# Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer's disease

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2022 · $434,655

## Abstract

ABSTRACT
Recent advances have helped to uncover critical roles for gut microbiota in a spectrum of neurological disorders
including many neurodegenerative diseases. In the case of Alzheimer’s disease (AD), it has been shown in both
AD patients and animal models that neurodegenerative disease progression is associated with large-scale
changes in gut microbiota composition. Moreover, recent data also suggest that ablation of the microbiome with
either germ-free re-derivation or chronic treatment with broad-spectrum antibiotics water limits amyloidosis in
mice that over-express amyloid beta (Ab). While these findings have led to excitement over the potential role for
microbial dysbiosis in AD, numerous fundamental questions still remain to be answered on this topic. For one,
all of these previous studies have only explored the impact of the murine microbiome on neurodegenerative
disease and have not investigated how the specific dysbiosis seen in AD patients affects neurological disease
progression. Given the major differences that exist between the mouse and human microbiome, it will be
important to specifically probe how alterations in human gut microbiota influence neurodegenerative disease
processes. In addition, little is currently known regarding how microbial dysbiosis affects tauopathy. To fill these
gaps in knowledge, we will transplant gut microbiota from either AD patients or age- and sex-matched controls
into germ-free 3xTg-AD mice, which is a well-described mouse model of AD that develops age-related and
progressive Ab-induced neurological disease and tauopathy. The impact of human AD-associated dysbiosis on
disease progression will then be determined by evaluating Ab deposition, tauopathy, neurodegeneration,
neuroinflammation, and cognitive performance (Aim 1). Recent studies in other non-AD models of
neurodegenerative disease suggest that the gut microbiota can influence disease progression via modulation of
the immune system and/or by promoting changes in metabolite generation. Therefore, in our second Aim, we
will next leverage cutting-edge single-cell RNA-sequencing (scRNA-seq) and metabolomics approaches to
provide a comprehensive and unbiased assessment of how AD-associated dysbiosis affects immune responses
and the metabolome in our human microbiota transplantation AD mouse model. Our overarching hypothesis is
that microbial dysbiosis in AD patients leads to exacerbated neurodegenerative disease progression and that
this is associated with dysregulation of immune responses and the metabolome. Successful completion of these
proposed research directions will break new ground in our understanding of the role of AD-associated dysbiosis
in neurodegenerative disease pathogenesis and will also begin to reveal prospective factors underpinning the
effects of the human AD microbiome on disease progression. Furthermore, findings from these studies are of
potential translational significance as they could help to establish the microbiome as...

## Key facts

- **NIH application ID:** 10370667
- **Project number:** 1R21AG075836-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** John R Lukens
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,655
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370667

## Citation

> US National Institutes of Health, RePORTER application 10370667, Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer's disease (1R21AG075836-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10370667. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*