Gut Microbiota as Modulators and Therapeutic Targets in Parkinson’s Disease

The gastrointestinal (GI) tract is a unique junction of the nervous system, immune system, and the gut microbiome. The gut microbiome, a complex community of bacteria, fungi, and viruses, is able to regulate host development, behavior, immunity, and disease. In Parkinson’s disease (PD), a neurodegenerative disorder characterized by motor dysfunction, α-synuclein (αSyn) pathology, and common GI symptoms, the gut bacterial composition is significantly altered, with depletions in beneficial, anti-inflammatory taxa compared to healthy controls. This thesis explores whether specific gut bacteria may be disease-protective. We first assembled a consortium of taxa that are reduced in individuals with PD across multiple cohorts and geographies. We find that both therapeutic and prophylactic oral administration of this consortium to Thy-1-αSyn overexpressing (Thy1-ASO) mice, a preclinical model of PD, improves select motor and GI deficits and reduces αSyn pathology in the brain. We next identified three taxa that independently drive motor function improvements, with Faecalibacterium prausnitzii producing the most pronounced effects. Further characterization of treatment with F. prausnitzii revealed improvements in GI symptoms, reduced αSyn aggregates in the brain, remodeling of the gut microbiome, and induction of anti-inflammatory and tissue-regenerative pathways in the colon. Collectively, these findings provide a foundation for developing specific bacterial species as novel therapeutics for PD and highlight the broader potential of the gut microbiome to transform the way we understand and treat human health and disease.