a-translational-preterm-piglet-model-for-neonatal-sepsis

A Translational Preterm Piglet Model For Neonatal Sepsis

Preterm infants are particularly vulnerable to bacterial infections that may rapidly progress to life-threatening sepsis, a state of excessive ...

University of Copenhagen

Breastfed infants have higher intestinal lipid absorption and neurodevelopmental outcomes compared to formula-fed infants, which may relate to a different surface layer structure of fat globules in infant formula. This study investigated if dairy-derived emulsifiers increased lipid absorption and neurodevelopment relative to soy lecithin in newborn preterm piglets. Piglets received a formula diet containing soy lecithin (SL) or whey protein concentrate enriched in extracellular vesicles (WPC-A-EV) or phospholipids (WPC-PL) for 19 days. Both WPC-A-EV and WPC-PL emulsions, but not the intact diets, increased in vitro lipolysis compared to SL. The main differences of plasma lipidomics analysis were increased levels of some sphingolipids, and lipid molecules with odd-chain (17:1, 19:1, 19:3) as well as mono- and polyunsaturated fatty acyl chains (16:1, 20:1, 20:3) in the WPC-A-EV and WPC-PL groups and increased 18:2 fatty acyls in the SL group. Indirect monitoring of intestinal triacylglycerol absorption showed no differences between groups. Diffusor tensor imaging measurements of mean diffusivity in the hippocampus were lower for WPC-A-EV and WPC-PL groups compared to SL indicating improved hippocampal maturation. No differences in hippocampal lipid composition or short-term memory were observed between groups. In conclusion, emulsification of fat globules in infant formula with dairy-derived emulsifiers altered the plasma lipid profile and hippocampal tissue diffusivity but had limited effects on other absorptive and learning abilities relative to SL in preterm piglets.

Dairy-Derived Emulsifiers in Infant Formula Show Marginal Effects on the Plasma Lipid Profile and Brain Structure in Preterm Piglets Relative to Soy Lecithin.

Deficient levels of milk osteopontin (OPN) in infant formula may partly account for developmental differences between infants fed formula or maternal milk. We hypothesized that a milk diet supplemented with bovine milk OPN improves gut, immunity and brain development and tested this in a preterm pig model. Preterm pigs delivered by cesarean section (90% gestation) were fed raw bovine milk (CON,  = 19) or the same diet supplemented with a physiologically relevant dose of OPN (46 mg/(kg·d),  = 16). Endpoints related to clinical outcomes, systemic immunity and neurocognitive development were assessed during the study and gut tissues were collected at Day 19. Growth pattern, early motor development and most systemic immune parameters were similar between OPN and CON pigs. The OPN pigs had higher villus-to-crypt ratios than CON pigs and higher monocyte and lymphocyte counts on Day 8. Gut digestive and absorptive functions and cognitive performance (T-maze test) were similar between OPN and CON pigs. In conclusion, dietary supplementation with OPN above basal bovine milk levels induced minor improvements in gut structure and systemic immunity without any effects on cognitive performance. The minimal levels of OPN in infant formula to secure optimal adaptation in the immediate neonatal period remain to be determined.

Milk Osteopontin for Gut, Immunity and Brain Development in Preterm Pigs.

Ready-to-feed liquid infant formula is increasingly used for preterm infants when human milk is unavailable. These formulas are sterilized by ultra-high temperature treatment, but heating and storage may reduce bioactivity and increase formation of Maillard reaction products with potential negative consequences for immature newborns.

Ultra-High Temperature Treatment and Storage of Infant Formula Induces Dietary Protein Modifications, Gut Dysfunction, and Inflammation in Preterm Pigs.

Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants.

Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.

Processing of whey protein concentrate (WPC) for infant formulas may induce protein modifications with severe consequences for preterm newborn development. The study investigates how conventional WPC and a gently processed skim milk-derived WPC (SPC) affect gut and immune development after birth.

A Gently Processed Skim Milk-Derived Whey Protein Concentrate for Infant Formula: Effects on Gut Development and Immunity in Preterm Pigs.

This study investigates the metabolic impact of skim milk whey-derived protein concentrate (SPC) for infant formula, including its heat-treated (HT-SPC) and stored (HTS-SPC) variants, on the plasma, urine, and gut metabolites of newborn piglets, compared to conventional whey protein concentrate (WPC). Preterm piglets were fed formula containing WPC, SPC, HT-SPC, or HT-SPC, HTS-SPC for 5 days. Metabolomic analysis of plasma, urine, and colon content was performed using 1H NMR. Relative to WPC, SPC mainly affected colon content metabolites, increasing 19 metabolites in the colon and tyrosine in plasma, while decreasing pyruvate in colon content and glycine in plasma. Heat-treatment and storage of SPC led to increased metabolite concentrations in colon contents and urine. Notably, significant correlations between gut metabolites and abundant gut bacteria genes were observed only in the SPC-fed pigs. SPC induced higher branched chain amino acid concentrations in the gut, but had minimal effects on plasma and urinary metabolites, likely due to differences in dietary proteins and in microbiota metabolism. While the clinical effects of SPC-induced gut branched chain amino acids remain unclear, the results from our study suggest that SPC-based infant formula is metabolically safe for sensitive newborns, comparable to WPC-based formulas.

Effects of Skim Milk Whey-Derived Proteins on Plasma, Urine, and Gut Metabolites in Preterm Piglets as a Model for Infants.

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.

Article	Year
Dairy-Derived Emulsifiers in Infant Formula Show Marginal Effects on the Plasma Lipid Profile and Brain Structure in Preterm Piglets Relative to Soy Lecithin. Nutrients\| PubMed ID: 33668360	2021
Milk Osteopontin for Gut, Immunity and Brain Development in Preterm Pigs. Nutrients\| PubMed ID: 34444835	2021
Ultra-High Temperature Treatment and Storage of Infant Formula Induces Dietary Protein Modifications, Gut Dysfunction, and Inflammation in Preterm Pigs. Molecular nutrition & food research\| PubMed ID: 36052940	2022
Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs. Frontiers in neuroscience\| PubMed ID: 37404461	2023
A Gently Processed Skim Milk-Derived Whey Protein Concentrate for Infant Formula: Effects on Gut Development and Immunity in Preterm Pigs. Molecular nutrition & food research\| PubMed ID: 38389157	2024
Effects of Skim Milk Whey-Derived Proteins on Plasma, Urine, and Gut Metabolites in Preterm Piglets as a Model for Infants. Molecular nutrition & food research\| PubMed ID: 40018800	2025
Harnessing the glycolysis-TCA cycle axis to boost host defense against neonatal infection. EMBO molecular medicine\| PubMed ID: 42260137	2026

Karoline Aasmul-Olsen

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