Role of altered gut immune response in Lewy Body Disease

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.