Metabolomics reveals changes in levels of fecal branched chain amino acids and organic acids in very preterm infants fed human milk fortified with bovine colostrum.

Background & Aims: Human milk is the optimal diet for very preterm infants (VPIs), but it requires nutrient fortification to support growth. Bovine colostrum (BC), rich in intact proteins and bioactive components, could serve as a novel fortifier with potential benefits to VPIs gut health. To evaluate a possible effect of feeding BC on intestinal metabolism, the gut microbiota, and their interaction, we studied the fecal metabolome of VPIs in the first month of life, as compared with a conventional fortifier (CF, based on infant formula ingredients).

Neonatal Gut and Immune Responses to β-Casein Enriched Formula in Piglets.

Background: β-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less β-casein than HM, but whether different concentrations of β-casein affect tolerability and gut and immune maturation in newborns is unknown.

Objectives: Using near-term piglets as a model for newborn infants, we investigated whether increasing the β-casein fraction in bovine-based formula is clinically safe and may improve gut and immune maturation.

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

Scope: 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.

Methods And Results: Newborn, preterm pigs used as a model of preterm infants were fed formula containing WPC, SPC, extra heat-treated SPC (HT-SPC), or stored HT-SPC (HTS-SPC) for 5 days.

Ultra-High Temperature Treatment of Liquid Infant Formula, Systemic Immunity, and Kidney Development in Preterm Neonates.

Scope: Ready-to-feed liquid infant formulas (IFs) are increasingly being used for newborn preterm infants when human milk is unavailable. However, sterilization of liquid IFs by ultra-high temperature (UHT) introduces Maillard reaction products (MRPs) that may negatively affect systemic immune and kidney development.

Methods And Results: UHT-treated IF without and with prolonged storage (SUHT) are tested against pasteurized IF (PAST) in newborn preterm pigs as a model for preterm infants.

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

Scope: 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.

Methods And Results: Using preterm pigs as a model for sensitive newborn infants, the study tests the intestinal responses of feeding experimental liquid formula within 5 days.

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

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).

Supplementary Bovine Colostrum Feedings to Formula-Fed Preterm Pigs Improve Gut Function and Reduce Necrotizing Enterocolitis.

Objectives: Exclusive feeding with bovine colostrum (BC) protects preterm pigs against necrotizing enterocolitis (NEC) and BC has recently been tested as a supplement to a mother's own milk or formula (FOR) for very preterm infants. Using preterm pigs as a model for infants, we investigated if BC has gut- and NEC-protective effects at different proportions of the daily enteral intake given as BC.

Methods: Sixty-eight caesarean-delivered preterm piglets (90% gestation) were allocated into four groups with increasing proportions of eight daily bolus feedings as BC: BC00 (only FOR feeding), BC25 (25% BC), BC50 (50% BC), or BC75 (75% BC).

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

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.

Sex-Specific Survival, Growth, Immunity and Organ Development in Preterm Pigs as Models for Immature Newborns.

After very preterm birth, male infants show higher mortality than females, with higher incidence of lung immaturity, neurological deficits, infections, and growth failure. In modern pig production, piglets dying in the perinatal period (up to 20%) often show signs of immature organs, but sex-specific effects are not clear. Using preterm pigs as model for immature infants and piglets, we hypothesized that neonatal survival and initial growth and immune development depend on sex.

Nutrient Restriction has Limited Short-Term Effects on Gut, Immunity, and Brain Development in Preterm Pigs.

Background: Extrauterine growth restriction (EUGR) in preterm infants is associated with higher morbidity and impaired neurodevelopment. Early nutrition support may prevent EUGR in preterm infants, but it is not known if this improves organ development and brain function in the short and long term.

Objective: Using pigs as models for infants, we hypothesized that diet-induced EUGR impairs gut, immunity, and brain development in preterm neonates during the first weeks after birth.

Alpha-Lactalbumin Enriched Whey Protein Concentrate to Improve Gut, Immunity and Brain Development in Preterm Pigs.

