Rethinking parenteral nutrition as supportive therapy for neonatal sepsis.

It is paramount to optimize prevention and therapy for severe neonatal infections, particularly in high-risk infants. This perspective highlights the lack of guidelines for parenteral nutrition (PN) during suspected or confirmed infections in vulnerable newborns, especially those born preterm. Drawing on insights from immunometabolism and translational preclinical models, we argue that nutritional support during infection should not only meet energy demands but also actively shape immunity by modulating inflammation, organ injury, and clinical outcome. Conventional glucose-rich PN may fuel excessive glycolysis-driven immune activation and harmful hyperinflammation. In contrast, alternative macronutrient strategies, including partial replacement of glucose with galactose, glucogenic amino acids, or ketone bodies, may redirect host metabolism toward balanced immune responses, reduced tissue damage, and improved survival. We propose that neonatal nutrition during infection should be viewed as a modifiable therapeutic intervention and call for clinical trials to develop targeted PN protocols for vulnerable newborns at risk of infection.