Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Parkinson’s disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker.

Methods

We performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls.

Results

We found increased Verrucomicrobiaceae ( Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae ( Prevotella copri) and Erysipelotrichaceae ( Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions.

Conclusions

Our data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.

Electronic supplementary material

The online version of this article (doi:10.1186/s13073-017-0428-y) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 43

Record: found
Abstract: not found
Article: not found

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

0 comments Cited 23666 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The inflammatory reflex.

Kevin J. Tracey (2002)

Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems.

0 comments Cited 438 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

Christopher Forsyth, Kathleen M Shannon, Jeffrey Kordower … (2011)

Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. Trial Registration Clinicaltrials.gov NCT01155492

0 comments Cited 230 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

J. R. Bedarf: Janis.bedarf@ukbonn.de

F. Hildebrand: falk.hildebrand@embl.de

L. P. Coelho: coelho@embl.de

S. Sunagawa: ssunagawa@ethz.ch

M. Bahram: bahram@ut.ee

F. Goeser: felix.goeser@ukbonn.de

P. Bork: +49 6221 387-0 , bork@EMBL-Heidelberg.de

U. Wüllner: + 49 228 287 15697 , wuellner@uni-bonn.de

Journal

Journal ID (nlm-ta): Genome Med

Journal ID (iso-abbrev): Genome Med

Title: Genome Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-994X

Publication date (Electronic): 28 April 2017

Publication date PMC-release: 28 April 2017

Publication date Collection: 2017

Volume: 9

Electronic Location Identifier: 39

Affiliations

[1 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department of Neurology, , University of Bonn, ; Bonn, Germany

[2 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, , German Centre for neurodegenerative disease research (DZNE), ; Bonn, Germany

[3 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department of Internal Medicine I, , University of Bonn, ; Bonn, Germany

[4 ]ISNI 0000 0004 0495 846X, GRID grid.4709.a, , European Molecular Biology Laboratory, EMBL, ; Heidelberg, Germany

[5 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, ETH Zurich, , Institute of Microbiology, ; Vladimir-Prelog-1-5/10, 8093 Zurich, Switzerland

[6 ]ISNI 0000 0004 0495 846X, GRID grid.4709.a, Molecular Medicine Partnership Unit (MMPU), , University of Heidelberg and European Molecular Biology Laboratory, ; Heidelberg, Germany

[7 ]ISNI 0000 0001 1014 0849, GRID grid.419491.0, , Max Delbrück Centre for Molecular Medicine, ; 13125 Berlin, Germany

[8 ]ISNI 0000 0001 1958 8658, GRID grid.8379.5, Department of Bioinformatics, , University of Würzburg, ; 97074 Würzburg, Germany

[9 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, , Evolutionary Biology Centre, Uppsala University, ; Norbyva ¨gen 18D, 75236 Uppsala, Sweden

[10 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, , Institute of Ecology and Earth Sciences, University of Tartu, ; 40 Lai St., 51005 Tartu, Estonia

[11 ]GRID grid.452463.2, , German Center for Infection Research (DZIF), ; Bonn-Cologne, Germany

[12 ]Sigmund-Freud-Str. 25, 53127 Bonn, Germany

[13 ]Meyerhofstraße 1, 69117 Heidelberg, Germany

Article

Publisher ID: 428

DOI: 10.1186/s13073-017-0428-y

PMC ID: 5408370

PubMed ID: 28449715

SO-VID: 923d4d76-8cfd-49be-b9c4-6161b69ab1da

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 November 2016

Date accepted : 8 April 2017

Funding

Funded by: PD Fonds Germany gGmbH

Funded by: European Union’s Horizon 2020 research and innovation program,

Award ID: no. 600375

Funded by: partly funded by grants of the German Center for Infection Research (DZIF)

Funded by: Helmut Horten Foundation

Funded by: Helge Ax:son Johnsons Stiftelse and PUT1317

Funded by: European Research Council (ERC) Microbios

Award ID: ERC-AdG-669830

Funded by: EU/EFPIA Innovative Medicines Initiative Joint Undertaking Aetionomy

Award ID: grant number 115568

Funded by: partly supported by the European Molecular Biology Laboratory (EMBL)

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: microbiome,bacteria,archaea,viruses,parkinson,enteric nervous system,gut-brain axis

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: microbiome, bacteria, archaea, viruses, parkinson, enteric nervous system, gut-brain axis

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

Read this article at

Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Bacterial extracellular vesicles

Most cited references 43

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

The inflammatory reflex.

Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 371

Cited by 229