Altered gut microbiome in Parkinson's disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model

Anastazja M. Gorecki, Leah Preskey, Megan C. Bakeberg, Jade E. Kenna, Christi Gildenhuys, Gabriella MacDougall, Sarah A. Dunlop, Frank L. Mastaglia, P. Anthony Akkari, Frank Koengten, Ryan S. Anderton

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number839
JournalFrontiers in Neuroscience
Volume13
Issue numberJUL
DOIs
Publication statusPublished - Aug 2019

Fingerprint

Synucleins
Parkinson Disease
Lipopolysaccharides
Gammaproteobacteria
16S Ribosomal RNA
RNA Sequence Analysis
alpha-Synuclein
Wild Animals
Tight Junctions
Microbiota
Mucins
Cadherins
Gastrointestinal Microbiome
Drinking Water
Immunohistochemistry
Cell Membrane

Cite this

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title = "Altered gut microbiome in Parkinson's disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model",
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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author = "Gorecki, {Anastazja M.} and Leah Preskey and Bakeberg, {Megan C.} and Kenna, {Jade E.} and Christi Gildenhuys and Gabriella MacDougall and Dunlop, {Sarah A.} and Mastaglia, {Frank L.} and {Anthony Akkari}, P. and Frank Koengten and Anderton, {Ryan S.}",
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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. / Gorecki, Anastazja M.; Preskey, Leah; Bakeberg, Megan C.; Kenna, Jade E.; Gildenhuys, Christi; MacDougall, Gabriella; Dunlop, Sarah A.; Mastaglia, Frank L.; Anthony Akkari, P.; Koengten, Frank; Anderton, Ryan S.

In: Frontiers in Neuroscience, Vol. 13, No. JUL, 839, 08.2019.

Research output: Contribution to journalArticle

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AU - Gildenhuys, Christi

AU - MacDougall, Gabriella

AU - Dunlop, Sarah A.

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