The magnitude, temporal dynamics, and physiological effects of intestinal microbiome responses to physiological stress are poorly characterized. This study used a systems biology approach and a multiple-stressor military training environment to determine the effects of physiological stress on intestinal microbiota composition and metabolic activity, as well as intestinal permeability (IP). Soldiers ( = 73) were provided three rations per day with or without protein- or carbohydrate-based supplements during a 4-day cross-country ski-march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62 ± 57% (mean ± SD, < 0.001) during STRESS independent of diet group and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased α-diversity and changes in the relative abundance of >50% of identified genera, including increased abundance of less dominant taxa at the expense of more dominant taxa such as Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Together, pre-STRESS Actinobacteria relative abundance and changes in serum IL-6 and stool cysteine concentrations accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation and with intestinal microbiota composition and metabolism. Associations between IP, the pre-STRESS microbiota, and microbiota metabolites suggest that targeting the intestinal microbiota could provide novel strategies for preserving IP during physiological stress. Military training, a unique model for studying temporal dynamics of intestinal barrier and intestinal microbiota responses to stress, resulted in increased intestinal permeability concomitant with changes in intestinal microbiota composition and metabolism. Prestress intestinal microbiota composition and changes in fecal concentrations of metabolites linked to the microbiota were associated with increased intestinal permeability. Findings suggest that targeting the intestinal microbiota could provide novel strategies for mitigating increases in intestinal permeability during stress.

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Posttraumatic stress disorder (PTSD) is defined by classic psychological manifestations, although among the characteristics are significantly increased rates of serious somatic comorbidities, such as cardiovascular disease, immune dysfunction, and metabolic syndrome. In this review, we assess the evidence for disturbances that may contribute to somatic pathology in inflammation, metabolic syndrome, and circulating metabolites (implicating mitochondrial dysfunction) in individuals with PTSD and in animal models simulating features of PTSD. The clinical and preclinical data highlight probable interrelated features of PTSD pathophysiology, including a proinflammatory milieu, metabolomic changes (implicating mitochondrial and other processes), and metabolic dysregulation. These data suggest that PTSD may be a systemic illness, or that it at least has systemic manifestations, and the behavioral manifestations are those most easily discerned. Whether somatic pathology precedes the development of PTSD (and thus may be a risk factor) or follows the development of PTSD (as a result of either shared pathophysiologies or lifestyle adaptations), comorbid PTSD and somatic illness is a potent combination placing affected individuals at increased physical as well as mental health risk. We conclude with directions for future research and novel treatment approaches based on these abnormalities.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

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Post-traumatic stress disorder (PTSD) is a debilitating disorder that develops in some people following trauma exposure. Trauma and PTSD have been associated with accelerated cellular aging. This study evaluated the effect of trauma and PTSD on accelerated GrimAge, an epigenetic predictor of lifespan, in traumatized civilians. This study included 218 individuals with current PTSD, 427 trauma-exposed controls without any history of PTSD and 209 subjects with lifetime PTSD history who are not categorized as current PTSD cases. The Traumatic Events Inventory (TEI) and Clinician-Administered PTSD Scale (CAPS) were used to measure lifetime trauma burden and PTSD, respectively. DNA from whole blood was interrogated using the MethylationEPIC or HumanMethylation450 BeadChips. GrimAge estimates were calculated using the methylation age calculator. Cortical thickness of 69 female subjects was assessed by using T1-weighted structural MRI images. Associations between trauma exposure, PTSD, cortical thickness, and GrimAge acceleration were tested with multiple regression models. Lifetime trauma burden (p = 0.03), current PTSD (p = 0.02) and lifetime PTSD (p = 0.005) were associated with GrimAge acceleration, indicative of a shorter predicted lifespan. The association with lifetime PTSD was replicated in an independent cohort (p = 0.04). In the MRI sub sample, GrimAge acceleration also associated with cortical atrophy in the right lateral orbitofrontal cortex (p adj = 0.03) and right posterior cingulate (p adj = 0.04), brain areas associated with emotion-regulation and threat-regulation. Our findings suggest that lifetime trauma and PTSD may contribute to a higher epigenetic-based mortality risk. We also demonstrate a relationship between cortical atrophy in PTSD-relevant brain regions and shorter predicted lifespan.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using crosssectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs −0.57, p = 0.001 and N = 53, 0.93 vs −1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease. Members of the PTSD Systems Biology Consortium are listed in Supplementary information.

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