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

Timothy R. Sampson, Justine W. Debelius, Taren Thron, Stefan Janssen, Gauri G. Shastri, Zehra Esra Ilhan, Collin Challis, Catherine E. Schretter, Sandra Rocha, Viviana Gradinaru, Marie Francoise Chesselet, Ali Keshavarzian, Kathleen M. Shannon, Rosa Krajmalnik-Brown, Pernilla Wittung-Stafshede, Rob Knight, Sarkis K. Mazmanian

Research output: Contribution to journalArticle

820 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1469-1480.e12
JournalCell
Volume167
Issue number6
DOIs
StatePublished - Dec 1 2016

Keywords

  • Parkinson's disease
  • gut-brain axis
  • microbiome
  • microglia
  • mouse model
  • short chain fatty acids
  • synuclein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., Chesselet, M. F., Keshavarzian, A., Shannon, K. M., Krajmalnik-Brown, R., Wittung-Stafshede, P., Knight, R., & Mazmanian, S. K. (2016). Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell, 167(6), 1469-1480.e12. https://doi.org/10.1016/j.cell.2016.11.018