Antibiotics Increase Gut Metabolism and Antioxidant Proteins and Decrease Acute Phase Response and Necrotizing Enterocolitis in Preterm Neonates

Background: The appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms. Methodology/Principal Findings: Preterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization-dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased. Conclusions/Significance: Depressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria-associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates. © 2012 Jiang et al.published_or_final_versio

Glucose transport by epithelia prepared from harvested enterocytes

Transformed and cultured cell lines have significant shortcomings for investigating the characteristics and responses of native villus enterocytes in situ. Interpretations of results from intact tissues are complicated by the presence of underlying tissues and the crypt compartment. We describe a simple, novel, and reproducible method for preparing functional epithelia using differentiated enterocytes harvested from the small intestine upper villus of adult mice and preterm pigs with and without necrotizing enterocolitis. Concentrative, rheogenic glucose uptake was used as an indicator of epithelial function and was demonstrated by cellular accumulation of tracer 14C d-glucose and Ussing chamber based short-circuit currents. Assessment of the epithelia by light and immunofluorescent microscopy revealed the harvested enterocytes remain differentiated and establish cell–cell connections to form polarized epithelia with distinct apical and basolateral domains. As with intact tissues, the epithelia exhibit glucose induced short-circuit currents that are increased by exposure to adenosine and adenosine 5′-monophosphate (AMP) and decreased by phloridzin to inhibit the apical glucose transporter SGLT-1. Similarly, accumulation of 14C d-glucose by the epithelia was inhibited by phloridzin, but not phloretin, and was stimulated by pre-exposure to AMP and adenosine, apparently by a microtubule-based mechanism that is disrupted by nocodazole, with the magnitudes of responses to adenosine, forskolin, and health status exceeding those we have measured using intact tissues. Our findings indicate that epithelia prepared from harvested enterocytes provide an alternative approach for comparative studies of the characteristics of nutrient transport by the upper villus epithelium and the responses to different conditions and stimuli

Time to full enteral feeding for very low-birth-weight infants varies markedly among hospitals worldwide but may not be associated with incidence of necrotizing enterocolitis:The NEOMUNE-NeoNutriNet Cohort Study

Background: Transition to enteral feeding is difficult for very low-birth-weight (VLBW; ≤1500 g) infants, and optimal nutrition is important for clinical outcomes. Method: Data on feeding practices and short-term clinical outcomes (growth, necrotizing enterocolitis [NEC], mortality) in VLBW infants were collected from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2947). Specifically, 5 NICUs in Guangdong province in China (GD), mainly using formula feeding and slow feeding advancement (n = 1366), were compared with the remaining NICUs (non-GD, n = 1581, Oceania, Europe, United States, Taiwan, Africa) using mainly human milk with faster advancement rates. Results: Across NICUs, large differences were observed for time to reach full enteral feeding (TFF; 8–33 days), weight gain (5.0–14.6 g/kg/day), ∆z-scores (−0.54 to −1.64), incidence of NEC (1%–13%), and mortality (1%–18%). Adjusted for gestational age, GD units had longer TFF (26 vs 11 days), lower weight gain (8.7 vs 10.9 g/kg/day), and more days on antibiotics (17 vs 11 days; all P <.001) than non-GD units, but NEC incidence and mortality were similar. Conclusion: Feeding practices for VLBW infants vary markedly around the world. Use of formula and long TFF in South China was associated with more use of antibiotics and slower weight gain, but apparently not with more NEC or higher mortality. Both infant- and hospital-related factors influence feeding practices for preterm infants. Multicenter, randomized controlled trials are required to identify the optimal feeding strategy during the first weeks of life

IL-1α Mediated Chorioamnionitis Induces Depletion of FoxP3+ Cells and Ileal Inflammation in the Ovine Fetal Gut

Endotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.Sheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.Intraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process