Exploring the relationship between GBA1 host genotype and gut microbiome in the 1 GBA1L444P/WT mouse model: Implications for Parkinson disease pathogenesis

Heterozygous GBA1 variants are the most common genetic risk factor for Parkinson's disease (PD), though their penetrance is incomplete. GBA1 dysfunction has been linked to gastrointestinal disturbances and microbiome alterations in preclinical models. Emerging evidence suggests that the microbiota-gut-brain axis may contribute to PD pathogenesis. However, whether GBA1 heterozygosity influences gut microbiome composition remains unclear. Fecal samples from GBA1L444P/WT and GBA1WT/WT mice at 3 and 6 months of age were analyzed using shotgun metagenomic sequencing to assess microbial diversity and composition. No significant differences in a- or ß-diversity were detected between genotypes at either time point. Overall, the gut microbiome composition and functional potential exhibited minimal variation between GBA1L444P/WT and GBA1 WT/WT mice over time. Heterozygosity for the GBA1 L444P variant does not appear to influence gut microbiome structure or composition in this mouse model. Future research exploring the impact of additional genetic or environmental factors on gut physiology and microbiome composition may help explain the incomplete penetrance of GBA1 variants in PD.