Glucose supply and glycolysis inhibition shape the clinical fate of Staphylococcus epidermidis–infected preterm newborns
Tik Muk, … , Karoline Aasmul-Olsen, Duc Ninh Nguyen
Tik Muk, … , Karoline Aasmul-Olsen, Duc Ninh Nguyen
Published May 3, 2022
Citation Information: JCI Insight. 2022;7(11):e157234. https://doi.org/10.1172/jci.insight.157234.
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Research Article Infectious disease Inflammation

Glucose supply and glycolysis inhibition shape the clinical fate of Staphylococcus epidermidis–infected preterm newborns

Abstract

Preterm infants are susceptible to bloodstream infection by coagulase-negative staphylococci (CONS) that can lead to sepsis. Glucose-rich parenteral nutrition is commonly used to support the infants’ growth and energy expenditure but may exceed endogenous regulation during infection, causing dysregulated immune response and clinical deterioration. Using a preterm piglet model of neonatal CONS sepsis induced by Staphylococcus epidermidis (S. epidermidis) infection, we demonstrate the delicate interplay between immunity and glucose metabolism to regulate the host infection response. Circulating glucose levels, glycolysis, and inflammatory response to infection are closely connected across the states of tolerance, resistance, and immunoparalysis. Furthermore, high parenteral glucose provision during infection induces hyperglycemia, elevated glycolysis, and inflammation, leading to metabolic acidosis and sepsis, whereas glucose-restricted individuals are clinically unaffected with increased gluconeogenesis to maintain moderate hypoglycemia. Finally, standard glucose supply maintaining normoglycemia or pharmacological glycolysis inhibition enhances bacterial clearance and dampens inflammation but fails to prevent sepsis. Our results uncover how blood glucose and glycolysis control circulating immune responses, in turn determining the clinical fate of preterm infants infected with CONS. Our findings suggest further refinements of the current practice of parenteral glucose supply for preterm infants during infection.

Authors

Tik Muk, Anders Brunse, Nicole L. Henriksen, Karoline Aasmul-Olsen, Duc Ninh Nguyen

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Figure 3

Parenteral glucose restriction protects S. epidermidis–infected preterm piglets from sepsis.

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Parenteral glucose restriction protects S. epidermidis–infected preterm ...
(A) Preterm newborn piglets were nourished exclusively with PN containing HG (21%; 30 g/kg/d) or LG (1.4%; 2 g/kg/d) concentrations (n = 10–11 per group), intra-arterially infected with 109 CFU/kg S. epidermidis, and cared for 12 hours after infection or until clinical signs of sepsis. Uninfected animals (n = 3) receiving LG PN served as a reference and were not included in the statistics. (B) Survival curve, based on sepsis diagnosis and humane euthanasia endpoint (i.e., blood pH < 7.1 and presence of septic shock symptoms). (C) S. epidermidis density from blood collected by jugular venous (3–6 hours) or heart (12 hours) puncture, by counting CFUs after plating onto tryptic soy agar containing 5% sheep’s blood and incubated for 24 hours at 37°C. (D–H) Blood-gas parameters derived from arterial blood samples collected via the umbilical arterial catheter at 3, 6, and 12 hours. (I) Time of first passaged meconium after infection. (J–M). Blood biochemical parameters measured in heparinized plasma from arterial blood collected at 12 hours. Data are presented as cumulative hazard curves (B and I) or violin dot plots including median (solid line) and IQR (dotted lines) (C–H and J–M). Data were analyzed using a Mantel-Cox test (B and I) or a linear mixed-effects model (C–H and J–M), including an interaction between group and time after infection (C–H). All analyzed data represent 2 independent litters. P for time (Ptime), Pglu, and P for interaction (Pint) denote probability values for effects over time across the HG and LG groups, group effect (HG vs. LG) over time, and interaction effect between time and group in the linear mixed effects interaction model, respectively. *P < 0.05, **P < 0.01, ***P < 0.001, compared with HG group at the same time point. ALAT, alanine aminotransferase; BUN, blood urea nitrogen; CON, control; pCO2, partial pressure of CO2. Panel A was created using Biorender.com.