Exploring the relationship between GBA1 host genotype and gut microbiome in the GBA1 L444P/WT mouse model: Implications for Parkinson disease pathogenesis

Elisa Menozzi ^1,2 Mallia Geiger ^2,3 Victoria Meslier ^2,3 Federico Fierli ^1,2 Marine Gilles ³ Kai-Yin Chau ^1,2 Aymeric David ^2,3 Revi Shahar Golan ^1,2 Alexandre Famechon ^2,3 Sofia Koletsi ^1,2 Christian Morabito ^2,3 Benoit Quinquis ^2,3 Nicolas Pons ^2,3 Stanislav Dusko Ehrlich ^1,2 Jane Macnaughtan ^2,4 Mathieu Almeida ^2,3 Anthony HV Schapira ^1,2*

• ¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, London, United Kingdom
• ² Aligning Science Across Parkinson’s (ASAP), Chevy Chase, Maryland, United States
• ³ MetaGenoPoliS, Université Paris-Saclay, Jouy-en-Josas, Île-de-France, France
• ⁴ Institute for Liver and Digestive Health, University College London, London, England, United Kingdom

Heterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete. GBA1 dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by host GBA1 genetics in heterozygosis has never been explored.To evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. Methods Faecal samples collected from GBA1 L444P/WT and GBA1 WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing.No differences in α-and β-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential between GBA1 L444P/WT and GBA1 WT/WT mice over time.Host GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1 L444P/WT mouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance of GBA1 variants in PD.