Yvette M. Petersen

Preterm Birth Affects the Intestinal Response to Parenteral and Enteral Nutrition in Newborn Pigs

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 sows 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 (SGLT-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.

Glucagon-like peptide 2 enhances maltase-glucoamylase and sucrase-isomaltase gene expression and activity in parenterally fed premature neonatal piglets.

Exogenous glucagon-like peptide 2 (GLP-2) mimics the stimulatory effect of enteral nutrition on intestinal mucosal growth in preterm neonatal pigs. Little is known about its effects on small intestinal function. In this study, we investigated whether the trophic actions of GLP-2 and enteral nutrition are paralleled by effects on small intestinal function. Cesarean-delivered piglets (92% of gestation) were given either a parenteral nutrient infusion [total parenteral nutrition (TPN), n = 7], TPN + human GLP-2 (25 nmol/kg/d, n = 8), or enteral nutrition (ENT, n = 6) for 6 d. Gene expression (mRNA) and activities of lactase phlorizin hydrolase (LPH), maltase-glucoamylase (MGA), sucrase-isomaltase (SI), aminopeptidase N (ApN), and A (ApA) and dipeptidyl peptidase IV (DPP IV) were measured. Both GLP-2 and enteral nutrition increased mucosal weight (+30–40%, p < 0.05) relative to TPN. GLP-2 stimulated jejunal MGA and SI mRNA abundance and activity levels but did not change LPH in parenterally fed pigs (p < 0.05). Enteral nutrition decreased jejunal LPH and MGA mRNA abundance and activity and increased ileal ApN, ApA, and DPP IV activities relative to TPN (p < 0.05). We conclude that GLP-2 and enteral nutrition exert different effects on intestinal enzyme function despite similar effects on intestinal growth. In addition, the effects of GLP-2 on intestinal function in these parenterally fed, premature neonatal pigs differed from those previously reported for similarly fed term neonates.

Glucagon-like peptide 2 stimulates intestinal nutrient absorption in parenterally fed newborn pigs.

Objectives: Parenteral nutrition is a critically important intervention for children with intestinal dysfunctions. However, total parenteral nutrition (TPN) with no enteral feeding is associated with small intestine atrophy and malabsorption, which complicate the transition to enteral nutrition. The objective of the present study was to evaluate the therapeutic potential of the intestinotrophic peptide glucagon-like peptide 2 (GLP-2), which reduces TPN-associated atrophy and maintains nutrient absorption in adult rats, for preventing nutrient malabsorption in neonates receiving TPN. Methods: Term pigs obtained by cesarean delivery received from birth TPN alone (TPN; n = 7) or TPN with GLP-2 (25 nmol · kg−1 · d−1; GLP-2; n = 8) or were fed sow milk enterally (n = 7). The small intestine was removed on postnatal day 6 to measure morphological responses and absorption of glucose, leucine, lysine and proline by intact tissues and brush border membrane vesicles and to quantify the abundances of mRNA and protein for enterocyte glucose transporters (SGLT-1 and GLUT2). Results: Relative to TPN alone, administration of GLP-2 resulted in small intestines that were larger (P < 0.01), had greater abundances of mRNA and protein for SGLT-1, but not for GLUT2, and had higher capacities to absorb nutrients (P < 0.01). Moreover, the intestines of GLP-2 pigs were comparable in size and absorptive capacities with those of pigs fed sow milk enterally. Conclusions: Providing GLP-2 to neonates receiving TPN prevents small intestine atrophy, results in small intestine absorptive capacities that are comparable to when nutrients are provided enterally and may accelerate the transition from TPN to enteral nutrition.

Glucagon-like peptide 2 treatment may improve intestinal adaptation during weaning.

Transition from sows milk to solid feed is associated with intestinal atrophy and diarrhea. We hypothesized that the intestinotrophic hormone glucagon-like peptide 2 (GLP-2) would induce a dose- and health status-dependent effect on gut adaptation. In Exp. 1, weaned pigs (average BW at weaning 4.98 ± 0.18 kg) were kept in a high-sanitary environment and injected with saline or short-acting GLP-2 (80 μg/(kg BW·12 h); n = 8). Under these conditions, there was no diarrhea and GLP-2 did not improve gastrointestinal structure or function. In Exp. 2, weaned pigs (average BW at weaning 6.68 ± 0.27 kg) were kept in a low-sanitary environment, leading to weaning diarrhea, and injected with saline or short-acting GLP-2 (200 µg/(kg BW·12 h); n = 11). Treatment with GLP-2 increased goblet cell density (P < 0.05) and reduced short chain fatty acid concentration in the colon (P < 0.01) but had limited effects on diarrhea. In Exp. 3, weaned pigs (average BW at weaning 6.90 ± 0.32 kg) were kept in a low-sanitary environment and injected with saline or a long-acting acylated GLP-2 analogue (25 µg/(kg BW·12 h); n = 8). In this experiment, GLP-2 increased intestinal weight (+22%; P < 0.01) and activity of brush border enzymes (+50-100%; P < 0.05). Circulating GLP-2 levels were in the pharmacological range in Exp. 3 (constant levels >20,000 pmol/L) and Exp. 2 (increases to 20,000 pmol/L for a few hours each day) while they were in the supraphysiological range in Exp. 1 (50-200 pmol/L). In conclusion, GLP-2 may improve gut structure and function in weanling pigs. However, the effects may be significant only under conditions of diarrhea and if GLP-2 exposure time is extended using long-acting analogues.

