A Biological Signature of Stress Resilience: Immunization with Either Mycobacterium vaccae NCTC 11659 or M. vaccae ATCC 15483 Prevents Stress-induced Changes to Proteomic, Metabolomic, Lipidomic, and Immunological Profiles in Adult Male Rodent Models

Abstract

Stress-related psychiatric disorders, including anxiety disorders, affective disorders, and trauma- and stressor-related disorders like posttraumatic stress disorder (PTSD), are characterized by chronic, low-grade inflammation and dysregulated neuroimmune signaling. In particular, increased activation of the sympathetic nervous system (SNS), decreased activation of the parasympathetic nervous system (PNS), and disrupted glucocorticoid signaling are common among persons with PTSD. In recent years, microbial-based therapeutics have gained attention for their potential to prevent and treat stress-related psychiatric disorders such as PTSD by mediating microbiome-gut-brain axis pathways. We have previously described stress-resilience and anti-inflammatory effects of a heat-killed preparation of Mycobacterium vaccae NCTC 11659 in rodent models. For the first time, I demonstrate that immunization with a heat-killed preparation of M. vaccae ATCC 15483 is as effective as M. vaccae NCTC 11659 at preventing anxiety-like defensive behavioral responses 24 hours after exposure to inescapable tail shock stress (IS) in adult male rats. Using proteomic, metabolomic, lipidomic, and gene expression data, I show that immunization with either M. vaccae strain promotes stress resilience at a physiological level as well as a behavioral level and that these two strains might generally converge on their mechanisms of action. Together, these data suggest that immunization with either M. vaccae strain attenuates SNS-induced release of proinflammatory monocytes from the bone marrow and monocyte/macrophage trafficking into the brain. These effects are associated with the prevention of IS-induced endothelial dysfunction, metabolic dysregulation, and neuroinflammation by both M. vaccae strains. These findings describe, for the first time, biological signatures of IS associated with anxiety-like behaviors and biological signatures of stress resilience. These results contribute to our understanding of mechanisms underlying stress vulnerability versus resilience and may provide novel targets for the prevention and treatment of stress-related psychiatric disorders. Collectively, data in this dissertation indicate that microbial-based interventions like M. vaccae NCTC 11659 or M. vaccae ATCC 15483 may be promising, novel therapeutics for use in clinical studies of stress-related psychiatric disorders.</p