The minimal enteral nutrient intake necessary to increase mucosal mass was 40% of total nutrient intake, whereas 60% enteral nutrition was necessary to sustain normal mucosal proliferation and growth. Our results imply that providing <40% of the total nutrient intake enterally does not have significant intestinal trophic effects.
Glucagon-like peptide 2 (GLP-2) is a gut hormone that stimulates mucosal growth in total parenteral nutrition (TPN)-fed piglets; however, the dose-dependent effects on apoptosis, cell proliferation, and protein synthesis are unknown. We studied 38 TPN-fed neonatal piglets infused iv with either saline or GLP-2 at three rates (2.5, 5.0, and 10.0 nmol.kg(-1).d(-1)) for 7 d. Plasma GLP-2 concentrations ranged from 177 +/- 27 to 692 +/- 85 pM in the low- and high-infusion groups, respectively. GLP-2 infusion dose-dependently increased small intestinal weight, DNA and protein content, and villus height; however, stomach protein synthesis was decreased by GLP-2. Intestinal crypt and villus apoptosis decreased and crypt cell number increased linearly with GLP-2 infusion rates, whereas cell proliferation and protein synthesis were stimulated only at the high GLP-2 dose. The intestinal activities of caspase-3 and -6 and active caspase-3 abundance decreased, yet procaspase-3 abundance increased markedly with increasing infusion rate and plasma concentration of GLP-2. The GLP-2-dose-dependent suppression of intestinal apoptosis and caspase-3 activity was associated with increased protein kinase B and glycogen-synthase kinase-3 phosphorylation, yet the expression phosphatidylinositol 3-kinase was unaffected by GLP-2. Intestinal endothelial nitric oxide synthase mRNA and protein expression was increased, but only at the high GLP-2 dose. We conclude that the stimulation of intestinal epithelial survival is concentration dependent at physiological GLP-2 concentrations; however, induction of cell proliferation and protein synthesis is a pharmacological response. Moreover, we show that GLP-2 stimulates intestinal cell survival and proliferation in association with induction of protein kinase B and glycogen-synthase kinase-3 phosphorylation and Bcl-2 expression.
Prematurity and overfeeding in infants are associated with insulin resistance in childhood and may increase the risk of adult disease. Total parenteral nutrition (TPN) is a major source of infant nutritional support and may influence neonatal metabolic function. Our aim was to test the hypothesis that TPN induces increased adiposity and insulin resistance compared with enteral nutrition (EN) in neonatal pigs. Neonatal pigs were either fed enteral formula orally or i.v. administered a TPN mixture for 17 d; macronutrient intake was similar in both groups. During the 17-d period, we measured body composition by dual-energy X-ray absorptiometry scanning; fasting i.v. glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP) were performed to quantify insulin resistance. On d 17, tissue was collected after 1-h, low-dose CLAMP for tissue insulin signaling assays. TPN pigs gained less lean and more body fat and developed hepatic steatosis compared with EN pigs. After 7 and 13 d, IVGTT showed evidence of insulin resistance in the TPN compared with the EN group. Fasting plasma glucose and insulin also were higher in TPN pigs. CLAMP showed that insulin sensitivity was markedly lower in TPN pigs than in EN pigs. TPN also reduced the abundance of the insulin receptor, insulin receptor substrate 1, and phosphatidylinositol 3 kinase in skeletal muscle and liver and the proliferation of total pancreatic cells and β-cells. Hepatic proinflammatory genes as well as c-Jun-N-terminal kinase 1 phosphorylation, plasma interleukin 6, and tumor necrosis factor-α were all higher in TPN pigs than in EN pigs. The results demonstrate that chronic TPN induces a hepatic inflammatory response that is associated with significant insulin resistance, hepatic steatosis, and fat deposition compared with EN in neonatal pigs. Further studies are warranted to establish the mechanism of TPN-induced insulin resistance and hepatic metabolic dysfunction and whether there are persistent metabolic consequences of this lifesaving form of infant nutritional support.
