title: Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice.
abstract: The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.
authors.affiliation: Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, D-89081 Ulm, Germany; Department of Behavioral and Molecular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany;
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Reber
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Philip H
authors.initials: PH
authors.lastname: Siebler
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Nina C
authors.initials: NC
authors.lastname: Donner
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: James T
authors.initials: JT
authors.lastname: Morton
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: David G
authors.initials: DG
authors.lastname: Smith
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Jared M
authors.initials: JM
authors.lastname: Kopelman
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Lowe
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Wheeler
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: James H
authors.initials: JH
authors.lastname: Fox
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: James E
authors.initials: JE
authors.lastname: Hassell
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Greenwood
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany;
authors.forename: Charline
authors.initials: C
authors.lastname: Jansch
authors.affiliation: Institute of Immunology, University of Regensburg, D-93042 Regensburg, Germany;
authors.forename: Anja
authors.initials: A
authors.lastname: Lechner
authors.affiliation: Institute of Immunology, University of Regensburg, D-93042 Regensburg, Germany;
authors.forename: Dominic
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany;
authors.forename: Nicole
authors.initials: N
authors.lastname: Uschold-Schmidt
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany;
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Füchsl
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, D-93053 Regensburg, Germany;
authors.forename: Dominik
authors.initials: D
authors.lastname: Langgartner
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan 2308, Australia;
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Walker
authors.affiliation: School of Psychological Science, La Trobe University, Bundoora 3086, Australia;
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hale
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Gerardo
authors.initials: G
authors.lastname: Lopez Perez
authors.affiliation: Biofrontiers Institute, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Will
authors.initials: W
authors.lastname: Van Treuren
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Halweg-Edwards
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309;
authors.forename: Monika
authors.initials: M
authors.lastname: Fleshner
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Charles L
authors.initials: CL
authors.lastname: Raison
authors.affiliation: Center for Clinical Microbiology, UCL (University College London), London WC1E 6BT, United Kingdom;
authors.forename: Graham A
authors.initials: GA
authors.lastname: Rook
authors.affiliation: Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Peddada
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Rob
authors.initials: R
authors.lastname: Knight
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309; christopher.lowry@colorado.edu.
authors.forename: Christopher A
authors.identifier: 0000-0003-3920-5575
authors.initials: CA
authors.lastname: Lowry
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications* / Q000503:physiopathology; D001428:Bacterial Vaccines / Q000008:administration & dosage*; D001522:Behavior, Animal; D003092:Colitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007114:Immunization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000254:growth & development*; D013315:Stress, Psychological / Q000150:complications* / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage*
chemical_list: D001428:Bacterial Vaccines; D015164:Vaccines, Inactivated
keywords: anxiety; chronic psychosocial stress; fear; microbiota; posttraumatic stress disorder