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Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

Mazmanian, Sarkis K. and Sampson, Timothy R. and Debelius, Justine W. and Thron, Taren and Janssen, Stefan and Shastri, Gauri G. and Ilhan, Esra and Challis, Collin and Schretter, Catherine E. and Rocha, Sandra and Gradinaru, Viviana and Chesselet, Marie-Francoise and Keshavarzian, Ali and Shannon, Kathleen M. and Krajmalnik-Brown, Rosa and Wittung-Stafshede, Pernilla and Knight, Rob (2016) Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell, 167 (6). pp. 1469-1480. ISSN 0092-8674. http://resolver.caltech.edu/CaltechAUTHORS:20161115-114016210

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Abstract

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.cell.2016.11.018DOIArticle
http://www.cell.com/cell/abstract/S0092-8674(16)31590-2PublisherArticle
http://www.cell.com/cell/ppt/S0092-8674(16)31590-2.pptPublisherSupplemental Material - Images
ORCID:
AuthorORCID
Mazmanian, Sarkis K.0000-0003-2713-1513
Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2016 Elsevier Inc. Received: June 29, 2016; Received in revised form: October 12, 2016; Accepted: November 10, 2016; Published: December 1, 2016. Supplemental Information includes seven figures and one table and can be found with this article online at http://dx.doi.org/10.1016/j.cell.2016.11.018. Author Contributions: Conceptualization, T.R.S., C.E.S., M.-F.C., and S.K.M.; Formal Analysis, J.W.D., S.J., and C.C.; Investigation, T.R.S., T.T., G.G.S., Z.E.I., and S.R.; Resources, A.K. and K.M.S.; Writing - Original Draft, T.R.S. and S.K.M.; Writing - Review and Editing, all authors; Supervision, V.G., R.K.-B., P.W.-S., R.K., and S.K.M.; Funding Acquisition, T.R.S., V.G., M.-F.C., A.K., P.W.-S., R.K., and S.K.M. We thank E. Hsiao, M. Sampson, and the S.K.M. laboratory for helpful critiques. We are grateful to K. Ly, A. Maskell, and M. Quintos for animal husbandry and Y. Garcia-Flores, G. Ackermann, G. Humphrey, and H. Derderian for technical support. Imaging and analysis was performed in the Caltech Biological Imaging Facility, with the support of the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation. T.R.S. is a Larry L. Hillblom Foundation postdoctoral fellow. This project was supported by funds from the Knut and Alice Wallenberg Foundation and Swedish Research Council to P.W.-S.; a gift from Mrs. and Mr. Larry Field to A.K.; the Heritage Medical Research Institute to V.G. and S.K.M.; and NIH grant NS085910 to S.K.M.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Caltech Beckman InstituteUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
Larry L. Hillblom FoundationUNSPECIFIED
Knut and Alice Wallenberg FoundationUNSPECIFIED
Swedish Research Council UNSPECIFIED
Mrs. and Mr. Larry FieldUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
NIHNS085910
Subject Keywords:microbiome, Parkinson’s disease, synuclein, gut-brain axis, mouse model, microglia, short chain fatty acids
Record Number:CaltechAUTHORS:20161115-114016210
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20161115-114016210
Official Citation:Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Sampson, Timothy R. et al. Cell , Volume 167 , Issue 6 , 1469 - 1480.e12
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72032
Collection:CaltechAUTHORS
Deposited By: Katherine Johnson
Deposited On:01 Dec 2016 18:33
Last Modified:01 Dec 2016 19:09

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