# Understanding the regulation of the intestinal epithelium in Alzheimer’s disease by commensal bacteria and the role it plays in preventing neurocognitive decline

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $36,260

## Abstract

ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid beta plaques
and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led
to the theory of microbial communities or infections as causative in the development of neuroinflammation,
immunosenescence, and inflamm-aging seen in AD. Our own research has demonstrated a decrease in gut
microbiota with anti-inflammatory properties and higher abundances of pro-inflammatory gut microbiota in AD
elders. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address
this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in blood,
serum cytokine profiling, and cognitive assessments of AD elders at 90-day intervals. This analysis identified
changes in B cell populations with an increased abundance of class-switched and decreased abundance of
naïve B cells at levels of greater cognitive impairment. To better understand how the microbiome may control
AD progression, we propose to investigate the connection between the AD microbiome and the adaptive immune
system with a focus on regulation of the intestinal epithelium by commensal gut bacteria. Specifically, we intend
to use stool and plasma samples collected from our AD cohort to measure makers of intestinal permeability and
determine whether metabolites secreted by the AD gut microbiome cause disruptions in the intestinal epithelium.
We will directly study the disruptive effects of AD stool by applying stool supernatants to intestinal epithelial cells,
quantifying changes in epithelial permeability using established assays, and determining whether specific taxa
depleted in AD are sufficient to cause epithelial disruption. In our previously published data, we have observed
the loss of the phytoestrogen-metabolizing bacteria, Adlercreutzia equolifaciens (AE), in the microbiome of AD
elders. My preliminary studies reveal that a metabolic product of AE, (S)-equol, prevents epithelial damage in
the setting of inflammation. Therefore, we aim to determine whether AE or its metabolic products protect the
intestinal epithelium. To untangle the role of the AD microbiome on our observed changes in class switched and
naïve B cells, I have collected preliminary data which demonstrates that colonization of mice with the microbiome
of AD elders promotes B cell class switching when compared with colonization of cognitively impaired elders
without AD. This application proposes to expand this finding and characterize the changes in the adaptive
immune system caused by the AD microbiome. This continuing work will further establish the connection
between AD related neurocognitive decline, the microbiome, and immune system.

## Key facts

- **NIH application ID:** 10990985
- **Project number:** 5F30AG079575-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ethan Bailey Loew
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,260
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990985

## Citation

> US National Institutes of Health, RePORTER application 10990985, Understanding the regulation of the intestinal epithelium in Alzheimer’s disease by commensal bacteria and the role it plays in preventing neurocognitive decline (5F30AG079575-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10990985. Licensed CC0.

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