Acute Fasting Suppresses Neutrophil Metabolism and Effector Function 2254957

Abstract Introduction Acute fasting is common in perioperative care and may create a transient window of vulnerability to hospital-acquired infections. Because Staphylococcus aureus drives significant bacteremia in this setting, we asked how a short-term (12-hour) fast alters neutrophil metabolism and antibacterial function. Methods Healthy adult participants underwent an overnight 12-hour fast. Neutrophils were isolated to assess the fasting state ex vivo, then the same individuals consumed standardized breakfast and lunch, and postprandial neutrophils were isolated for repeat assays. Readouts included glycolytic and mitochondrial activity using extracellular flux analysis and quantifying the oxidative burst, NET release, and bactericidal activity upon S. aureus stimulation. In mice, a single 12-hour fast preceded systemic S. aureus challenge and outcomes included survival, tissue burdens, and in vivo neutrophil function. Results During the fasting state, human neutrophils showed reduced glycolytic and mitochondrial activity and failed to mount an oxidative burst or release NETs in response to S. aureus resulting in impaired bactericidal activity compared to postprandial neutrophils. In mice, a 12-hour fast markedly increased susceptibility to staphylococcal bacteremia. This was not explained by uniformly elevated tissue burdens; rather, in vivo analyses revealed tissue-specific neutrophil dysfunction consistent with impaired early containment and progression to excessive, nonproductive inflammation. Conclusion A brief, clinically relevant fast induces a reversible state that suppresses neutrophil metabolism and effector programs, heightening vulnerability to severe S. aureus infection. These findings position acute fasting as a modifiable perioperative risk factor and motivate practical mitigation strategies around feeding timing. Funding Source 1R35GM154838 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)