# Investigating how the microbiota modulates neuroinflammatory signaling and neurodegeneration in Parkinson's disease and dementia

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $482,138

## Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are complex diseases involving gene-
environment interplay that lead to alpha-synuclein (a-synuclein aggregation). Recent investigations suggest that
the gut microbiome can modulate neuroinflammatory responses to hallmark a-synuclein aggregation, but little is
known about specific gut microbial mediators. Studying rare kindreds with inherited forms of neurodegeneration
that closely mimic sporadic disease has proved invaluable to the field, offering a window to understand idiopathic
disease in a more controlled genetic and environmental background. We are investigating environmental
determinants of disease penetrance utilizing microbiome samples from such a family harboring an alpha-
synuclein (a-synuclein) E46>K mutation and exhibiting a spectrum of clinical PD dementia (PDD)/DLB outcomes,
that pathologically mimic sporadic forms of these diseases. We hypothesize that gut microbiota contributes
to the development of PDD/DLB through the secretion of metabolites that affect neuroinflammatory
signaling and neuronal function. In our preliminary data, first we identified specific bacterial species
associated with PDD/DLB disease penetrance, some of which have been previously reported to be altered in
PD. Second, we found that transfer of the PDD/DLB gut microbiota into a PD mouse model (with amplified E46>K
mutation) enhanced motor and cognitive deficits. Third, PDD/DLB microbiome transfer altered microglial
transcriptional profiles suggesting that changes in microbiota could contribute to disease pathogenesis through
neuroimmune modulation. In this proposal, we aim to identify microbes and metabolites which are linked with
PDD/DLB pathogenesis using in vivo models and evaluate whether these metabolites directly affect microglial
function and neuronal survival in vitro in PDD/DLB induced pluripotent stem cell (iPSC)-derived cultures. First,
to investigate potential gut-brain axis mechanisms associated with altered motor and cognitive function, we will
identify changes in the gut metagenome and metabolites, analyze altered microglia transcriptional profiles and
evaluate a-synuclein pathology in PDD/DLB-microbiota colonized mice, when compared to mice colonized with
either healthy control or CNS asymptomatic E46K carrier microbiome. Second, to determine the impact of
microbial metabolites on pathways involved in PDD/DLB, we will treat E46K PDD/DLB patient and gene
corrected iPSC-derived microglia and neuronal cultures with either bacterial supernatants from in-house isolated
microbial species abundant in E46K PDD/DLB individuals, or media from bacteria-sensitized microglia. We will
evaluate the neuroinflammatory cytokine and chemokine profile, microglia transcriptional profiles, neurite
outgrowth and survival, and a-synuclein pathology to determine the mechanistic impact of PDD/DLB microbial
metabolites on variable disease penetrance in vitro. The knowledge gained and model systems established...

## Key facts

- **NIH application ID:** 10575564
- **Project number:** 1R21NS130500-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Laura Michelle Cox
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $482,138
- **Award type:** 1
- **Project period:** 2022-09-06 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10575564

## Citation

> US National Institutes of Health, RePORTER application 10575564, Investigating how the microbiota modulates neuroinflammatory signaling and neurodegeneration in Parkinson's disease and dementia (1R21NS130500-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10575564. Licensed CC0.

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