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Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson’s disease

Peipei Li, Bryan A. Killinger, Ian Beddows, Elizabeth Ensink, Ali Yilmaz, Noah Lubben, Jared Lamp, Meghan Schilthuis, Irving E. Vega, Markus Britschgi, J. Andrew Pospisilik, Patrik Brundin, Lena Brundin, Stewart Graham, Viviane Labrie
doi: https://doi.org/10.1101/2020.09.26.279851
Peipei Li
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
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  • For correspondence: peipei.li@vai.org
Bryan A. Killinger
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
2Department of Neurological Sciences, Rush Medical College, Chicago, IL, 60612 USA
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Ian Beddows
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
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Elizabeth Ensink
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
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Ali Yilmaz
3Metabolomics Department, Beaumont Health-Research Institute, Royal Oak, MI, 48073 USA
4Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309 USA
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Noah Lubben
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
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Jared Lamp
5Integrated Mass Spectrometry Unit, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
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Meghan Schilthuis
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
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Irving E. Vega
5Integrated Mass Spectrometry Unit, Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
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Markus Britschgi
6Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center, 13 Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
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J. Andrew Pospisilik
7Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, 49503 USA
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Patrik Brundin
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
8Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
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Lena Brundin
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
8Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
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Stewart Graham
3Metabolomics Department, Beaumont Health-Research Institute, Royal Oak, MI, 48073 USA
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Viviane Labrie
1Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503 USA
8Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503 USA
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Abstract

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD) patients. Here, we investigate changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. We find microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for secondary bile acid synthesis. Proteomic and transcript analysis corroborates a disruption in cholesterol homeostasis and lipid catabolism. Bile acid analysis reveals an increase in microbially-derived, toxic secondary bile acids. Synucleinopathy in mice induces similar microbiome alterations to those of PD patients. The mouse model of synucleinopathy has elevated DCA and LCA. An analysis of blood markers shows evidence of biliary abnormalities early in PD, including elevated alkaline phosphatase and bilirubin. Increased bilirubin levels are also evident before PD diagnosis. In sum, microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.

Competing Interest Statement

MB is a full-time employee at Roche and may additionally hold Roche stock/stock options. P.B. has received commercial support as a consultant from Axial Biotherapeutics, Calico, CuraSen, Fujifilm-Cellular Dynamics International, IOS Press Partners, LifeSci Capital LLC, Lundbeck A/S, Idorsia and Living Cell Technologies LTD. He has received commercial support for grants/research from Lundbeck A/S and Roche. He has ownership interests in Acousort AB and Axial Biotherapeutics and is on the steering committee of the NILO-PD trial. No other authors have conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 28, 2020.
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Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson’s disease
Peipei Li, Bryan A. Killinger, Ian Beddows, Elizabeth Ensink, Ali Yilmaz, Noah Lubben, Jared Lamp, Meghan Schilthuis, Irving E. Vega, Markus Britschgi, J. Andrew Pospisilik, Patrik Brundin, Lena Brundin, Stewart Graham, Viviane Labrie
bioRxiv 2020.09.26.279851; doi: https://doi.org/10.1101/2020.09.26.279851
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Gut microbiome dysbiosis is associated with elevated toxic bile acids in Parkinson’s disease
Peipei Li, Bryan A. Killinger, Ian Beddows, Elizabeth Ensink, Ali Yilmaz, Noah Lubben, Jared Lamp, Meghan Schilthuis, Irving E. Vega, Markus Britschgi, J. Andrew Pospisilik, Patrik Brundin, Lena Brundin, Stewart Graham, Viviane Labrie
bioRxiv 2020.09.26.279851; doi: https://doi.org/10.1101/2020.09.26.279851

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