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.
View: Text | PDF
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

×

Figure 5

Glycolysis inhibition decreases inflammation in S. epidermidis–challenged preterm cord blood.

Options: View larger image (or click on image) Download as PowerPoint
Glycolysis inhibition decreases inflammation in S. epidermidis–challenge...
(A and B) TNF-α levels in cord blood of preterm piglets (n = 6) following stimulation with S. epidermidis, with and without presence of a glycolysis inhibitor: rapamycin (500 nM), DCA (10 mM), and FX11 (100 μM) at 37°C and 5% CO2 incubation (n = 6) (A); and DCA (0.1–10 mM) (B). (C) Cord blood neutrophil phagocytosis (n = 10, from 2 independent litters) measured by fraction of neutrophils having phagocytic capacity in cord blood with and without 10 mM DCA added at normo- or hyperglycemic conditions. In vitro phagocytosis assay was performed by incubating samples with pHrodo-conjugated E. coli for 30 minutes at 37°C and 5% CO2 and analyzed by flow cytometry. (D) Bacterial density in preterm cord blood following stimulation with S. epidermidis (theoretical dose from 105 to 107 CFU/mL) for 30 minutes or 1 hour with and without preincubation with 10 mM DCA (n = 6). (E) Effects of DCA (10 mM) on S. epidermidis growth (n = 3). (F–J) Heatmaps from transcriptomic analyses of cord blood samples with or without S. epidermidis (5 × 105 CFU/mL) and DCA incubation. (F) The top 30 DEGs from the comparison between control (CON) and S. epidermidis–challenged samples. (G–J) Selective DEGs related to inflammation (G), OXPHOS (H), antiinflammatory effect (I), and phagocytosis and endocytosis (J) and obtained from the comparison between S. epidermidis–stimulated samples without versus with DCA addition. For each DEG (row), z-scores of the expression levels are depicted in colors from blue (low) to red (high). (A–E) Data are presented as violin dot plots with median and IQR and were analyzed using a linear mixed-effect model with inhibitor treatment as a fixed factor and pig ID as the random factor. *P < 0.05, ***P < 0.001. (B) Values not sharing the same letters are significantly different (P < 0.05). SE, S. epidermidis.