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

慢性心理社会应激是现代生活的主要负担，是大量躯体和情感障碍的明显危险因素，其中大多数与免疫激活状态和慢性低度炎症有关。考虑到包括创伤后应激障碍(PTSD)在内的许多这些障碍与调节性T细胞(Treg)的减少进一步相关，免疫调节的失败很可能会促进炎性应激反应的过度反应，从而使个人容易患上应激相关障碍，特别是PTSD。重要的是，成年期心理压力/心理创伤对心理健康的不利影响因人而异，有些人比另一些人更有韧性。鉴于过度反应的炎症应激/创伤反应与包括创伤后应激障碍在内的应激相关疾病的发展之间的详细联系，所有促进成年人免疫(重新)活动的遗传和环境因素都可能增加他们的应激/创伤脆弱性。根据这样一个假设，其中一个这样的因素是早期生活中的逆境，心理社会压力已被反复证明可以激活外周炎症途径，并且在有早期生活虐待和/或忽视史的人中，这种作用更明显，这些人在成年生活中因创伤暴露而患上创伤后应激障碍的风险也显著增加。重要的是，我们在雄性小鼠身上进一步表明，反复预免疫(S.C.)母牛分枝杆菌是一种丰富的土壤腐生植物，具有免疫调节特性，使用母牛分枝杆菌热灭活制剂(国家模式培养物收藏11659)，能够预防应激诱导的焦虑、自发性结肠炎和葡聚糖硫酸钠诱导的结肠炎(一种炎症性肠病的小鼠模型)加重。这项拨款提案中提供的未发表的初步老鼠数据进一步表明，早期生活逆境(=第一次打击)具有负面行为后果，并以性别依赖的方式增加成年后对慢性应激(=第二次打击)的易感性，这些负面压力效应可以通过重复S.C.在目前的方案中，我们将探讨母牛分枝杆菌接种的详细机制(Treg计数和功能、脑小胶质细胞激活和IL-4信号、外周和中枢副交感抗炎反射活性、肠道微生物群的作用)，以揭示母牛分枝杆菌的负面应激后果和保护作用。总之，这些研究可能有助于开发新的治疗方法，特别是使用具有免疫调节潜力的生物免疫调节剂，以减轻或预防在生命不同阶段发生的多种心理社会应激源的长期不良后果。

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.