Harnessing the glycolysis-TCA cycle axis to boost host defense against neonatal infection

Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to mediate newborn host infection defense remains poorly understood. Here, we identify tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes. First, in a birth cohort of 700 children, elevated plasma TCA metabolite levels were associated with reduced infection burdens and systemic inflammation. Next, in a piglet neonatal sepsis model, sustained hepatic TCA cycle activity was associated with survival. These led us to explore clinically relevant nutritional strategies boosting TCA cycle activity. Substituting glucose in parenteral nutrition for galactose or glucogenic amino acids improved both pathogen clearance and preserved glucose homeostasis and prevented lethal sepsis. Mechanistically, these interventions promoted hepatic metabolic rewiring from glycolysis toward TCA-cycle-based oxidative phosphorylation, while mitigating excessive inflammation and organ injury. Our findings establish a clear connection between systemic energy metabolism and neonatal infection defense, suggesting clinically relevant strategies to improve outcomes in vulnerable newborns.