Preterm birth is associated with immature digestive function that may require the use of total parenteral nutrition and special oral feeding regimens. Little is known about the responses to oral food in the preterm neonate and how enteral nutrients affect the immature gastrointestinal tract (GIT). In vivo studies are difficult to perform in laboratory rodents because of their small body size and that of immature organs at birth, and this makes the large farm animals (e.g., pigs, cattle, sheep) more attractive models in this field. In these species, preterm delivery at 88%-95% gestation is associated clinical complications and degrees of GIT immaturity similar to those in infants born at 70%-90% gestation. Studies in both animals and infants indicate that the immature GIT responds to the first enteral food with rapid increases in gut mass and surface area, blood flow, motility, digestive capacity, and nutrient absorption. To a large extent, the enteral food responses are birth independent, and can be elicited also in utero, at least during late gestation. Nevertheless, preterm neonates show compromised GIT structure, function, and immunology, particularly when delivered by caesarean section and fed diets other than mother's milk. Formula-fed preterm infants are thus at increased risk of developing diseases such as necrotizing enterocolitis, unless special care is taken to avoid excessive nutrient fermentation and bacterial overgrowth. The extent to which results obtained in preterm animals (most notably the pig) can be used to reflect similar conditions in preterm infants is discussed.

Maturation of gastrointestinal (GI) function in neonates is stimulated by enteral nutrition, whereas parenteral nutrition induces GI atrophy and malfunction. We investigated whether preterm birth alters the GI responses to parenteral and enteral nutrition. Pigs were delivered either preterm (107 d gestation) or at term (115 d gestation) and fed total parenteral nutrition (TPN) or enteral sow's milk (ENT) for 6 d after birth. Immaturity of the preterm pigs was documented by reduced blood pH, oxygen saturation and neutrophil granulocyte function, impaired intestinal immunoglobulin G uptake from colostrum, and altered relative weights of visceral organs (small intestine, liver, spleen, pancreas, and adrenals). For both ages at delivery, increases occurred in pancreatic weight (30-75%) and amylase activity (0.5- to 13-fold) after birth, but much more in ENT than in TPN pigs (P < 0.05). Six days of TPN feeding was associated with reduced intestinal weight for both delivery groups (60% of values in ENT, P < 0.001), but only in term TPN pigs was the weight lower than at birth (-20%, P < 0.05). Likewise, it was only in term TPN pigs that intestinal maltase activity increased, compared with ENT, and the absorption of glucose and proline decreased. Only in preterm pigs did TPN feeding increase lactase activity (+50% compared with ENT, P < 0.05). For both delivery ages, the mRNA of lactase-phloridzin hydrolase and sodium-coupled glucose transporter 1 were increased in TPN, compared with ENT. In conclusion, the trophic effect of enteral vs. parenteral nutrition on the GI tract is also present after preterm birth, but the postnatal maturation of many GI functions is modified, compared with term birth. The effects of nutritional regimen on the maturation of the gut epithelium in neonates depend on gestational age at birth.

Uptake of colostrum just after birth is essential to stimulate intestinal growth and function, and in many species, including pigs, colostrum also provides immunological protection via the absorption of immunoglobulin G (IgG). In this study, intestinal growth, IgG absorptive capacity and enzyme activities were investigated in newborn pigs in response to different diets. Newborn piglets were bottle-fed porcine colostrum (PC), bovine colostrum (BC), porcine plasma (PP), porcine milk (PM), bovine colostrum containing porcine plasma (BCP) or a milk replacer (MR) every 3 h (15 mL/kg) for up to 2 d. Bovine serum albumin (BSA) was added to the diets as a macromolecule marker. The percentage of absorbed BSA just after birth was highest for piglets fed the PC diet (30-50%), lower for those fed the BC and BCP diets (23-30%) and lowest for the PP, PM and MR diet-fed piglets (7-20%, P < 0.05 relative to those fed colostrum). Porcine IgG was absorbed more efficiently than bovine IgG. Intestinal closure occurred earlier in MR and BCP piglets (within 12 h after birth) than in PC pigs. At 2 d of age, intestinal mucosal weight (+120% increase from birth) and villus morphology were similar in the PC, BCP and MR groups. All 3 groups also had increased aminopeptidase A activity compared with values at birth (+100% increase). Compared with PC pigs, the BCP group had higher sucrase and maltase activities (+50% and +200%, respectively) and lower aminopeptidase N activity (-50%, P < 0.05). Similarly, MR pigs showed elevated sucrase activity (+40%) and lowered maltase, lactase and aminopeptidase N activities (-20% to -50%, P < 0.05) compared with PC pigs. We conclude that porcine and bovine colostrum contain factors that stimulate the intestinal endocytotic and enzymatic capacity in newborn pigs. A milk replacer can produce normal gut growth, but may be inefficient in mediating normal macromolecule transport and disaccharidase activity. Bovine colostrum mixed with porcine plasma proteins may be a useful substitute for porcine colostrum in artificial rearing of newborn pigs.