Human milk is rich in nutritional factors, such as alpha-lactalbumin (α-Lac), and important for neonatal development, but nutrient supplementation may be required for optimal growth. Using a pig model, we hypothesized that α-Lac-enriched whey protein concentrate (WPC) supplementation improves neonatal development. Cesarean-delivered preterm pigs were fed either dilute bovine milk (REF) or REF milk supplemented with WPC with normal (STANDARD-ALPHA) or high (HIGH-ALPHA) α-Lac.

Bovine Milk Oligosaccharides with Sialyllactose Improves Cognition in Preterm Pigs.

Optimal nutrition is important after preterm birth to facilitate normal brain development. Human milk is rich in sialic acid and preterm infants may benefit from supplementing formula with sialyllactose to support neurodevelopment. Using pigs as models, we hypothesized that sialyllactose supplementation improves brain development after preterm birth.

Bovine Milk Oligosaccharides with Sialyllactose for Preterm Piglets.

Oligosaccharides support gut development and bacterial colonization in term infants, but it is unknown if they benefit preterm infants. Using preterm pigs, we investigated effects of bovine milk supplements enriched with oligosaccharides to improve gut development and colonization. Caesarean-delivered preterm pigs (n = 57) were reared for 19 days.

Human Milk Oligosaccharides to Prevent Gut Dysfunction and Necrotizing Enterocolitis in Preterm Neonates.

This review focuses on the evidence for health benefits of human milk oligosaccharides (HMOs) for preterm infants to stimulate gut adaptation and reduce the incidence of necrotizing enterocolitis (NEC) in early life. The health benefits of breastfeeding are partly explained by the abundant HMOs that serve as prebiotics and immunomodulators. Gut immaturity in preterm infants leads to difficulties in tolerating enteral feeding and bacterial colonization and a high sensitivity to NEC, particularly when breast milk is insufficient.

Bioactive Whey Protein Concentrate and Lactose Stimulate Gut Function in Formula-fed Preterm Pigs.

Objective: Formula feeding is associated with compromised intestinal health in preterm neonates compared with maternal milk, but the mechanisms behind this are unclear. We hypothesized that the use of maltodextrin and whey protein concentrates (WPCs) with reduced bioactivity owing to thermal processing are important factors.

Method: Ninety-two cesarean-delivered preterm pigs were fed increasing doses of formulas for 5 days (24-120 mL · kg · day).

Pasteurization Procedures for Donor Human Milk Affect Body Growth, Intestinal Structure, and Resistance against Bacterial Infections in Preterm Pigs.

Holder pasteurization (HP) destroys multiple bioactive factors in donor human milk (DM), and UV-C irradiation (UVC) is potentially a gentler method for pasteurizing DM for preterm infants. We investigated whether UVC-treated DM improves gut maturation and resistance toward bacterial infections relative to HP-treated DM. Bacteria, selected bioactive components, and markers of antioxidant capacity were measured in unpasteurized donor milk (UP), HP-treated milk, and UVC-treated milk (all from the same DM pool).

Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis.

Background: The risk factors for necrotizing enterocolitis (NEC) are well known, but the factors involved in the different NEC presentations remain unclear.

Objectives: We hypothesized that digestive dysfunction and intestinal inflammation are mainly affected by severe NEC lesions.

Methods: In 48 preterm pigs, the association between the macroscopic NEC score (range 1-6) and the expression of 48 genes related to inflammation, morphological, and digestive parameters in the distal small intestine was investigated.

Human milk oligosaccharide effects on intestinal function and inflammation after preterm birth in pigs.

Unlabelled: Human milk oligosaccharides (HMOs) may mediate prebiotic and anti-inflammatory effects in newborns. This is particularly important for preterm infants who are highly susceptible to intestinal dysfunction and necrotizing enterocolitis (NEC). We hypothesized that HMO supplementation of infant formula (IF) improves intestinal function, bacterial colonization and NEC resistance immediately after preterm birth, as tested in a preterm pig model.

Minimal short-term effect of dietary 2'-fucosyllactose on bacterial colonisation, intestinal function and necrotising enterocolitis in preterm pigs.

