Ketone metabolism promotes disease tolerance and survival in experimental neonatal sepsis

Neonatal sepsis remains a major cause of morbidity and mortality in preterm infants and is characterized by dysregulated inflammation and metabolic dysfunction. Excessive glycolysis has been linked to inflammatory injury during neonatal infection, but whether metabolic reprogramming can improve host defense and survival remains unclear. We investigated whether ketone-supported mitochondrial metabolism, together with anti-inflammatory signaling actions of beta-hydroxybutyrate (BHB), promotes disease tolerance during neonatal sepsis. Using a preterm piglet model of Staphylococcus epidermidis bloodstream infection, we assessed the effects of glycolytic inhibition with 2-deoxyglucose and parenteral BHB supplementation on survival, acid-base balance, bacterial burden, systemic inflammation, plasma metabolome, and hepatic transcriptional responses. Mechanistic studies were performed in infected THP-1 macrophages, and human relevance was explored in a cohort of 538 children with plasma metabolomics and cytokine profiling. Animal data were analyzed using additive linear or linear mixed-effects models with estimated marginal means and Tukey adjustment for multiple comparisons; in vitro comparisons used paired t-tests or Wilcoxon signed-rank tests, as appropriate. Glycolytic inhibition protected infected piglets from lethal sepsis and was associated with reduced inflammatory responses and induction of mitochondrial and ketone-associated metabolic pathways. BHB supplementation prevented sepsis-related mortality, improved acid-base homeostasis, and promoted a disease-tolerant phenotype without reducing bacterial burden. Hepatic transcriptomics showed suppression of inflammatory pathways together with activation of mitochondrial and organic-acid metabolic programs. In infected THP-1 macrophages, BHB reduced pro-inflammatory cytokine expression, and this effect persisted despite blockade of ATP synthesis, supporting anti-inflammatory actions beyond metabolic modulation. In the pediatric cohort, higher circulating ketone levels were associated with higher IL-10 and lower interferon-gamma concentrations, consistent with an anti-inflammatory effect of BHB in humans. Ketone supplementation promotes disease tolerance and survival in experimental neonatal sepsis through combined metabolic and anti-inflammatory effects, with data supporting a signaling-active role for BHB in shaping inflammatory responses. These findings identify BHB as a candidate host-directed intervention for neonatal sepsis and support further translational evaluation in preterm infants.