Shotgun metagenomic analysis reveals taxonomic and functional alterations in the gut microbiome across prodromal and symptomatic Lewy body disease.

Background: Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut-brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Methods: Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Results: Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. Discussion: These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.