Impaired peripheral mononuclear cell metabolism in patients at risk of developing sepsis: A cohort study

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Introduction: Dysregulated immune responses are central to progression of sepsis and closely associated with impaired cellular metabolism. However, most existing studies have focused on late-stage sepsis, leaving metabolic alterations during earlier stages of infection poorly characterised. This study aimed to determine whether immune cell metabolic impairment is already present during uncomplicated infection, prior to the development of sepsis, and to evaluate its potential as an early indicator of immune dysfunction and risk of progression. Materials and methods: Forty patients with sepsis (fulfilling Sepsis-3 criteria) and 27 patients with uncomplicated infection were recruited from the emergency department along with 20 healthy volunteers. Whole blood samples were collected to assess gene expression, cytokine levels, and cellular metabolic functions, including mitochondrial respiration, oxidative stress, and apoptosis in immune cells. Results: Mitochondrial respiration was significantly impaired in immune cells from both uncomplicated infection and sepsis patients compared with healthy controls (p < 0.05), with more pronounced impairment in established sepsis. Downregulation of BCL2 and BBC3 gene expression was observed in sepsis patients (p < 0.05), but not in uncomplicated infection, potentially contributing to differences in the severity of metabolic impairment. Impaired mitochondrial respiration was significantly associated with increased mitochondrial oxidative stress (p < 0.05), which was elevated in uncomplicated infection and further increased in sepsis. Oxidative stress levels also correlated with tumour necrosis factor-α (r = 0.330) and the expression of CYCS, TP53, SLC25A24, and TSPO (rs = -0.4926, -0.4422, 0.4382, and 0.4835, respectively). Despite these metabolic alterations, no significant differences in immune cell apoptosis were observed between uncomplicated infection and sepsis patients. Conclusions: Immune cell metabolic dysfunction is present in patients with uncomplicated infection before the clinical onset of sepsis. Early mitochondrial dysfunction and oxidative stress may represent promising targets for further investigation as early biomarkers of immune dysfunction and sepsis risk.

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