title: Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke.
abstract: Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome.
  
  
  
  We have identified a bidirectional communication along the brain-gut microbiota-immune axis and show that the gut microbiota is a central regulator of immune homeostasis. Acute brain lesions induced dysbiosis of the microbiome and, in turn, changes in the gut microbiota affected neuroinflammatory and functional outcome after brain injury. The microbiota impact on immunity and stroke outcome was transmissible by microbiota transplantation. Our findings support an emerging concept in which the gut microbiota is a key regulator in priming the neuroinflammatory response to brain injury. These findings highlight the key role of microbiota as a potential therapeutic target to protect brain function after injury.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Vikramjeet
authors.identifier: 0000-0002-7361-8317
authors.initials: V
authors.lastname: Singh
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Stefan
authors.identifier: 0000-0001-6823-2981
authors.initials: S
authors.lastname: Roth
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Gemma
authors.initials: G
authors.lastname: Llovera
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sadler
authors.affiliation: Max-von-Pettenkofer Institute, Klinikum der Universität München, 80336 Munich, Germany, and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: Garzetti
authors.affiliation: Max-von-Pettenkofer Institute, Klinikum der Universität München, 80336 Munich, Germany, and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Martin
authors.identifier: 0000-0002-0654-387X
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, 81377 Munich, Germany, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany, Arthur.Liesz@med.uni-muenchen.de.
authors.forename: Arthur
authors.identifier: 0000-0002-9069-2594
authors.initials: A
authors.lastname: Liesz
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000209:etiology; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D064806:Dysbiosis / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D004660:Encephalitis / Q000150:complications* / Q000209:etiology*; D005243:Feces / Q000382:microbiology; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology; D005769:Gastrointestinal Motility / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D045823:Ileus / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064307:Microbiota / Q000276:immunology / Q000502:physiology*; D020521:Stroke / Q000150:complications* / Q000209:etiology; D000072717:Tertiary Lymphoid Structures / Q000473:pathology
chemical_list: D017252:CD3 Complex; D018398:Homeodomain Proteins; C064658:RAG-1 protein
keywords: T cells; inflammation; microbiota; stroke