Exploring the relationship between GBA1 host genotype and gut microbiome in the GBA1L444P/WT mouse model: implications for Parkinson’s disease pathogenesis

Abstract

Background: Heterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson’s 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. Objectives: This study aimed to evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. Methods: Faecal samples collected from GBA1L444P/WT and GBA1WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing. Results: No differences in α- and β-diversities were detected between genotyped groups, at either time point. Overall, we found a little variation in the gut microbiome composition and functional potential between GBA1L444P/WT and GBA1WT/WT mice over time. Conclusion: Host GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1L444P/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.