Production of short-chain fatty acids (SCFA) in the intestinal lumen may play an important role in the maintenance of the intestinal barrier. However, overproduction/accumulation of SCFA in the bowel may be toxic to the intestinal mucosa and has been hypothesized to play a role in the pathogenesis of neonatal necrotizing enterocolitis (NEC). By using a Caco-2 cell monolayer model of intestinal barrier, we report here that the effect of butyrate on the intestinal barrier is paradoxical. Butyrate at a low concentration (2 mM) promotes intestinal barrier function as measured by a significant increase in transepithelial electrical resistance (TER) and a significant decrease in inulin permeability. Butyrate at a high concentration (8 mM) reduces TER and increases inulin permeability significantly. Butyrate induces apoptosis and reduces the number of viable Caco-2 cells in a dose-dependent manner. Intestinal barrier function impairment induced by high concentrations of butyrate is most likely related to butyrate-induced cytotoxicity due to apoptosis. We conclude that the effect of butyrate on the intestinal barrier is paradoxical; i.e. whereas low concentrations of butyrate may be beneficial in promoting intestinal barrier function, excessive butyrate may induce severe intestinal epithelial cell apoptosis and disrupt intestinal barrier. (Pediatr Res 61: 37-41, 2007)

Background: Amino acid (AA) metabolic patterns have emerged as an analytical technique to characterize biomarkers compromising normal growth and elucidate underlying nutritional exposure. This study aimed to identify AA metabolites most likely associated with poor growth and examine the association between AA metabolites and nutrition regimens in preterm infants during transition from parenteral nutrition (PN) to enteral nutrition (EN), using gas chromatography-mass spectrometry (GC-MS).Methods: This observational cohort study was conducted in infants born at <32 weeks' gestation with birth weight of <1,500 g. The outcome of extrauterine growth retardation (EUGR) based on whether the weight was <10th percentile for post-menstrual age, was evaluated when full EN reached. Samples were collected at four sampling points according to nutritional status. AA profiles in dried sampling point spots (DBS) were quantified using GC-MS; and were compared simultaneously. The correlation of AA concentration with growth and nutritional parameters was examined using multivariate analysis.Results: We identified 40 eligible infants: 20 in the EUGR group and 20 in the non-EUGR group. AA deficiency progressively emerged during the transition. Lower concentrations of four AAs, including citrulline (Cit), were associated with increased risk of EUGR when adjusted for gestational age, birth weight z-score, age when trophic EN was started, as well as average energy and protein intakes in synchronous nutritional period. Moreover, a lower Cit concentration was positively correlated with the compromised protein and energy deficits in EN during early transition. Conclusion:A low Cit concentration during transition from PN to full EN should be noticed by the clinician to more closely examine nutrition practices to prevent EUGR.

Necrotizing enterocolitis (NEC) is one of the most widespread and devastating gastrointestinal diseases in neonates. Destruction of the intestinal barrier is the main underlying cause of NEC. The aim of this study was to determine the role of lactadherin in preventing NEC in a neonatal rat model and investigate the molecular mechanism of lactadherin-mediated protection of the intestinal barrier. Neonatal rats were divided into three groups: dam feeding (DF), NEC (NEC), and NEC supplemented with 10 μg/(g·day) recombinant human lactadherin (NEC+L). Intestinal permeability, tissue damage, and cell junction protein expression and localization were evaluated. We found that lactadherin reduced weight loss caused by NEC, reduced the incidence of NEC from 100% to 46.7%, and reduced the mean histological score for tissue damage to 1.40 compared with 2.53 in the NEC group. Intestinal permeability of lactadherintreated rats was significantly reduced when compared with that of the NEC group. In addition, the expression levels of JAM-A, claudin 3, and E-calcium in the ileum of NEC group animals increased compared with those in the ileum of DF group animals, and these levels decreased in the NEC+L group.Lactadherin changed the localization of claudin 3, occludin, and E-cadherin in epithelial cells. The mechanism underlying lactadherin-mediated protection of the intestinal barrier might be restoring the correct expression levels and localization of tight junction and adherent junction proteins. These findings suggest a new candidate agent for the prevention of NEC in newborns. K E Y W O R D Scell junctions, intestinal barrier, lactadherin, necrotizing enterocolitis, permeability SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.