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Cited by 184Parkinson's Disease Mechanisms and TreatmentsGut microbiota and healthNeuroinflammation and Neurodegeneration Mechanisms

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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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Gorecki, Anastazja M., Preskey, Leah, Bakeberg, Megan C., Kenna, Jade E., Gildenhuys, Christi, MacDougall, Gabriella, Dunlop, Sarah A., Mastaglia, Frank L., Akkari, P. Anthony, Koengten, Frank, Anderton, Ryan S.·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2019.00839PMC PMC6693556
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Abstract

The interaction between the gut microbiota and alpha-synuclein (Syn) 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 Syn over-expressing mouse model of PD (Thy1-αSyn). Stool samples from patients with confirmed PD and Thy1-Syn mice were analysed 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-Syn 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-Syn 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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FIGURE 1 Mean class abundance in people with Parkinson’s disease and healthy controls. Individuals with Parkinson’s disease (PD) were grouped by a clinician. Pie charts illustrate the mean relative abundance of bacterial classes in healthy controls and individuals with mild or severe PD (A). Comparison of the six most abundant classes demonstrates a significant increase in Gammaproteobacteria in mild PD compared to controls (621.22× fold, p < 0.05), and significantly elevated levels of Verrucomicrobiae in severe PD patients, when compared to mild PD patients (4.35× fold, p < 0.05) (B).
FIGURE 1 Mean class abundance in people with Parkinson’s disease and healthy controls. Individuals with Parkinson’s disease (PD) were grouped by a clinician. Pie charts illustrate the mean relative abundance of bacterial classes in healthy controls and individuals with mild or severe PD (A). Comparison of the six most abundant classes demonstrates a significant increase in Gammaproteobacteria in mild PD compared to controls (621.22× fold, p < 0.05), and significantly elevated levels of Verrucomicrobiae in severe PD patients, when compared to mild PD patients (4.35× fold, p < 0.05) (B).CC BY · PubMed Central
FIGURE 2 Progessively increasing brain αSyn levels are not associated with notable motor impairments in 12-week old mice. Compared to WT mice, the Thy1-αSyn mice exhibit progressively increasing human and total αSyn in whole brain lysates compared to WT mice at 4, 8 and 12 weeks of age (A). There were no significant differences in hind-limb clasp scores (B) or nasal adhesive removal (C) between animal groups. The weight of both groups increased with age, where the Thy1-αSyn mice consistently weighed less (D).
FIGURE 2 Progessively increasing brain αSyn levels are not associated with notable motor impairments in 12-week old mice. Compared to WT mice, the Thy1-αSyn mice exhibit progressively increasing human and total αSyn in whole brain lysates compared to WT mice at 4, 8 and 12 weeks of age (A). There were no significant differences in hind-limb clasp scores (B) or nasal adhesive removal (C) between animal groups. The weight of both groups increased with age, where the Thy1-αSyn mice consistently weighed less (D).CC BY · PubMed Central
FIGURE 3 Thy1-αSyn mice do not demonstrate a pro-inflammatory gut microbiome at 8 weeks of age. Bacteroidia, Clostridia and Bacilli account for the majority of the microbiome in both WT and Thy1-αSyn mice as per 16S rRNA sequencing at 8 weeks of age (A). Thy1-αSyn mice exhibit a significantly lower abundance of Verrucomicrobiae, however, the mean relative abundance of Bacteroidia, Clostridia, Bacilli, Coriobacteria and Betaproteobacteria are not significantly different (B).
FIGURE 3 Thy1-αSyn mice do not demonstrate a pro-inflammatory gut microbiome at 8 weeks of age. Bacteroidia, Clostridia and Bacilli account for the majority of the microbiome in both WT and Thy1-αSyn mice as per 16S rRNA sequencing at 8 weeks of age (A). Thy1-αSyn mice exhibit a significantly lower abundance of Verrucomicrobiae, however, the mean relative abundance of Bacteroidia, Clostridia, Bacilli, Coriobacteria and Betaproteobacteria are not significantly different (B).CC BY · PubMed Central
FIGURE 4 Gammaproteobacteria-produced LPS treatment increases intestinal permeability in vitro. IEC-6 cells express TLR4, a known LPS receptor (A). Acute LPS treatment (10 μg/ml for 4 h) resulted in a noticeable reduction of and alteration in the distribution of ZO-1 (B) and e-Cadherin (C).
FIGURE 4 Gammaproteobacteria-produced LPS treatment increases intestinal permeability in vitro. IEC-6 cells express TLR4, a known LPS receptor (A). Acute LPS treatment (10 μg/ml for 4 h) resulted in a noticeable reduction of and alteration in the distribution of ZO-1 (B) and e-Cadherin (C).CC BY · PubMed Central
FIGURE 5 LPS treatment mildly exacerbates motor impairments in Thy1-αSyn mice. After LPS consumption (10 μg/ml) in drinking water for 12 nights, mean hindlimb clasp reflex (HC) score was significantly higher than baseline (A) and compared to untreated Thy1-αSyn mice (E), while WT scores remained normal at all time points (B,F). Mean adhesive removal time for Thy1-αSyn mice demonstrated a non-significant increase compared to baseline (C), however, was lower than untreated 10-week-old Thy1-αSyn mice (G). LPS-treated WT mice were non-significantly faster than baseline (D) and slightly slower than untreated animals at 10-week old (H).
FIGURE 5 LPS treatment mildly exacerbates motor impairments in Thy1-αSyn mice. After LPS consumption (10 μg/ml) in drinking water for 12 nights, mean hindlimb clasp reflex (HC) score was significantly higher than baseline (A) and compared to untreated Thy1-αSyn mice (E), while WT scores remained normal at all time points (B,F). Mean adhesive removal time for Thy1-αSyn mice demonstrated a non-significant increase compared to baseline (C), however, was lower than untreated 10-week-old Thy1-αSyn mice (G). LPS-treated WT mice were non-significantly faster than baseline (D) and slightly slower than untreated animals at 10-week old (H).CC BY · PubMed Central

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  1. Ouyang, 2012, Direct Data Submission 2012/03/09., MGI Dir. Data Submission.

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Authors
Gorecki, A. M., Preskey, L., Bakeberg, M. C., Kenna, J. E., Gildenhuys, C., MacDougall, G., Dunlop, S. A., Mastaglia, F. L., Akkari, P. A., Koengten, F., & Anderton, R. S.
Affiliations
  • The University of Western Australia (AU)
  • The University of Notre Dame Australia (AU)
  • Perron Institute for Neurological and Translational Science (AU)
  • Murdoch University (AU)
Corresponding author
Anderton, Ryan S.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-08-07
Volume
13
Pages
839-839
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2019.00839
PMC
PMC6693556
OpenAlex
W2965437143
Cited by
184
References
76
Citations by year
2026: 7 · 2025: 22 · 2024: 35 · 2023: 28 · 2022: 30 · 2021: 43 · 2020: 19
FWCI
15.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Murdoch University Research Portal (submittedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by)
  • ResearchOnline@ND (The University of Notre Dame) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Armstrong Foundation
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Parkinson's disease, gut microbiota, alpha-synuclein, lipopolysaccharide, Gammaproteobacteria, intestinal barrier function, tight junctions, ZO-1, E-cadherin, motor symptoms, neuroinflammation, microbiome-gut-brain axis

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