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Author Notes:

Adjunct Prof. Dr. med. Filip Scheperjans, Department of Neurology, Helsinki University Hospital, and Clinicum, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland; E‐mail: filip.scheperjans@hus.fi

Conceptualization: A.X., E.E., P.L., J.G., L.L.M., and V.L.; data curation: E.E., V.T.E.A., M.C.H., K.R., L.P., P.A.B.P., M.G.T., P.A., and F.S.; formal analysis: AX; funding acquisition: J.A.P., P.B., L.B., F.S., and V.L.; investigation: P.B., L.B., F.S., and V.L.; methodology: A.X., L.B., and V.L.; visualization: A.X.; writing—original draft: A.X.; writing—review and editing: A.X., E.E., S.G., P.B., L.B., P.A.B.P., V.T.E.A., M.C.H., K.R., M.G.T., and F.S. The authors read and approved the final manuscript.

We dedicate this paper in memory of our research adviser, mentor, and friend, Viviane Labrie. We thank the Van Andel Institute Genomics and Bioinformatics and Biostatistics Cores. Open access funding enabled and organized by Projekt DEAL.

P.B. has received commercial support as consultant from Axial Therapeutics, Calico, CuraSen, Fujifilm‐Cellular Dynamics Inc., 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 Therapeutics. S.G. receives commercial support as consultant from Coleman Research and Biogen. V.T.E.A., P.A.B.P., L.P., P.A., and F.S. have patents issued (FI127671B, EP3149205B1, and US10139408B2) and pending (US20190137493A1, US20210109098A1, and EP3789501A1) that are assigned to NeuroBiome Ltd. F.S. is founder and CEO of NeuroInnovation Oy and NeuroBiome Ltd., is a member of the scientific advisory board, and has received consulting fees and stock options from Axial Biotherapeutics. F.S. has received grants from the Academy of Finland, the Hospital District of Helsinki and Uusimaa, OLVI‐Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Wilhelm and Else Stockmann Foundation, the Emil Aaltonen Foundation, the Yrjö Jahnsson Foundation, and Renishaw and honoraria from AbbVie, Orion, GE Healthcare, Merck, Teva, Bristol Myers Squibb, Sanofi, and Biogen. M.G.T. is an ex‐employee of Xencor Inc. and coinventor of dominant‐negative TNF inhibitor (XPro1595) as well as consultant for INmune Bio and holds stock ownership in the company. She is a consultant for and/or collaborates with Longevity Biotech, Cerebral Therapeutics, Innoviva, iMetabolic Pharma, Amylyx, Biogen/IONIS, Nanobiotix, and Jaya. She serves on the Medical Scientific Advisory Board of the Alzheimer's Association and the World Parkinson Coalition and is advisor for the Weston Family Foundation, The Michael J. Fox Foundation for Parkinson's Research, and the Quebec Parkinson's Network. She is editor‐in‐chief of Nature's Parkinson's Disease and serves on the editorial boards of Science Advances, Experimental Neurology, Neurobiology of Disease, Journal of Neuroinflammation, Journal of Parkinson's Disease, and PLoS ONE. Her research is funded by The Michael J. Fox Foundation, the NIH, and the Parkinson's Foundation. L.B. was supported by the Farmer Family Foundation and the Michigan State University Gibby and Friends versus Parky Parkinson's Disease Research for this project. Other support she received include NIH R01 MH118211 and MJFF grant 010296. K.R., P.L., J.A.P., A.X., L.L.M., M.C.H., and E.E. have nothing to disclose.

Subject:

Research Funding:

This work was supported by a Farmer Family Foundation grant award and a Gibby & Friends versus Parky Award to P.B., with L.B., J.A.P., and V.L. F.S. received funding from The Michael J. Fox Foundation for Parkinson's Research, the Academy of Finland (295724 and 310835), the Hospital District of Helsinki and Uusimaa (UAK1014004, UAK1014005, and TYH2018224), the Finnish Medical Foundation, and the Finnish Parkinson Foundation.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • Parkinson's disease
  • DNA methylation
  • microbiome
  • epigenetics
  • gut brain axis
  • LD SCORE REGRESSION
  • CHAIN FATTY-ACIDS
  • SODIUM-BUTYRATE
  • GUT MICROBIOTA
  • ENRICHMENT ANALYSIS
  • SUBSEQUENT RISK
  • METHYLATION
  • METABOLISM
  • BLOOD
  • DIET

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms

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Journal Title:

MOVEMENT DISORDERS

Volume:

Volume 37, Number 8

Publisher:

, Pages 1644-1653

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives: Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods: Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results: We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions: Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Copyright information:

© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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