title: Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.
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.
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: trsamps@caltech.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sampson
authors.affiliation: Department of Pediatrics, University of California, San Diego, San Diego, CA 92110, USA.
authors.forename: Justine W
authors.initials: JW
authors.lastname: Debelius
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Taren
authors.initials: T
authors.lastname: Thron
authors.affiliation: Department of Pediatrics, University of California, San Diego, San Diego, CA 92110, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssen
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Shastri
authors.affiliation: Swette Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Zehra Esra
authors.initials: ZE
authors.lastname: Ilhan
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Collin
authors.initials: C
authors.lastname: Challis
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Schretter
authors.affiliation: Biology and Biological Engineering Department, Chalmers University of Technology, Gothenburg 41296, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rocha
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Gradinaru
authors.affiliation: Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Chesselet
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.affiliation: Department of Neurological Sciences, Section of Movement Disorders, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Shannon
authors.affiliation: Swette Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Krajmalnik-Brown
authors.affiliation: Biology and Biological Engineering Department, Chalmers University of Technology, Gothenburg 41296, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wittung-Stafshede
authors.affiliation: Department of Pediatrics, University of California, San Diego, San Diego, CA 92110, USA; Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA 92093, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.affiliation: Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.
authors.forename: Sarkis K
authors.initials: SK
authors.lastname: Mazmanian
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D064806:Dysbiosis / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000382:microbiology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology* / Q000503:physiopathology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D051844:alpha-Synuclein
keywords: Parkinson’s disease; gut-brain axis; microbiome; microglia; mouse model; short chain fatty acids; synuclein