title: Individual differences in stress vulnerability: The role of gut pathobionts in stress-induced colitis.
abstract: Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius-free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories.
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Langgartner
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peterlik
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Foertsch
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Füchsl
authors.affiliation: Animal Research Facility, University of Ulm, 89081 Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Brokmann
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
authors.affiliation: Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Zeli
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Uschold-Schmidt
authors.affiliation: Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Department of Physical Medicine & Rehabilitation and Center for Neuroscience, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Rocky Mountain Mental Illness Research Education and Clinical Center, Denver, CO 80220, USA; Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany. Electronic address: stefan.reber@uniklinik-ulm.de.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Reber
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001007:Anxiety / Q000382:microbiology; D003092:Colitis / Q000150:complications / Q000382:microbiology*; D000069196:Gastrointestinal Microbiome; D016998:Helicobacter / Q000472:pathogenicity*; D016481:Helicobacter Infections; D007206:Individuality; D007249:Inflammation / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size; D013315:Stress, Psychological / Q000150:complications / Q000382:microbiology*; D013950:Thymus Gland / Q000473:pathology
keywords: Chronic psychosocial stress; Chronic subordinate colony housing (CSC); Colitis; Enterohepatic Helicobacter species (EHS); Inflammation; Inflammatory bowel disease (IBD); Microbiota; Pathobionts; Stress resilience; Stress vulnerability