# Role of altered gut immune response in Lewy Body Disease

> **NIH NIH U01** · STANFORD UNIVERSITY · 2024 · $465,704

## Abstract

PROJECT SUMMARY/ABSTRACT
Lewy Body Diseases (LBD), which include Parkinson's Disease (PD) and dementia with Lewy bodies (DLB),
represents a spectrum of progressive, debilitating neurological disorders for which there is no cure. Emerging
evidence indicates that for some individuals with LBD and those with prodromal LBD (pLBD), including those
with isolated REM Sleep Behavior Disorder (iRBD), peripheral organs are involved including the gut.
Furthermore, peripheral insults including alterations to the gut microbiota, immune dysregulation, and toxin
exposure have been implicated in disease pathogenesis. However, few studies have provided comprehensive
characterization of pathologic, immunologic, microbiologic and physiologic parameters in patients with PD or
iRBD thereby precluding definitive conclusions about the role peripheral organs have in pathobiology and
disease signatures. The proposed multidisciplinary study will integrate novel technologies and
concepts exploring the interplay between the gut microbiota and the immune system in the
pathogenesis of LBD. We have found that a population of gut macrophages (MΦs) residing in the enteric
nervous system (ENS), an autonomous branch of the peripheral nervous system that spans the
gastrointestinal (GI) tract, shares genetic and functional characteristics with microglia, the predominant brain
MΦ population critical to both pathogenesis and prevention of neurodegenerative disease. We identified
clearance of α-synuclein (α-SYN) aggregates, the pathologic hallmark of LBD, as a homeostatic function of
these MΦs. We propose a novel paradigm whereby the gut microbiome influences neurodegenerative disease
through immune mechanisms. We hypothesize that altered gut neuro-immune interactions, mediated by
microbial derived factors, promotes LBD progression. We will test this hypothesis through the following Aims:
Aim 1 will use a multi-modal approach to characterized peripheral involvement in PD, iRBD and healthy
controls. Our analysis will include use of (i) a novel wearable HR-EGG-EEG device to interrogate gut-brain
function, (ii) seed amplification assay on biopsy tissue to investigate enteric Lewy pathology, (iii) fecal analysis
to evaluate microbiota structure/function, and (iv) characterization of immune response with flow cytometry,
NanoString analysis, and immunoassays on colon biopsies and paired serum. Aim 2 will assess whether the
microbiota promotes LBD by gut immune mechanisms. We will directly test stool collected in Aim 1 on mice
using fecal microbiota transplants and evaluate effects on gut immune phenotype/function. We will utilize an α-
SYN gut injection model to explore how microbiota modulation affects PD progression. Successful completion
of the proposed studies will help understand critical pathophysiological pathways involved in early-stage
PD and inform novel strategies to prevent, risk stratify, and treat those at risk for LBD.

## Key facts

- **NIH application ID:** 10988065
- **Project number:** 1U01DK140939-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Laren Becker
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,704
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988065

## Citation

> US National Institutes of Health, RePORTER application 10988065, Role of altered gut immune response in Lewy Body Disease (1U01DK140939-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10988065. Licensed CC0.

---

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