Human milk decreases the risk of necrotising enterocolitis (NEC), a severe gastrointestinal disease that occurs in 5-10 % of preterm infants. The prebiotic and immune-modulatory effects of milk oligosaccharides may contribute to this protection. Preterm pigs were used to test whether infant formula enriched with α1,2-fucosyllactose (2'-FL, the most abundant oligosaccharide in human milk) would benefit gut microbial colonisation and NEC resistance after preterm birth.

Bovine colostrum improves neonatal growth, digestive function, and gut immunity relative to donor human milk and infant formula in preterm pigs.

Mother's own milk is the optimal first diet for preterm infants, but donor human milk (DM) or infant formula (IF) is used when supply is limited. We hypothesized that a gradual introduction of bovine colostrum (BC) or DM improves gut maturation, relative to IF during the first 11 days after preterm birth. Preterm pigs were fed gradually advancing doses of BC, DM, or IF (3-15 ml·kg(-1)·3 h(-1), n = 14-18) before measurements of gut structure, function, microbiology, and immunology.

α1,2-Fucosyllactose Does Not Improve Intestinal Function or Prevent Escherichia coli F18 Diarrhea in Newborn Pigs.

Objectives: Infectious diarrhea, a leading cause of morbidity and deaths, is less prevalent in breastfed infants compared with infants fed infant formula. The dominant human milk oligosaccharide (HMO), α-1,2-fucosyllactose (2'-FL), has structural homology to bacterial adhesion sites in the intestine and may in part explain the protective effects of human milk. We hypothesized that 2'-FL prevents diarrhea via competitive inhibition of pathogen adhesion in a pig model for sensitive newborn infants.

Processing of whey modulates proliferative and immune functions in intestinal epithelial cells.

Whey protein concentrate (WPC) is often subjected to heat treatment during industrial processing, resulting in protein denaturation and loss of protein bioactivity. We hypothesized that WPC samples subjected to different degrees of thermal processing are associated with different levels of bioactive proteins and effects on proliferation and immune response in intestinal epithelial cells (IEC). The results showed that low-heat-treated WPC had elevated levels of lactoferrin and transforming growth factor-β2 compared with that of standard WPC.

Preterm Birth Reduces Nutrient Absorption With Limited Effect on Immune Gene Expression and Gut Colonization in Pigs.

Objectives: The primary risk factors for necrotizing enterocolitis (NEC) are preterm birth, enteral feeding, and gut colonization. It is unclear whether feeding and colonization induce excessive expression of immune genes that lead to NEC. Using a pig model, we hypothesized that reduced gestational age would upregulate immune-related genes and cause bacterial imbalance after birth.

Provision of Amniotic Fluid During Parenteral Nutrition Increases Weight Gain With Limited Effects on Gut Structure, Function, Immunity, and Microbiology in Newborn Preterm Pigs.

Background: Small enteral boluses with human milk may reduce the risk of subsequent feeding intolerance and necrotizing enterocolitis in preterm infants receiving parenteral nutrition (PN). We hypothesized that feeding amniotic fluid, the natural enteral diet of the mammalian fetus, will have similar effects and improve growth and gastrointestinal (GI) maturation in preterm neonates receiving PN, prior to the transition to milk feeding.

Materials And Methods: Twenty-seven pigs, delivered by cesarean section at ~90% of gestation, were provided with PN and also fed boluses with amniotic fluid (AF; n = 13, 24-72 mL/kg/d) or no oral supplements (nil per os [NPO]; n = 14) until day 5 when blood, tissue, and fecal samples were collected for analyses.

Transforming growth factor-β2 and endotoxin interact to regulate homeostasis via interleukin-8 levels in the immature intestine.

A balance between pro- and anti-inflammatory signals from milk and microbiota controls intestinal homeostasis just after birth, and an optimal balance is particularly important for preterm neonates that are sensitive to necrotizing enterocolitis (NEC). We suggest that the intestinal cytokine IL-8 plays an important role and hypothesize that transforming growth factor-β2 (TGF-β2) acts in synergy with bacterial lipopolysaccharide (LPS) to control IL-8 levels, thereby supporting intestinal homeostasis. Preterm pigs were fed colostrum (containing TGF-β2) or infant formula (IF) with or without antibiotics (COLOS, n = 27; ANTI, n = 11; IF, n = 40).