Tu195 - Derangements of the Systemic Immunome in Parkinson’s Disease May Reshape the Microbiome: Possible Pathogenic Relevance on the Gut-brain Axis

Abstract Text: Background
The pathogenic relevance of the gut-brain axis in Parkinson’s Disease (PD) remains poorly understood, despite a growing evidence showing anomalies of the immune system, and reduction of certain species in the gut flora. We hypothesize that the systemic immunome in PD is deranged and targets gut bacteria that may influence dopamine production.

Approach
We employed high-dimensionality CyTOF and scRNA-seq to explore the systemic immunome in PD patients (n=13), age and gender matched with healthy controls (n=14). Based on a meta-analysis of PD microbiome, we focused on a Lachnospiraceae species which is consistently reduced in PD and potentially linked to dopamine production. We obtained its bacterial extract and engineered a protein encompassing the catalytic site of SadA, a key protein for dopamine synthesis, using both as targets for in-vitro immune responses.

Results
The immunome architecture in PD differed significantly from healthy subjects, with network relationships between regulatory and inflammatory subsets indicating an imbalance. An aberrant, species-specific, pro-inflammatory response was detected, marked by SadA-specific cytotoxic T cells (CD8A+ NKG7+), expressing CCL4 and suggesting transit through gut mucosa. Pro-inflammatory monocytes expressing CD93, S100A8, S100A9, and integrin receptor ITGB8, also suggesting their transit through the gut mucosa, were detected after stimulation with bacterial extract.

Conclusion
Our data opens a novel perspective on the gut-brain axis in PD, highlighting immune aberrations, that drive the ablation of bacterial species, probably useful in reducing the dependency of endogenous dopamine production, which is inherently impaired in PD.