α-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice
Abstract
Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson’s disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.
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© 2024, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Acknowledgement
We thank Dr. Gil Sharon for help with tissue dissections, Taren Thron for animal breeding, Yvette Garcia-Flores for logistical assistance, and Dr. Catherine Oikonomou for critical review of the manuscript. Metabolomics data collection, preprocessing, analysis, and interpretation were provided by the Alzheimer’s Gut Microbiome Project (AGMP) and the Alzheimer’s Disease Metabolomics Consortium (ADMC), funded wholly or in part by the following grants and supplements: R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, U19AG063744, 3U19AG063744-04S1, RF1AG058942, U01AG061359, R01MH108348, R01AG081322 and FNIH: #DAOU16AMPA awarded to R.K.M. at Duke University in partnership with a large number of academic institutions. As such, the investigators within the AGMP and the ADMC, not listed specifically in this publication’s author list, provided data along with its pre-processing and prepared it for analysis, but did not participate in analysis or writing of this manuscript. A listing of AGMP Investigators can be found at https://alzheimergut.org/meet-the-team/. A complete listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/. L.H.M. was partially supported by an American Parkinson’s Disease Association postdoctoral fellowship during the study. This research was funded in part by Aligning Science Across Parkinson’s (ASAP-020495 and ASAP-000375) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF) to S.K.M. For the purpose of open access, the authors have applied a CC BY public copyright license to all Author Accepted Manuscripts arising from this submission.
Data Availability
The datasets generated and analyzed in this study are available from: https://doi.org/10.5281/zenodo.10841426.
Code Availability
The underlying code for this study is available in GitHub and can be accessed via https://doi.org/10.5281/zenodo.10841426
Conflict of Interest
L.H.M., J.C.B., and S.M.D. declare no financial or non-financial competing interests. R.K.D. is an inventor on a series of patents on the use of metabolomics for the diagnosis and treatment of central nervous system diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. S.K.M. is a co-founder of Axial Therapeutics and Nuanced Health, and declares no competing interests with this study.
Supplemental Material
Supplementary information contents:
• Supplementary Figures 1-3
• Legend for Supplementary Data
Supplementary data: 41531_2024_816_MOESM2_ESM.xlsx
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Additional details
- Alternative title (English)
- Alpha-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice
- Aligning Science Across Parkinson's
- ASAP-020495
- Aligning Science Across Parkinson's
- ASAP-000375
- American Parkinson Disease Association
- Postdoctoral Fellowship -
- National Institutes of Health
- R01AG046171
- National Institutes of Health
- RF1AG051550
- National Institutes of Health
- RF1AG057452
- National Institutes of Health
- R01AG059093
- National Institutes of Health
- U19AG063744
- National Institutes of Health
- 3U19AG063744-04S1
- National Institutes of Health
- RF1AG058942
- National Institutes of Health
- U01AG061359
- National Institutes of Health
- R01MH108348
- National Institutes of Health
- R01AG081322
- Foundation for the National Institutes of Health
- DAOU16AMPA
- Accepted
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2024-10-10Accepted
- Available
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2024-10-30Published online
- Caltech groups
- Division of Biology and Biological Engineering (BBE)
- Publication Status
- Published