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| Status |
Public on Aug 01, 2021 |
| Title |
Gut microbiome dysregulation is associated with elevated toxic bile acids in Parkinson’s disease |
| Organism |
mouse gut metagenome |
| Experiment type |
Other
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| Summary |
The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. The vermiform appendix is a lymphoid tissue implicated in the storage and regulation of the gut microbiome. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. In the PD appendix, we find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Likewise, proteomic and transcript analysis in the PD gut corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis in the PD appendix reveals an increase in the microbially-derived, toxic secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA). Synucleinopathy in mice induces similar microbiome alterations to those of PD patients and heightens microbial changes to gut inflammation. As observed in PD, the mouse model of synucleinopathy has elevated DCA and LCA. Raised levels of DCA and LCA can lead to liver injury, and an analysis of blood markers of liver dysfunction shows evidence of biliary abnormalities in PD patients, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis, in individuals at-risk of developing PD. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.
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| Overall design |
The cecal patch microbiome was profiled in a mouse model of synucleinopathy as well as in response to gut inflammation. We examined microbiome changes by 16S rRNA sequencing of the V3-V4 hypervariable region. Microbiome changes were profiled in wild-type mice and in the synucleinopathy model: hemizygous Tg(Thy1-SNCA*A30P)18Pjk mice (A30P α-syn), which overexpress human α-syn with the A30P mutation under the neuron-selective Thy1 promoter. A30P α-syn mice have been maintained on a C57BL/6 background for over 10 generations. Gut inflammation was induced using dextran sodium sulfate (DSS), a widely used model of ulcerative colitis. Adult wild-type and A30P α-syn mice (3-months of age) were exposed to a chronic DSS protocol that began at DSS concentration of 2.5% and increased to 4% over 4 cycles (+0.5% increment per cycle). One cycle consisted of 5 days of DSS, followed by 2 days of water (DSS: 160110, MP Biomedicals, LLC). The non-DSS colitis groups were administered normal drinking water. Mice were then given a 4-week-long recovery period during which they received normal drinking water, followed by tissue harvest.
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| Contributor(s) |
Li P, Killinger BA, Beddows I, Ensink E, Yilmaz A, Lubben N, Lamp J, Schithuis M, Vega I, Britschgi M, Pospisilik A, Brundin P, Brundin L, Graham S, Labrie V |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Aug 21, 2020 |
| Last update date |
Aug 01, 2021 |
| Contact name |
Peipei Li |
| E-mail(s) |
[email protected]
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| Phone |
6162345547
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| Organization name |
Van Andel Research Institute
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| Department |
Center for Neurodegenerative Science
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| Lab |
Labrie lab
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| Street address |
333 Bostwick Ave N.E.
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| City |
Grand Rapids |
| State/province |
MI |
| ZIP/Postal code |
49503 |
| Country |
USA |
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| Platforms (1) |
| GPL21051 |
Illumina MiSeq (mouse gut metagenome) |
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| Samples (40)
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| Relations |
| BioProject |
PRJNA658581 |
| SRA |
SRP278405 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE156647_feature-table.biom.tsv.gz |
1.4 Mb |
(ftp)(http) |
TSV |
| GSE156647_level-1.csv.gz |
357 b |
(ftp)(http) |
CSV |
| GSE156647_level-2.csv.gz |
1.0 Kb |
(ftp)(http) |
CSV |
| GSE156647_level-3.csv.gz |
1.5 Kb |
(ftp)(http) |
CSV |
| GSE156647_level-4.csv.gz |
1.8 Kb |
(ftp)(http) |
CSV |
| GSE156647_level-5.csv.gz |
3.1 Kb |
(ftp)(http) |
CSV |
| GSE156647_level-6.csv.gz |
6.3 Kb |
(ftp)(http) |
CSV |
| GSE156647_level-7.csv.gz |
6.8 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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