Metabolism meets immunity: TCA-cycle activation protects the vulnerable newborn

Preterm neonates are highly susceptible to infections which can easily develop into sepsis. Neonatal sepsis remains a major global burden, as no clear pathophysiological characteristics and biomarkers are defined, diagnosis remains challenging, and therapy is limited to antibiotics and general supportive care. Furthermore, how the immune system interacts with the energy metabolism of preterm infants upon infection is poorly understood. In this issue, Wu et al (2026) demonstrate a clear link between systemic energy metabolism and neonatal defense mechanisms during infection. The authors identified tricarboxylic acid (TCA) cycle metabolites as key regulators of immune function associated with reduced infection burdens in early childhood. Boosting TCA cycle activity by providing parenteral nutrition (PN) with galactose or glucogenic amino acids improved glucose homeostasis, enhanced pathogen clearance, and dampened excessive inflammation, ultimately reducing lethality in a piglet neonatal sepsis model. Together, these findings propose therapeutic strategies to improve the outcome of preterm newborns. T. Vanderhaeghen, C. Libert and J. Vandewalle discuss the study by Wu et al, in this issue of EMBO Mol Med, that identifies tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes.