Ole Bæk

Introduction: Preterm infants are highly susceptible to sepsis and hyperglycemia may exacerbate inflammation and worsen outcomes. We examined how glucose provision influences systemic and cardiac responses during neonatal sepsis in preterm pigs. Methods: Preterm piglets (90 % gestation) were infused with Staphylococcus epidermidis to induce sepsis. In Experiment 1, three ventilated and anesthetized piglets were continuously monitored for mean arterial pressure (MAP) and blood gases to characterize acute cardiovascular and metabolic deterioration. In Experiment 2, thirty-three piglets were randomized to standard (14 g/kg/day) or reduced (3.5 g/kg/day) glucose provision, with or without infection, and followed for 20h. Results: Infection in Experiment 1 caused progressive hypotension, acidosis, and hypoxia, mirroring clinical neonatal sepsis. In Experiment 2, reduced glucose provision improved survival (77 % vs 46 %, p = 0.06) and attenuated systemic inflammation, with lower IL-6 and higher IL-10 concentrations. Infection induced mild cardiac neutrophil infiltration, without affecting plasma troponin T but clearly reduced cardiomyocyte mitotic density and triggered upregulation of inflammatory transcriptional pathways (NF-κB, JAK-STAT) and suppression of oxidative phosphorylation. In infected animals. glucose restriction preserved cardiomyocyte mitotic density but did not alter cardiac structure, injury markers or gene expression. Conclusion: Neonatal infection induced circulatory failure, suppression of cardiomyocyte proliferation and upregulation of inflammatory genes in cardiac tissue, while reduced glucose provision mitigated systemic immune responses and preserved cardiomyocyte proliferation.

Background: Otitis media is highly prevalent during early life, yet the molecular factors that predispose children to recurrent episodes are poorly defined. Metabolomics captures dynamic biochemical changes and may help identify pathways influencing otitis susceptibility. We examined whether longitudinal infant plasma metabolomic profiles were associated with development of stringently‐defined otitis proneness in the Rochester Combined Cohort (RCC; Rochester, NY). Methods: Global plasma metabolomic profiling was performed in RCC samples collected between ~6 and 18 months of age using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Children were classified as stringently‐defined otitis prone (sOP) if they experienced ≥3 acute otitis media (AOM) episodes within a 6‐month period or ≥4 AOM episodes within a 12‐month period during the first 3 years of life; all AOM episodes were tympanocentesis‐confirmed. Generalized additive mixed models (GAMMs) assessed age‐dependent differences in plasma metabolite levels between sOP and non‐otitis‐prone (nOP) children, adjusting for potential confounders. Results: Several metabolites demonstrated age‐related declines in lipid and amino acid pathways, with consistently lower metabolite trajectories in the sOP group. Compared with nOP children, sOP children exhibited significantly lower levels of 16 metabolites related to inflammatory lipid signaling, redox metabolism, and fatty acid metabolism ( p < 4.4 × 10 ⁻⁴ ) and higher levels of glycerophosphoinositol ( p = 2.9 × 10 ⁻⁴ ). These findings were directionally consistent in a sensitivity analysis additionally adjusted for recent antibiotic use. Conclusion: Children who subsequently met sOP criteria by age 3 years exhibited distinct plasma metabolomic signatures during infancy, suggesting altered immune–metabolic programming preceding recurrent otitis media. Longitudinal metabolomics provides a promising framework to identify biochemical mechanisms underlying otitis proneness.

Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to mediate newborn host infection defense remains poorly understood. Here, we identify tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes. First, in a birth cohort of 700 children, elevated plasma TCA metabolite levels were associated with reduced infection burdens and systemic inflammation. Next, in a piglet neonatal sepsis model, sustained hepatic TCA cycle activity was associated with survival. These led us to explore clinically relevant nutritional strategies boosting TCA cycle activity. Substituting glucose in parenteral nutrition for galactose or glucogenic amino acids improved both pathogen clearance and preserved glucose homeostasis and prevented lethal sepsis. Mechanistically, these interventions promoted hepatic metabolic rewiring from glycolysis toward TCA-cycle-based oxidative phosphorylation, while mitigating excessive inflammation and organ injury. Our findings establish a clear connection between systemic energy metabolism and neonatal infection defense, suggesting clinically relevant strategies to improve outcomes in vulnerable newborns.

Background/Objectives: Randomized clinical trials (RCTs) suggest that n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation during pregnancy may protect against childhood asthma. However, the underlying mechanisms remain unclear. Methods: To explore the transcriptional effects of various concentrations of n-3 LCPUFA and vitamin D supplementation on in utero lung development, we cultured human lung organoids derived from BILX and SEHP human-induced pluripotent stem cell lines at the Sanger Institute (Cambridge, UK). The organoids were treated with either no supplementation, or low (0.01 µL/mL) or high (0.1 µL/mL) concentrations of n-3 LCPUFA, as well as no supplementation, or low (5 pM) or high (50 pM) concentrations of vitamin D. Organoids were matured for 50 days, with foregut spheroids embedded in Matrigel and later re-embedded individually to ensure robust growth. We then assessed the impact of these supplementations using RNA sequencing. Results: RNA sequencing of four replicates per condition (36 total samples) revealed that n-3 LCPUFA supplementation had a more substantial impact on gene regulation than vitamin D (differentially expressed genes, n = 907 vs. n = 23). CPT1A and ANGPTL4 genes were highly expressed in media cultured with a high concentration of n-3 LCPUFA, while CYP24A1 was among the highly expressed genes in media cultured with a high concentration of vitamin D. Enrichment analysis showed activation of PPAR pathways, suggesting that n-3 LCPUFA supplementation may protect against asthma by regulating lipid metabolism and inflammation. Conclusions: We identified several genes and pathways that may provide insights into the biological effects of n-3 LCPUFA and vitamin D supplementation on asthma pathophysiology.

Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage, and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree of metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options for reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after the 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, a liver-derived anti-inflammatory 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.

We reveal that medium-chain triacylglycerol (MCT) intake increases postprandial ketogenesis and metabolic rate and reduces plasma glucose levels in humans. Notably, these responses persist in individuals with obesity and are maintained following chronic MCT supplementation. Some medium-chain fatty acids entered the circulation, suggesting that these, together with ketone bodies, act as signaling molecules/substrates in peripheral tissues. The findings highlight health beneficial effects of dietary MCT in individuals with obesity and reveal new insights into lipid biology.

Summary Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options of reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both 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, a liver derived anti-inflammatory 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.