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Integrated multi-cohort analysis of the Parkinson's disease gut metagenome

Boktor, Joseph C. and Sharon, Gil and Verhagen Metman, Leo A. and Hall, Deborah A. and Engen, Phillip A. and Zreloff, Zoe and Hakim, Daniel J. and Bostick, John W. and Ousey, James and Lange, Danielle and Humphrey, Gregory and Ackermann, Gail and Carlin, Martha and Knight, Rob and Keshavarzian, Ali and Mazmanian, Sarkis K. (2022) Integrated multi-cohort analysis of the Parkinson's disease gut metagenome. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220722-769622000

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Abstract

Background: The gut microbiome is altered in several neurologic disorders including Parkinson's disease (PD). Objectives: Profile the fecal gut metagenome in PD for alterations in microbial composition, taxon abundance, metabolic pathways, and microbial gene products, and their relationship with disease progression. Methods: Shotgun metagenomic sequencing was conducted on 244 stool donors from two independent cohorts in the United States, including individuals with PD (n=48, n=47, respectively), environmental Household Controls (HC, n=29, n=30), and community Population Controls (PC, n=41, n=49). Microbial features consistently altered in PD compared to HC and PC subjects were identified. Data were cross-referenced to public metagenomic datasets from two previous studies in Germany and China to determine generalizable microbiome features. Results: The gut microbiome in PD shows significant alterations in community composition. Robust taxonomic alterations include depletion of putative "beneficial" gut commensals Faecalibacterium prausnitzii and Eubacterium and Roseburia species, and increased abundance of Akkermansia muciniphila and Bifidobacterium species. Pathway enrichment analysis and metabolic potential, constructed from microbial gene abundance, revealed disruptions in microbial carbohydrate and lipid metabolism and increased amino acid and nucleotide metabolism. These global gene-level signatures indicate an increased response to oxidative stress, decreased cellular growth and microbial motility, and disrupted inter-community signaling. Conclusions: A metagenomic meta-analysis of PD shows consistent and novel alterations in taxonomic representation, functional metabolic potential, and microbial gene abundance across four independent studies from three continents. These data reveal stereotypic changes in the gut microbiome are a consistent feature of PD, highlighting potential diagnostic and therapeutic avenues for future research.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.07.20.500694DOIDiscussion Paper
https://www.biorxiv.org/content/10.1101/2022.07.20.500694v1.supplementary-materialPublisherSupporting Information
https://github.com/jboktor/PD_Metagenomic_Analysis.gitRelated ItemScripts
ORCID:
AuthorORCID
Boktor, Joseph C.0000-0003-2456-1913
Sharon, Gil0000-0002-4605-9943
Verhagen Metman, Leo A.0000-0002-5503-1475
Engen, Phillip A.0000-0002-5276-5174
Bostick, John W.0000-0001-8925-2447
Ousey, James0000-0003-4886-0053
Ackermann, Gail0000-0002-3901-4931
Carlin, Martha0000-0001-5115-1974
Knight, Rob0000-0002-0975-9019
Keshavarzian, Ali0000-0002-7969-3369
Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This work was funded by grants from the Department of Defense (PD160030) to A.K., and S.K.M., Aligning Science Across Parkinson’s (ASAP-020495) to S.K.M., and the Michael J. Fox Foundation (Grant #15780) to S.K.M. The authors thank Yvette Garcia-Flores for administrative and technical assistance, and Gabriella Sanzo and Alex Yerkan for assistance with patient recruitment and data collection. We thank Dr. Viviana Gradinaru, Dr. Catherine Oikonomou, and members of the Mazmanian laboratory for insightful evaluation of the manuscript. This research was funded in part by the Department of Defense (PD160030) to A.K., and S.K.M., Aligning Science Across Parkinson’s (ASAP-020495) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF) to S.K.M., and the MJFF (Grant #15780) to S.K.M. For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission. Author's Roles: Design, J.C.B., M.C., A.K., S.K.M.; execution, J.C.B., L.A.V.M., D.A.H., P.A.E., Z.Z., D.L., G.H., G.A.; analysis, J.C.B., G.S., J.O., D.J.H., J.W.B., R.K., S.K.M.; writing, J.C.B., S.K.M.; editing, all authors. Competing Interest Statement: S.K.M. declares financial interests unrelated to this work in Axial Therapeutics, Nuanced Health, and Seed Health. Data Sharing: Metagenomic sequencing data are available via Qiita study IDs 14476 and 12975 and EBI-ENA accessions ERP138197 and ERP138199 for TBC and RUMC cohorts, respectively. Detailed scripts to reproduce all analysis and data visualization are available at: https://github.com/jboktor/PD_Metagenomic_Analysis.git. In addition, we have made an interactive shiny R app available via the link above for exploration of metagenomic features of interest in our datasets (Fig. S6).
Funders:
Funding AgencyGrant Number
Department of DefensePD160030
Aligning Science Across Parkinson’sASAP-020495
Michael J. Fox Foundation15780
Subject Keywords:Parkinson’s disease, gut microbiome, shotgun metagenomics, dysbiosis, microbial metabolism
DOI:10.1101/2022.07.20.500694
Record Number:CaltechAUTHORS:20220722-769622000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220722-769622000
Official Citation:Integrated multi-cohort analysis of the Parkinson's disease gut metagenome Joseph C. Boktor, Gil Sharon, Leo A. Verhagen Metman, Deborah A. Hall, Phillip A. Engen, Zoe Zreloff, Daniel J. Hakim, John W. Bostick, James Ousey, Danielle Lange, Gregory Humphrey, Gail Ackermann, Martha Carlin, Rob Knight, Ali Keshavarzian, Sarkis K. Mazmanian bioRxiv 2022.07.20.500694; doi: https://doi.org/10.1101/2022.07.20.500694
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115803
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:26 Jul 2022 17:26
Last Modified:26 Jul 2022 17:26

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