The Premature Newborn Calf: How to Use Steroids to Improve Survival?

In all farm animals, premature birth may occur spontaneously or is required in certain states of acute disease for the pregnant mother or its fetus. Under such circumstances, it is crucial to be able to maximize the chances of survival for the neonate. Prenatal organ maturation is known to be stimulated by glucocorticoids and maternal dexamethasone treatment is used for both humans and cattle prior to premature delivery, albeit with variable success. We tested the hypothesis that an ACTH-stimulated increase in fetal glucocorticoid secretion is more effective in stimulating fetal organ maturation than treatment of the pregnant mother with synthetic glucocorticoids. At 248 d gestation (term = 275 d), intra-vascular catheters were implanted into 13 calf fetuses. After 4-5 days, ACTH-treated calves (250 mg ACTH 1-24 4 times daily, n=6) and control calves (n=7) were exposed to 20 h of maternal dexamethasone treatment (DEX, 25 mg, i.m.) after which all calves were delivered by caesarean section. 24 h after birth the two groups of premature calves (ACTH+DEX and DEX alone) were killed and compared with a group of 24 h-old control calves delivered at full term (TERM).

Inflammatory Bowel Disease in Newborn Pigs: The Role of Formula-Feeding and Premature Birth

Various forms of inflammatory bowel disease are commonly observed among farm animals in the immediate postnatal period. At this critical time, only mild detrimental effects on body metabolism and fluid balance are tolerated and digestive disturbances contribute significantly to a high neonatal mortality among farm animals. We hypothesized that 1) colostrum contains factors that protect against intestinal disease, and 2) intestinal disease is particularly prevalent in pigs born prematurely. The rationale for these hypotheses was derived from the observation that preterm birth coupled with formula-feeding is associated with markedly increased incidence of necrotizing enterocolitis (NEC) in humans. This intestinal disease is the most common and most severe intestinal disease in premature infants. Premature pigs were delivered by elective caesarean section (105 d gestation, term = 115

The Birth Process Makes the Immature Small Intestine Sensitive to Feeding-Induced Intestinal Disease

Many newborn animals suffer from severe intestinal disease in the immediate postnatal period. We have shown that such disease is particularly prevalent when animals are born prematurely and fed a milk-placer (in stead of mother s colostrum). By feeding a milk-replacer to fetuses in utero and comparing them with corresponding pigs fed ex utero, we tested the hypothesis that the response of the immature intestine to oral feeding depends on the process of birth. Under anaesthesia, eight fetuses in 2 pregnant sows (105-106 d gestation, term = 115 d) were prepared with a feeding tube inserted into the fetal esophagus. After the operation, the fetuses were fed either sow s colostrum (n=4) or a milk-replacer (formula, n=4) for 24 h while in utero (15 ml/kg/3 h). After the 24 h feeding, the operated fetuses were removed from the sows by caesarean section and killed for tissue collection. From these and some other pregnant sows (105-107 d gestation) we also removed some unoperated control fetuses. These were either killed at birth (no feed, n=4) or postnatally after 24 h of feeding (colostrum, n=7, formula, n=8). Results from all 5 treatment groups are shown below.

Brush border enzymes are differentially regulated by glucagon-like peptide 2 in the newborn pig maintained on total parenteral nutrition

BRUSH BORDER ENZYMES ARE DIFFERENTIALLY REGULATED BY GLUCAGON-LIKE PEPTIDE 2 IN THE NEWBORN PIG MAINTAINED ON TOTAL PARENTERAL NUTRITION. Yvette M. Petersen, Jan Elnif, Mette H. Schmidt, Douglas G. Burrin, Bollette Hartmann, Jens 1. Holst, Per T. Sangild, Royal Veterinary and Agricul Univ, Copenhagen, Denmark; Childrens Nutrition Research Ctr, Houston, TX; Univ of Copenhagen, Copenhagen, Denmark.