We wished to determine whether exogenous glucagon-like peptide (GLP)-2 infusion stimulates intestinal growth in parenterally fed immature pigs. Piglets (106-108 days gestation) were given parenteral nutrient infusion (TPN), TPN + human GLP-2 (25 nmol. kg(-1). day(-1)), or sow's milk enterally (ENT) for 6 days. Intestinal protein synthesis was then measured in vivo after a bolus dose of [1-(13)C]phenylalanine, and degradation was calculated from the difference between protein accretion and synthesis. Crypt cell proliferation and apoptosis were measured in situ by 5-bromodeoxyuridine (BrdU) and terminal dUTP nick-end labeling (TUNEL), respectively. Intestinal protein and DNA accretion rates and villus heights were similar in GLP-2 and ENT pigs, and both were higher (P < 0.05) than in TPN pigs. GLP-2 decreased fractional protein degradation rate, whereas ENT increased fractional protein synthesis rate compared with TPN pigs. Percentage of TUNEL-positive cells in GLP-2 and ENT groups was 48 and 64% lower, respectively, than in TPN group (P < 0.05). However, ENT, but not GLP-2, increased percentage of BrdU-positive crypt cells above that in TPN piglets. We conclude that GLP-2 increases intestinal growth in premature, TPN-fed pigs by decreasing proteolysis and apoptosis, whereas enteral nutrition acts via increased protein synthesis and cell proliferation and decreased apoptosis.

Preterm birth interrupts normal fetal growth with consequences for postnatal growth and organ development. In preterm infants, many physiological deficits adapt and disappear with advancing postnatal age, but some may persist into childhood. We hypothesized that preterm birth would induce impaired organ growth and function during the first postnatal week in pigs, while motor abilities and behavioral characteristics would show more persistent developmental delay. Cesarean-delivered preterm (n = 112, 90% gestation) or term (n = 56, 100% gestation) piglets were reared under identical conditions and euthanized for blood and organ collection on postnatal days 0, 5, or 26. Body weight gain remained lower in preterm vs. term pigs up to day 26 (25.5 ± 1.5 vs. 31.0 ± 0.5 g·kg(-1)·day(-1), P < 0.01) when relative weights were higher for brain and kidneys and reduced for liver and spleen. Neonatal preterm pigs had reduced values for blood pH, Po2, glucose, lactate, hematocrit, and cortisol, but at day 26, most values were normalized, although plasma serotonin and IGF 1 levels remained reduced. Preterm pigs showed delayed neonatal arousal and impaired physical activity, coordination, exploration, and learning, relative to term pigs (all P < 0.05). Supplementation of parenteral nutrition during the first 5 days with an enteral milk diet did not affect later outcomes. In preterm pigs, many physiological characteristics of immaturity disappeared by 4 wk, while some neurodevelopmental deficits remained. The preterm pig is a relevant animal model to study early dietary and pharmacological interventions that support postnatal maturation and neurodevelopment in preterm infants.

