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Chronic psychosocial stress is a burden of modern society 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. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability.In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females.Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes.Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.

Chronic psychosocial stress is a burden of modern society 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. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability. In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae ( M. vaccae ; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females. Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes. Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders., Competing Interests: GM, DL and SOR have nothing to declare. CAL is Cofounder, Board Member, and Chief Scientific Officer of Mycobacteria Therapeutics Corporation, and is a member of the faculty of the Integrative Psychiatry Institute, Boulder, Colorado, the Institute for Brain Potential, Los Banos, California, and Intelligent Health Ltd, Reading, UK.., (© 2023 The Authors.)