You are what you eat: Short-term western diet rewires neutrophil metabolism and enables Staphylococcus aureus to suppress NETosis 2254949

Abstract Introduction Immunometabolism ties diet to frontline antibacterial defense. Neutrophils rely on glycolysis to power the oxidative burst and on mitochondrial metabolism to drive neutrophil extracellular trap (NET) release. We asked whether brief exposure to a high-fat, high-calorie western diet (WD), in the absence of obesity or diabetes, is sufficient to alter neutrophil function during Staphylococcus aureus infection. Methods C57BL/6 mice were fed a WD for 2 weeks, then challenged systemically with S. aureus. Outcomes included survival, weight loss, organ bacterial burdens, and organ-specific neutrophil function. Ex vivo, neutrophil metabolism was quantified by extracellular flux analysis and effector functions (oxidative burst, NETosis) quantified by flow cytometry after S. aureus stimulation. Results In a 4-day systemic S. aureus infection model, short-term WD worsened infection outcomes, with higher bacterial burdens in the liver. Ex vivo, fatty acid oxidation (FAO) supports NETosis, indicating that fatty acid availability can fuel this effector program. However, despite increased fatty acid availability in mice on a western diet, NETosis was decreased because S. aureus exploits WD-derived fatty acids to generate or modify lipoproteins that actively suppress NET release. In addition, neutrophils from WD-fed mice display a diminished oxidative burst, consistent with Randle cycle-driven substrate competition that diverts metabolism away from glycolysis-dependent NADPH oxidase activity. Conclusion Together, these findings reveal a rapid, diet-driven vulnerability in innate immunity that S. aureus can leverage. Rather than fueling NETosis through FAO, the same fatty acids are used by S. aureus to blunt NET release, while the Randle cycle dampens the oxidative burst. Defining how diet shifts neutrophil fuel choice and how S. aureus capitalizes on that shift points to metabolic and nutritional strategies to restore NETosis and oxidative burst during infection. Funding Source NIH T32 IMP, NIH 1R35GM15838 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)