150. Metabolic reprogramming of immune cells in PTSD correlates with symptom severity

Abstract

Abstract Background Post-traumatic stress disorder (PTSD) is characterised not only by psychological symptoms but also by chronic immune activation and systemic metabolic alterations. Growing evidence indicates that immune cell metabolism is a critical regulator of inflammatory and stress-response pathways, yet its contribution to PTSD pathophysiology remains underexplored. Aims & Objectives We aimed to, for the first time, characterise metabolic alterations across immune cell subsets in individuals with PTSD, to identify pathway-specific metabolic signatures using flow-cytometric profiling, and to explore associations between immunometabolic markers and PTSD symptom severity. Method In this exploratory case-control study, we investigated immunometabolic alterations in PTSD on cellular, systemic, and transcriptional levels. We performed metabolic flow cytometry on peripheral blood mononuclear cells to quantify protein expression of key rate-limiting enzymes in major metabolic pathways (glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway, fatty acid synthesis, fatty acid oxidation, and adenosine triphosphate (ATP) synthesis). Systemic inflammation and metabolic dysfunction were assessed by measuring serum levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), lactate, and growth differentiation factor-15 (GDF-15). To capture transcriptional signatures of immune activation, we quantified gene expression of TNF, NFKB1, and NR3C1, representing key regulators of inflammatory and stress-response pathways relevant to PTSD. Finally, we examined associations between these immunometabolic markers and PTSD symptom severity. Results The PTSD group exhibited consistently elevated levels of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD) across multiple immune cell subsets, reflecting heightened engagement of glycolysis and the pentose phosphate pathway - metabolic programs typically associated with immune cell activation. Systemic markers were consistent with this activated immune phenotype, with the PTSD group showing increased circulating IL-6. Expression levels of inflammatory and stress-related genes were largely comparable between groups. Glucose transporter 1 (GLUT1) expression in CD4+ T cells showed a significant positive association with overall PTSD symptom severity. Among symptom domains, the Arousal and Reactivity domain exhibited the strongest and most consistent relationships with immunometabolic markers. Discussion & Conclusions These findings suggest that PTSD may be associated with systemic metabolic reprogramming across both adaptive and innate immune cells, characterised by increased engagement of glycolysis and the pentose phosphate pathway. The observed associations with PTSD symptom severity, particularly within the Arousal and Reactivity domain, highlight the relevance of immunometabolism for the clinical expression of PTSD. Together, these results provide initial evidence for immunometabolic alterations in PTSD at both cellular and systemic levels, supporting emerging mechanistic models of immune involvement in the disorder and motivating further investigation into immunometabolic pathways in PTSD.