W202 - Investigating Microbiota-immune Interactions in the 3KL Model of Parkinson’s Disease

Abstract Text: The gut microbiome and inflammation are implicated in Parkinson's disease (PD), yet the specific microbial players and immunologic mechanisms remain unclear. To explore how gut microbes influence PD progression, we used individual antibiotics to deplete specific bacterial populations in the 3KL mouse model of PD. Mice were treated with metronidazole, neomycin, or penicillin from 7-12 months of age, followed by motor function testing. Longitudinal stool samples were analyzed via 16S rRNA sequencing, and microglial responses were characterized using RNA sequencing.
We found that metronidazole slowed motor dysfunction progression in male 3KL mice, measured by hindlimb clasping. 16S sequencing revealed that metronidazole selectively depleted Alistipes muris, but not Alistipes in mice treated with neomycin or penicillin. KEGG pathway analysis of microglial RNA sequencing indicated that metronidazole altered disease-relevant processes such as PD and mitophagy, and modulated immune processes including Th17 cell differentiation and IL-17 signaling. These findings suggest that metronidazole slowed motor dysfunction by reducing Alistipes and dampening peripheral inflammatory responses, along with altering microglial transcriptional profiles associated with PD and inflammation.
Further experiments with Alistipes muris revealed that its administration worsened the motor phenotype, increased pro-inflammatory cytokine production, and enhanced CD8+ T cell IFN-γ and γδ T cell IL-17 secretion. These results suggest that Alistipes, abundant in PD, exacerbates disease through its effects on microglia and peripheral immunity, particularly via IL-17 signaling, offering potential targets for therapeutic intervention.