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Novel prevention and treatment strategies are urgently needed to reduce the burden of post-traumatic stress disorder (PTSD). Using a murine model of PTSD, the chronic subordinate colony housing (CSC) model, we found immunization with a heat-killed preparation of Mycobacterium vaccae, a bioimmunomodulatory agent previously shown to activate regulatory T cells(Treg) and increase production of anti-inflammatory cytokines, prevented development of a PTSD-like syndrome. Immunization with M. vaccae antigen induced a more proactive emotional coping style during exposure to a dominant aggressor, prevented development of a fear-like state, and inhibited stress-induced development of spontaneous colitis and aggravation of colitis in a model of inflammatory bowel disease. Protective effects of immunization were absent following Treg depletion. These data provide a hypothetical framework for prevention of PTSD.