A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis.

BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was up-regulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.

Poor Adherence to US Dietary Guidelines for Children and Adolescents in the National Health and Nutrition Examination Survey Population.

BACKGROUND: Poor diet quality in childhood and adolescence is associated with adverse health outcomes throughout life, yet the dietary habits of American children and how they change across childhood and adolescence are unknown. OBJECTIVES: This study sought to describe diet quality among children and adolescents by assessing adherence to the 2010 Dietary Guidelines for Americans (DGA) and to determine whether any differences in adherence occurred across childhood. DESIGN, SETTING, AND PARTICIPANTS: We employed a cross-sectional design using data from the National Health and Nutrition Examination Survey (NHANES). Of 9,280 children aged 4 to 18 years who participated in NHANES from 2005 to 2010, those with insufficient data on dietary recall (n=852) or who were pregnant or lactating during the time of interview (n=38) were excluded from the final study sample (n=8,390). MAIN OUTCOME MEASURES: We measured adherence to the DGA using the Healthy Eating Index 2010 (HEI-2010) and stratified participants into three age groups (4 to 8, 9 to 13, and 14 to 18 years of age). We analyzed each of 12 HEI-2010 components and total HEI-2010 score. RESULTS: The youngest children had the highest overall diet quality due to significantly greater scores for total fruit, whole fruit, dairy, and whole grains. These children also had the highest scores for sodium, refined grains, and empty calories. Total HEI-2010 scores ranged from 43.59 to 52.11 out of 100, much lower than the minimum score of 80 that is thought to indicate a diet associated with good health. CONCLUSIONS: Overall, children and adolescents are failing to meet the DGA and may be at an increased risk of chronic diseases throughout life. By analyzing which food groups show differences between age groups, we provide data that can inform the development of dietary interventions to promote specific food groups targeting specific ages and improve diet quality among children and adolescents.