# Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury.

> **NIH NIH R56** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $611,829

## Abstract

PROJECT SUMMARY / ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in cognitive decline. The
neuroinflammatory events that are associated with the pathology of AD exacerbate neurodegeneration. Elderly
people with dementia or AD have a higher risk of falling because their cognitive function is affected. They lose
their orientation and are very prone to breaking their hips, other bones, or even more severe falls that can cause
brain trauma. Although they are treated in the hospitals with subsequent rehabilitation, their weakened immune
state typically affects their recovery phases. We need to develop new treatments for AD patients who have had
a traumatic brain injury (TBI). This vulnerable population could be particularly amenable to precision-microbiota
therapy. Although not fully understood, the brain-gut-microbiota axis plays a major role in the onset and severity
of many neurological diseases. We plan to develop precision-microbiota therapy to protect against
neurodegeneration and functional behavior in AD mice after TBI. The gut microbiome is emerging as an essential
neuromodulator of brain-gut axis signaling. It can significantly impact brain inflammation and outcome after CNS
trauma and alter anxiety- and depression-like behaviors. This research proposal is based on the scientific
premise that gut bacteria can impact behavior and that brain injury can disrupt diversity in a healthy gut
microbiome. The overarching hypothesis is that the gut microbiota dysfunction caused by brain trauma
contributes directly to neuroinflammation and neurodegeneration responses in AD mice, and the microbiota
modulation will delay the progression of AD neuropathology. Our preliminary data indicate how the microbiota of
AD mice affected adversely to TBI outcomes and how probiotics help brain recovery in C57B6/J young mice.
This proposal investigates the mechanistic linkage between gut microbiota and AD progression following TBI
and explores potential intervention strategies. We will test this premise with the following three Specific Aims:
we 1) will determine if the gut microbiome plays a role in accelerating AD pathology and cognitive decline induced
by TBI, and 2) will investigate the impact of fecal transplants on AD pathology and cognitive decline after TBI,
and 3) will assess the ability of multi-strain probiotics to reduce AD pathology after TBI. We expect to identify a
particularly vulnerable patient population by defining which inflammatory responses associated with brain trauma
accelerate AD pathogenesis and are regulated by brain-gut-microbiome signals. Our approach is significant
because we will establish a “translatable” foundation for the potential of therapeutic approaches for AD after TBI
by using the gut as a non-CNS target of precision-microbiota therapy.

## Key facts

- **NIH application ID:** 10929519
- **Project number:** 5R56AG080920-02
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Sonia Villapol
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $611,829
- **Award type:** 5
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929519

## Citation

> US National Institutes of Health, RePORTER application 10929519, Microbiota-targeted approaches to resolve dysbiosis-induced AD neuropathology following brain injury. (5R56AG080920-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10929519. Licensed CC0.

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