Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates.

Preterm neonates are susceptible to gastrointestinal disorders such as necrotizing enterocolitis (NEC). Maternal milk and colostrum protects against NEC via growth promoting, immunomodulatory, and antimicrobial factors. The fetal enteral diet amniotic fluid (AF), contains similar components, and we hypothesized that postnatal AF administration reduces inflammatory responses and NEC in preterm neonates. Preterm pigs (92% gestation) were delivered by caesarean section and fed parental nutrition (2 days) followed by enteral (2 days) porcine colostrum (COLOS, n = 7), infant formula (FORM, n = 13), or AF supplied before and after introduction of formula (AF, n = 10) in experiment 1, and supplied only during the enteral feeding period in experiment 2 (FORM, n = 16; AF, n = 14). The NEC score was reduced in both AF and COLOS pigs, relative to FORM, when AF was provided prior to full enteral feeding (9.9 and 7.7 compared with 17.3, P < 0.05). There was no effect of AF when provided only during enteral feeding. AF pigs showed decreased bacterial abundance in colon and intestinal inflammation-related genes (e.g., TNF-α, IL-1α, IL-6, NOS) were downregulated, relative to FORM pigs with NEC. Anti-inflammatory properties of AF were supported by delayed maturation and decreased TNF-α production in murine dendritic cells, as well as increased proliferation and migration, and downregulation of IL-6 expression in intestinal cells (IEC-6, IPEC-J2). Like colostrum, AF may reduce NEC development in preterm neonates by suppressing the proinflammatory responses to enteral formula feeding and gut colonization when provided before the onset of NEC.

Bovine colostrum is superior to enriched formulas in stimulating intestinal function and necrotising enterocolitis resistance in preterm pigs.

Milk contains immunomodulatory compounds that may be important to protect the immature intestine in preterm neonates from harmful inflammatory reactions involved in disorders like necrotising enterocolitis (NEC). We hypothesised that bovine colostrum and milk formulas enriched with sialic acids (SL), gangliosides (Gang) or osteopontin (OPN) would improve gastrointestinal function and NEC resistance in preterm neonates. Forty-seven caesarean-delivered preterm pigs were given total parenteral nutrition for 2 d followed by 1·5 d of enteral feeding. In Expt 1, a control formula was compared with an OPN-enriched formula (n 13), while Expt 2 compared a control formula with bovine colostrum or formulas enriched with Gang or SL (n 4-6). OPN enrichment decreased NEC severity relative to control formula (P < 0·01), without any significant effects on NEC incidence, digestive enzyme activities and hexose absorption. Neither SL- nor Gang-enriched formulas improved NEC resistance or digestive functions, while all the intestinal functional parameters were significantly improved in pigs fed bovine colostrum, relative to formula. The effects in vivo were supported in vitro by bacteria- and dose-dependent modulation by colostrum whey of the cytokine response from bacteria-stimulated murine bone marrow-derived dendritic cells (DC). In conclusion, OPN had only moderate NEC-protective effects, while formulas enriched with Gang or SL were ineffective. The observed modulation of DC cytokine response by bovine colostrum whey in vitro may be due to a synergistic action of various milk bioactives, and it may explain its beneficial effects on NEC development and intestinal function in a piglet model of preterm infants.

Carbohydrate maldigestion induces necrotizing enterocolitis in preterm pigs.

Necrotizing enterocolitis (NEC) remains the most severe gastrointestinal disorder in preterm infants. It is associated with the initiation of enteral nutrition and may be related to immature carbohydrate digestive capacity. We tested the hypothesis that a formula containing maltodextrin vs. a formula containing lactose as the principal source of carbohydrate would predispose preterm pigs to a higher NEC incidence. Cesarean-derived preterm pigs were given total parenteral nutrition for 48 h followed by total enteral nutrition with a lactose-based (n = 11) or maltodextrin-based (n = 11) formula for 36 h. A higher incidence (91% vs. 27%) and severity (score of 3.3 vs. 1.8) of NEC were observed in the maltodextrin than in the lactose group. This higher incidence of NEC in the maltodextrin group was associated with significantly lower activities of lactase, maltase, and aminopeptidase; reduced villus height; transiently reduced in vivo aldohexose uptake; and reduced ex vivo aldohexose uptake capacity in the middle region of the small intestine. Bacterial diversity was low for both diets, but alterations in bacterial composition and luminal concentrations of short-chain fatty acids were observed in the maltodextrin group. In a second study, we quantified net portal absorption of aldohexoses (glucose and galactose) during acute jejunal infusion of a maltodextrin- or a lactose-based formula (n = 8) into preterm pigs. We found lower net portal aldohexose absorption (4% vs. 42%) and greater intestinal recovery of undigested carbohydrate (68% vs. 27%) in pigs acutely perfused with the maltodextrin-based formula than those perfused with the lactose-based formula. The higher digestibility of the lactose than the maltodextrin in the formulas can be attributed to a 5- to 20-fold higher hydrolytic activity of tissue-specific lactase than maltases. We conclude that carbohydrate maldigestion is sufficient to increase the incidence and severity of NEC in preterm pigs.