title: Microbiota differences between commercial breeders impacts the post-stroke immune response.
abstract: Experimental reproducibility between laboratories is a major translational obstacle worldwide, particularly in studies investigating immunomodulatory therapies in relation to brain disease. In recent years increasing attention has been drawn towards the gut microbiota as a key factor in immune cell polarization. Moreover, manipulation of the gut microbiota has been found effective in a diverse range of brain disorders. Within this study we aimed to test the impact of microbiota differences between mice from different sources on the post-stroke neuroinflammatory response. With this rationale, we have investigated the correlation between microbiota differences and the immune response in mice from three commercial breeders with the same genetic background (C57BL/6). While overall bacterial load was comparable, we detected substantial differences in species diversity and microbiota composition on lower taxonomic levels. Specifically, we investigated segmented filamentous bacteria (SFB)-which have been shown to promote T cell polarization-and found that they were absent in mice from one breeder but abundant in others. Our experiments revealed a breeder specific correlation between SFB presence and the ratio of Treg to Th17 cells. Moreover, recolonization of SFB-negative mice with SFB resulted in a T cell shift which mimicked the ratios found in SFB-positive mice. We then investigated the response to a known experimental immunotherapeutic approach, CD28 superagonist (CD28SA), which has been previously shown to expand the Treg population. CD28SA treatment had differing effects between mice from different breeders and was found to be ineffective at inducing Treg expansion in SFB-free mice. These changes directly corresponded to stroke outcome as mice lacking SFB had significantly larger brain infarcts. This study demonstrates the major impact of microbiota differences on T cell polarization in mice during ischemic stroke conditions, and following immunomodulatory therapies.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Feodor-Lynen Strasse 17, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sadler
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Feodor-Lynen Strasse 17, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Vikramjeet
authors.initials: V
authors.lastname: Singh
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Feodor-Lynen Strasse 17, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Benakis
authors.affiliation: Max-von-Pettenkofer Institute, Klinikum der Universität München, 80336 Munich, Germany; German Center for Infection Research (DZIF), Partner Site Munich, 80336 Munich, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: Garzetti
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Brea
authors.affiliation: Max-von-Pettenkofer Institute, Klinikum der Universität München, 80336 Munich, Germany; German Center for Infection Research (DZIF), Partner Site Munich, 80336 Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Feodor-Lynen Strasse 17, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: Arthur.Liesz@med.uni-muenchen.de.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000008:administration & dosage / Q000276:immunology; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism; D005260:Female; D000069196:Gastrointestinal Microbiome; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008297:Male; D008810:Mice, Inbred C57BL; D015203:Reproducibility of Results; D020521:Stroke / Q000276:immunology* / Q000628:therapy; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018106:CD28 Antigens
keywords: Immunology; Microbiota; Neuroinflammation; Stroke; T cells