Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice

Stefan O. Reber, Philip H. Siebler, Nina C. Donner, James T. Morton, David G. Smith, Jared M. Kopelman, Kenneth R. Lowe, Kristen J. Wheeler, James H. Fox, James E. Hassell, Benjamin N. Greenwood, Charline Jansch, Anja Lechner, Dominic Schmidt, Nicole Uschold-Schmidt, Andrea M. Füchsl, Dominik Langgartner, Frederick R. Walker, Matthew W. Hale, Gerardo Lopez PerezWill Van Treuren, Antonio González, Andrea L. Halweg-Edwards, Monika Fleshner, Charles L. Raison, Graham A. Rook, Shyamal D. Peddada, Rob Knight, Christopher A. Lowry

Research output: Contribution to journalArticlepeer-review

163 Scopus citations


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 1-2wk 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.

Original languageEnglish (US)
Pages (from-to)E3130-E3139
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - May 31 2016


  • Anxiety
  • Chronic psychosocial stress
  • Fear
  • Microbiota
  • Posttraumatic stress disorder

ASJC Scopus subject areas

  • General


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