We quantified the effects of a diet containing animal plasma protein on small intestinal growth and mucosal morphology in early weaned pigs. Ninety-six pigs [14 d old, 4 kg body weight (BW)] were assigned in groups of 32 to three dietary treatments as follows: 1) free access to control diet (C), 2) free access to plasma protein diet (P), and 3) plasma protein, pair-fed to C (PPF). Eight pigs from each group were killed at 2, 4, 8 or 16 d. Over a 16-d period, weight gain in the P group was 43% greater (P < 0.05) than that in C pigs; weight gain was similar in C and PPF groups. Protein intake in the P group was 33% higher (P < 0.05) than that in the PPF group; no significant difference was observed between the C and P groups. Dietary protein conversion efficiencies in both the P and PPF groups were approximately 18% greater (P < 0.05) than those in the C group. Intestinal masses in the three groups did not differ at 2, 4 and 8 d. By 16 d, the jejunal and ileal protein and DNA masses (mg/kg BW) in both the P and PPF groups were lower than those in the C group (P < 0.05). Dietary plasma protein did not affect crypt cell proliferation, crypt depth or villous height in either the jejunum or ileum. However, the intravillous lamina propria cell density in the jejunum was significantly lower (P < 0.05) in P and PPF pigs than in C pigs. Plasma urea concentrations were also 40 and 42% lower (P< 0.05) in the P and PPF groups, respectively, than in the C group. Our results indicate that dietary plasma protein reduces the cellularity of the lamina propria, but not epithelial cell surface of the small intestine. Feeding plasma protein also increased the efficiency of dietary protein utilization, in part, by decreasing amino acid catabolism.
Our objective was to determine the minimum enteral intake level necessary to increase the protein accretion rate (PAR) in the neonatal small intestine. Seven-day-old piglets received an equal total daily intake of an elemental diet, with different proportions given enterally (0, 10%, 20%, 40%, 60%, 80%, and 100%). After 7 days, piglets were infused intravenously with [(2)H(3)]leucine for 6 h, and the fractional protein synthesis rate (FSR) was measured in the proximal (PJ) and distal jejunum (DJ) and the proximal (PI) and distal ileum (DI). The jejunal FSR increased from 45%/day to 130%/day between 0 and 60% enteral intake, whereas the FSR in the ileum was less sensitive to enteral intake level. At 0% enteral intake, PAR was significantly negative in the PJ, DJ, and PI (range -70 to -43 mg/day) and positive in the DI (49 mg/day), whereas intestinal protein balance occurred at 20% enteral intake. At 100% enteral intake, the PAR was greatest in the DI, even though the rates of protein turnover were 50% lower than in the PJ. We conclude that there is net intestinal protein loss at 0% enteral intake, protein balance at 20% enteral intake, and maximal intestinal protein accretion at 60% enteral intake.
Glutamate (Glu) is a major intestinal oxidative fuel, key neurotransmitter, and may be a useful dietary supplement to augment health of the infant gut. We quantified the metabolic fate of various supplemental dietary Glu intakes in young pigs surgically implanted with vascular, intraduodenal (ID), or intragastric (IG) catheters and a portal blood flow probe. Piglets were acutely fed a range of dietary Glu intakes using a basal milk formula (100%) supplemented with varying amounts of monosodium Glu (up to 400%) via ID or IG routes. We quantified the gastrointestinal metabolic fate of dietary Glu using [U-(13)C] Glu tracer. The Glu net absorption in the basal 100% group was low in both ID and IG groups, ranging from 13 to 17% of intake. Enteral Glu supplementation significantly increased the absolute absorption rate and arterial concentration of Glu. In both the ID and IG groups, enteral [(13)C]Glu absorption was limited (<5% tracer input) at the basal Glu intake (100%) but increased nearly 4-fold ( approximately 20% input) in the 300% intake group. A substantial fraction (33-50%) of the enteral [(13)C]Glu input was oxidized by the gut to (13)CO(2) in both the 100 and 300% intake groups. We conclude that extensive gut metabolism limits the absorption of supplemental dietary Glu even at excessive intakes.
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