title: Depletion of Cultivatable Gut Microbiota by Broad-Spectrum Antibiotic Pretreatment Worsens Outcome After Murine Stroke.
abstract: Antibiotics disturbing microbiota are often used in treatment of poststroke infections. A bidirectional brain-gut microbiota axis was recently suggested as a modulator of nervous system diseases. We hypothesized that gut microbiota may be an important player in the course of stroke.
  
  
  
  We investigated the outcome of focal cerebral ischemia in C57BL/6J mice after an 8-week decontamination with quintuple broad-spectrum antibiotic cocktail. These microbiota-depleted animals were subjected to 60 minutes middle cerebral artery occlusion or sham operation. Infarct volume was measured using magnetic resonance imaging, and mice were monitored clinically throughout the whole experiment. At the end point, tissues were preserved for further analysis, comprising histology and immunologic investigations using flow cytometry.
  
  
  
  We found significantly decreased survival in the middle cerebral artery occlusion microbiota-depleted mice when the antibiotic cocktail was stopped 3 days before surgery (compared with middle cerebral artery occlusion specific pathogen-free and sham-operated microbiota-depleted mice). Moreover, all microbiota-depleted animals in which antibiotic treatment was terminated developed severe acute colitis. This phenotype was rescued by continuous antibiotic treatment or colonization with specific pathogen-free microbiota before surgery. Further, infarct volumes on day one did not differ between any of the experimental groups.
  
  
  
  Conventional microbiota ensures intestinal protection in the mouse model of experimental stroke and prevents development of acute and severe colitis in microbiota-depleted mice not given antibiotic protection after cerebral ischemia. Our experiments raise the clinically important question as to whether microbial colonization or specific microbiota are crucial for stroke outcome.
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winek
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Odilo
authors.initials: O
authors.lastname: Engel
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Priscilla
authors.initials: P
authors.lastname: Koduah
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Dames
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Caterina
authors.initials: C
authors.lastname: Curato
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Oyama
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.affiliation: From the Department of Experimental Neurology (K.W., O.E., P.K., N.O., A.M., U.D.), NeuroCure Clinical Research (K.W., C.C., A.M., U.D.), Center for Stroke Research Berlin (K.W., O.E., P.K., A.M., U.D.), Department of Microbiology and Hygiene (M.M.H., A.F., S.B.), Institute for Medical Immunology (C.D., C.M.), and Department of Neurology (A.M., U.D.), Charité - Universitätsmedizin Berlin, Germany; Institute of Veterinary Pathology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany (O.K., A.D.G.); German Rheumatism Research Center (DRFZ), Berlin, Germany (C.C.); and German Center for Neurodegeneration Research (DZNE), partner site Berlin, Germany (U.D.). ulrich.dirnagl@charite.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020521:Stroke / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents
keywords: animal model; antibiotic; brain–gut microbiota axis; ischemic stroke; microbiota depletion