5 research outputs found
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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
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
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Effects of Immunization With the Soil-Derived Bacterium Mycobacterium vaccae on Stress Coping Behaviors and Cognitive Performance in a "Two Hit" Stressor Model
Previous studies demonstrate that Mycobacterium vaccae NCTC 11659 (M. vaccae), a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, is a potentially useful countermeasure against negative outcomes to stressors. Here we used male C57BL/6NCrl mice to determine if repeated immunization with M. vaccae is an effective countermeasure in a "two hit" stress exposure model of chronic disruption of rhythms (CDR) followed by acute social defeat (SD). On day -28, mice received implants of biotelemetric recording devices to monitor 24-h rhythms of locomotor activity. Mice were subsequently treated with a heat-killed preparation of M. vaccae (0.1 mg, administered subcutaneously on days -21, -14, -7, and 27) or borate-buffered saline vehicle. Mice were then exposed to 8 consecutive weeks of either stable normal 12:12 h light:dark (LD) conditions or CDR, consisting of 12-h reversals of the LD cycle every 7 days (days 0-56). Finally, mice were exposed to either a 10-min SD or a home cage control condition on day 54. All mice were exposed to object location memory testing 24 h following SD. The gut microbiome and metabolome were assessed in fecal samples collected on days -1, 48, and 62 using 16S rRNA gene sequence and LC-MS/MS spectral data, respectively; the plasma metabolome was additionally measured on day 64. Among mice exposed to normal LD conditions, immunization with M. vaccae induced a shift toward a more proactive behavioral coping response to SD as measured by increases in scouting and avoiding an approaching male CD-1 aggressor, and decreases in submissive upright defensive postures. In the object location memory test, exposure to SD increased cognitive function in CDR mice previously immunized with M. vaccae. Immunization with M. vaccae stabilized the gut microbiome, attenuating CDR-induced reductions in alpha diversity and decreasing within-group measures of beta diversity. Immunization with M. vaccae also increased the relative abundance of 1-heptadecanoyl-sn-glycero-3-phosphocholine, a lysophospholipid, in plasma. Together, these data support the hypothesis that immunization with M. vaccae stabilizes the gut microbiome, induces a shift toward a more proactive response to stress exposure, and promotes stress resilience.
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A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk
A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c -statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a “universal” surrogate end point for cardiovascular risk