Project 2

Facilitating stress resilience by “Old friends”: Immunization with Mycobacterium vaccae prevents the negative effects of early life stress on chronic stress vulnerability during adulthood

Chronic psychosocial stress is a major burden of modern life and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Given that many of these disorders, including posttraumatic stress disorder (PTSD), are further associated with decreases in regulatory T cells (Treg), it is likely that a failure of immunoregulation promotes an over-reacting of the inflammatory stress responses and, thus, predisposes an individual to develop stress-related disorders in general, and PTSD in particular. Importantly, adverse consequences of psychological stress/traumatization during adulthood on mental health vary strongly between individuals, with some individuals being more resilient than others. Given the above detailed link between an over-reacting inflammatory stress/trauma response and the development of stress-associated disorders including PTSD, all genetic and environmental factors facilitating an adult’s immune (re-) activity are, therefore, likely to increase their stress/trauma vulnerability. In line with the hypothesis that one such factor is early life adversity, psychosocial stress has been shown repeatedly to activate peripheral inflammatory pathways, and to do so more robustly in people with histories of early life abuse and/or neglect who are also at significantly heightened risk for PTSD development in response to trauma exposure in adult life. Importantly, we have further shown in male mice that immunoregulation induced by repeated preimmunization (s.c.) with a heat-killed preparation of Mycobacterium vaccae (National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, was able to prevent stress-induced anxiety, spontaneous colitis, and aggravation of dextran sulfate sodium (DSS)-induced colitis, a murine model of inflammatory bowel disease. As own unpublished preliminary mouse data presented in this grant proposal further indicate that early life adversity (=first hit) has negative behavioral consequences and increases the vulnerability to chronic stress during adulthood (=second hit) in a sex dependent manner and that these negative stress effects can be ameliorated/prevented by repeated s.c. M. vaccae administrations, we in the current proposal will investigate the detailed mechanisms (Treg counts and functionality, brain microglia activation and IL-4 signaling, peripheral and central parasympathetic anti-inflammatory reflex activity, role of intestinal microbiome) underlying both the negative stress consequences and the protective effects of M. vaccae. Together, these studies may help to develop novel therapeutic approaches, specifically the use of biological immunomodulators with immunoregulatory potential, to attenuate or prevent long-term adverse consequences of multiple psychosocial stressors occurring at different phases of life.

Funding: German Research Foundation, RE 2911/21-1