Objective: This study explores whether host genetics such as specific VPS35 genetic variations linked to PD can shape the gut microbiome.

Background: Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. Recent research underscores the role of gut microbial dysbiosis in the development of PD; however, the link between genetic change and gut microbiota dysbiosis remain poorly understood.

Method: PARK17 has been modeled by heterozygous VPS35(D620N/+) knockin mouse in our group, exhibiting late-onset pathological and behavioral phenotypes of PD. Gut microbiota composition was analyzed by 16S rRNA gene sequencing and data analysis.

Results: We observed significant neurodegeneration in 18-month-old VPS35(D620N/+) knockin mice, with a greater than 70% reduction in TH-positive dopaminergic neurons in the SNpc compared to 12-week-old wild-type C57BL/6J controls, which were accompanied by severe motor deficits, including a 50% reduction in rotarod performance and a 60% increase in pole test descent time. 16S rRNA gene sequencing of fecal samples revealed significant alteration of gut microbiota composition in the PD group compared to WT controls. While α-diversity, representing species richness and evenness, remained similar across groups, β-diversity metrics, including Bray-Curtis dissimilarity and UniFrac distances, indicated distinct microbial community structures between the groups. Both groups were predominantly composed of the bacterial phyla Firmicutes, Bacteroidetes, Proteobacteria, TM7, and Deferribacteres; however, at the genus level, the PD group exhibited higher abundances of Odoribacter, Candidatus Arthromitus, Prevotella, Flexispira, and Anaeroplasma, while the control group was enriched in Coprococcus, Allobaculum, and Anaerostipes.

Conclusion: These findings suggest that PARK17 associated VPS35 genetic variation can cause dysbiosis of gut microbiota.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alterations-in-gut-microbiota-composition-in-vps35-associated-park17-mouse-model/