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Altered Gut Microbiome in Parkinson’s Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model.

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2019

Front Neurosci. 2019 Aug 7;13:839. doi: 10.3389/fnins.2019.00839. eCollection 2019.

Altered Gut Microbiome in Parkinson's Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model.

AM Gorecki;L Preskey;MC Bakeberg;JE Kenna;C Gildenhuys;G MacDougall;SA Dunlop;FL Mastaglia;PA Akkari;F Koengten;RS Anderton

Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia. Centre for Neuromuscular & Neurological Disorders, The University of Western Australia, Crawley, WA, Australia. Ozgene Pty Ltd., Bentley, WA, Australia. School of Medicine, The University of Notre Dame Australia, Fremantle, WA, Australia. Institute for Health Research and School of Health Sciences, The University of Notre Dame Australia, Fremantle, WA, Australia. School of Biological Sciences, The University of Western Australia, Nedlands, WA, Australia. The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia.

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Abstract

The interaction between the gut microbiota and alpha-synuclein (αSyn) aggregation in Parkinson's disease (PD) is receiving increasing attention. The objective of this study was to investigate gut microbiota, and effects of an inflammatory lipopolysaccharide (LPS) trigger in a human αSyn over-expressing mouse model of PD (Thy1-αSyn). Stool samples from patients with confirmed PD and Thy1-αSyn mice were analyzed using 16S ribosomal RNA sequencing. Compared to healthy controls, the relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients. In mice, the abundance of Gammaproteobacteria was negligible in both Thy1-αSyn and wild-type (WT) animals, while Verrucomicrobiae were reduced in Thy1-αSyn mice. The effect of LPS on intestinal barrier function was investigated in vitro using intestinal epithelial (IEC-6) cells, and in vivo via administration of LPS in drinking water to Thy1-αSyn mice. Acute exposure to LPS in vitro resulted in a reduction and altered distribution of the tight junction markers ZO-1 and e-Cadherin around the cell membrane in IEC-6 cells, as shown by immunohistochemistry. LPS administration in Thy1-αSyn mice resulted in the emergence of early motor manifestations at 10 weeks, compared to untreated mice who were still asymptomatic at this age. This study reaffirms that an altered microbiome exists in patients with PD, and supports the notion of a proinflammatory gut microbiome environment as a trigger for PD pathogenesis.

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