173-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Robert S B Clark
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996196

## Citation

> US National Institutes of Health, RePORTER application 9996196, Gut microbial metabolite-mediated neuroprotection in traumatic brain injury (1R21NS115173-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996196. Licensed CC0.

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