Following preterm birth, bacterial colonization and enteral formula feeding predispose neonates to gut dysfunction and necrotizing enterocolitis (NEC), a serious gastrointestinal inflammatory disease. We hypothesized that administration of probiotics would beneficially influence early bacterial colonization, thereby reducing the susceptibility to formula-induced gut atrophy, dysfunction, and NEC. Caesarean-delivered preterm pigs were provided total parenteral nutrition (1.5 d) followed by enteral feeding (2 d) with porcine colostrum (COLOS; n = 5), formula (FORM; n = 9), or formula with probiotics (FORM-P; Bifidobacterium animalis and Lactobacillus: L. acidophilus, L. casei, L. pentosus, L. plantarum; n = 13). Clinical NEC scores were reduced (P < 0.05) in FORM-P (2.0 +/- 0.2) and COLOS groups (1.7 +/- 0.5) compared with FORM pigs (3.4 +/- 0.6). Lower NEC scores were associated with elevated intestinal weight, mucosa proportion, villus height, RNA integrity, and brush border aminopeptidase A and N activities, and lower gastric organic acid concentration in the FORM-P and COLOS groups (P < 0.05). Diversity of the mucosa-associated bacteria in the distal small intestine was similar among formula-fed pigs, yet the abundance of specific bacterial groups differed between FORM-P and FORM pigs. FORM-P pigs had lower colonization density of a potential pathogen, Clostridium perfringens, and had commensal Lactobacillus bacteria more closely associated with enterocytes along the villus-crypt axis relative to FORM pigs. These results suggest that probiotic administration immediately after birth promotes the colonization of a beneficial commensal microbiota capable of limiting the formula-induced mucosal atrophy, dysfunction, and pathogen load in preterm neonates, thereby reducing the incidence and severity of NEC.

Fortified blended foods (FBF), especially corn soy blend, are used as food aid for millions of people worldwide, especially malnourished individuals and vulnerable groups. There are only a few studies evaluating the effect of FBF on health outcomes, and the potential negative effect of antinutrients has not been examined. Different lines of evidence suggest that dairy proteins have beneficial effects on vulnerable groups. Here we review the evidence on the effects of adding whey or skimmed milk powder to FBF used for malnourished infants and young children or people living with HIV or AIDS. Adding whey or skimmed milk powder to FBF improves the protein quality, allowing a reduction in total amount of protein, which could have potential metabolic advantages. It also allows for a reduced content of soy and cereal and thereby a reduction of potential antinutrients. It is possible that adding milk could improve weight gain, linear growth, and recovery from malnutrition, but this needs to be confirmed. Bioactive factors in whey might have beneficial effects on the immune system and muscle synthesis, but evidence from vulnerable groups is lacking. Milk proteins will improve flavor, which is important for acceptability in vulnerable groups. The most important disadvantage is a considerable increase in price. Adding 10-15% milk powder would double the price, which means that such a product should be used only in well-defined vulnerable groups with special needs. The potential beneficial effects of adding milk protein and lack of evidence in vulnerable groups call for randomized intervention studies.

Shen RL, Thymann T, Østergaard MV, Støy AC, Krych Ł, Nielsen DS, Lauridsen C, Hartmann B, Holst JJ, Burrin DG, Sangild PT. Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs. Am J Physiol Gastrointest Liver Physiol 309: G310 -G323, 2015. First published July 2, 2015; doi:10.1152/ajpgi.00163.2015.-It is unclear when and how to start enteral feeding for preterm infants when mother's milk is not available. We hypothesized that early and slow advancement with either formula or bovine colostrum stimulates gut maturation and prevents necrotizing enterocolitis (NEC) in preterm pigs, used as models for preterm infants. Pigs were given either total parenteral nutrition (TPN, n ϭ 14) or slowly advancing volumes (16 -64 ml·kg Ϫ1 ·day Ϫ1 ) of preterm infant formula (IF, n ϭ 15) or bovine colostrum (BC, n ϭ 13), both given as adjunct to parenteral nutrition. On day 5, both enteral diets increased intestinal mass (27 Ϯ 1 vs. 22 Ϯ 1 g/kg) and glucagon-like peptide 2 release, relative to TPN (P Ͻ 0.05). The incidence of mild NEC lesions was higher in IF than BC and TPN pigs (60 vs. 0 and 15%, respectively, P Ͻ 0.05). Only the IF pigs showed reduced gastric emptying and gastric inhibitory polypeptide release, and increased tissue proinflammatory cytokine levels (IL-1␤ and IL-8, P Ͻ 0.05) and expression of immunerelated genes (AOAH, LBP, CXCL10, TLR2), relative to TPN. The IF pigs also showed reduced intestinal villus-to-crypt ratio, lactose digestion, and some plasma amino acids (Arg, Cit, Gln, Tyr, Val), and higher intestinal permeability, compared with BC pigs (all P Ͻ 0.05). Colonic microbiota analyses showed limited differences among groups. Early feeding with formula induces intestinal dysfunction whereas bovine colostrum supports gut maturation when mother's milk is absent during the first week after preterm birth. A dietdependent feeding guideline may be required for newborn preterm infants.