Ketone and glycolytic metabolism are key modulators of inflammation during neonatal sepsis

Neonatal sepsis is a life-threatening condition in preterm infants, primarily due to a dysregulated immunometabolic response to infection. Sepsis and infection mortality are associated with excessive glycolysis-induced inflammation, impaired mitochondrial oxidative phosphorylation (OXPHOS) and loss of disease tolerance. Reduced glucose intake can reverse these dysregulations, but it is unclear how the mechanistic control of glycolysis-OXPHOS balance drives defense strategies and infection outcomes. Here, in a preterm piglet model of neonatal sepsis, glycolysis inhibition with 2-deoxyglucose (2-DG) completely prevents acute infection mortality, reduces systemic inflammation and markers of liver injury, accompanied by enhanced mitochondrial metabolism and disease tolerance. Strikingly, this protection by 2-DG is conferred despite elevated blood glucose levels and higher bacterial burdens than the infected controls. Alternatively, partial replacement of glucose intake with the ketone beta-hydroxybutyrate (BHB) abolishes sepsis-related mortality via improving disease tolerance and clinical parameters. Overall design: Liver samples (2-13 replicates/condition: 10% Glucose (control), 2.5% Glucose + 2.5% BHB (BHB treated), 2.5% Glucose (restricted Glucose), infected and uninfected) were subjected to bulk RNAseq