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 1-2 wk 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.anxiety | chronic psychosocial stress | fear | microbiota | posttraumatic stress disorder

Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically relevant, animal models for studying the effects of chronic stress, the detailed behavioral, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic and continuous situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, to help bridge this gap. The main aim of the current review article is to provide a detailed summary of the behavioral, physiological, neuronal, and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to the human situation.

SignificanceOur results show that a standardized laboratory psychosocial stressor causes a greater inflammatory response in young healthy participants with an urban upbringing in the absence of pets, relative to young healthy participants with a rural upbringing in the presence of farm animals. In view of the known links between persistent inflammatory states and psychiatric disturbances, and considering that many stress-associated physical and mental disorders are more prevalent in environments offering a narrow range of microbial exposures, we feel that our findings are of general interest and significance. Moreover, we feel our study is timely, as urbanization and the associated socioeconomic consequences are increasing.

Mice exposed to chronic subordinate colony housing (CSC) stress show glucocorticoid (GC) resistance of in vitro lipopolysaccharide (LPS)-stimulated splenocytes, increased anxiety and colitis. Similar effects were reported in wounded mice exposed to social disruption (SDR). Here we show that CSC exposure induced GC resistance in isolated and in vitro LPS-stimulated, but not unstimulated, splenocytes, and these effects were absent when CD11b+ splenocytes were depleted. Moreover, re-active coping behaviour during CSC correlated with the attacks and bites received by the resident, which in turn highly correlated with the dimension of splenic GC resistance, as with basal and LPS-induced in vitro splenocyte viability. Importantly, social stress promoted spleen cell activation, independent of bite wounds or CD11b+/CD11b− cell phenotype, whereas GC resistance was dependent on both bite wounds and the presence of CD11b+ cells. Together, our findings indicate that the mechanisms underlying splenic immune activation and GC resistance following social stress in male mice are paradigm independent and, to a large extent, dependent on wounding, which, in turn, is associated with a re-active coping style.

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There is a considerable body of evidence indicating that chronic adverse experience, especially chronic psychosocial stress/trauma, represents a major risk factor for the development of many somatic and affective disorders, including inflammatory bowel disease (IBD) and posttraumatic stress disorder (PTSD). However, the mechanisms underlying the development of chronic stress-associated disorders are still in large part unknown, and current treatment and prevention strategies lack efficacy and reliability. A greater understanding of mechanisms involved in the development and persistence of chronic stress-induced disorders may lead to novel approaches to prevention and treatment of these disorders. In this review, we provide evidence indicating that increases in immune (re-)activity and inflammation, potentially promoted by a reduced exposure to immunoregulatory microorganisms (“Old Friends”) in today’s modern society, may be causal factors in mediating the vulnerability to development and persistence of stress-related pathologies. Moreover, we discuss strategies to increase immunoregulatory processes and attenuate inflammation, as for instance contact with immunoregulatory Old Friends, which appears to be a promising strategy to promote stress resilience and to prevent/treat chronic stress-related disorders.

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.