Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns

Abstract

SummaryPreterm infants are susceptible to neonatal sepsis, which may stem from their distinct immune phenotype, high parenteral glucose provision and poor glucose regulatory capacity. Using a preterm pig model of neonatal sepsis, we previously showed that a high glucose supply during infection predisposed to sepsis via exaggerated glycolysis-induced inflammation. Now we explored options of reducing glucose intake to decrease sepsis risk, without causing hypoglycemia. A selective reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and gluconeogenesis, and dampened circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance. Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.