IL-17-related signature genes linked to human necrotizing enterocolitis.

OBJECTIVE: Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units all over the world. The objective of the present study was to take advantage of RNA-Seq data from the analysis of intestinal specimens of preterm infants diagnosed with NEC. Function enrichments with Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to analyse previous data in order to identify biological and functional processes, which could provide more insight into the pathogenesis of NEC in infants. RESULTS: Gene set enrichment analysis indicated that the most significant biological pathways over-represented in NEC neonates were closely associated with innate immune functions. One of the striking observations was the highly modulated expression of inflammatory genes related to the IL-17 pathway including such as pro-inflammatory cytokines (CXCL8), chemokines (CXCL5 and CXCL10) and antimicrobials (DEF5A, DEF6A, LCN2, NOS2) in the intestine of neonates diagnosed with NEC. Interestingly, the increase in IL-17 expression appeared to be under the IL-17F form, as reported in Crohn's disease, another inflammatory bowel disease. Further investigation is thus still needed to determine the precise role of IL-17F and its downstream targets in NEC.

Early neurodevelopmental outcomes of infants with intestinal failure.

BACKGROUND: The survival rate of infants and children with intestinal failure is increasing, necessitating a greater focus on their developmental trajectory. AIMS: To evaluate neurodevelopmental outcomes in children with intestinal failure at 0-15months corrected age. STUDY DESIGN: Analysis of clinical, demographic and developmental assessment results of 33 children followed in an intestinal rehabilitation program between 2011 and 2014. Outcome measures included: Prechtl's Assessment of General Movements, Movement Assessment of Infants, Alberta Infant Motor Scale and Mullen Scales of Early Learning. Clinical factors were correlated with poorer developmental outcomes at 12-15months corrected age. RESULTS: Thirty-three infants (17 males), median gestational age 34weeks (interquartile range 29.5-36.0) with birth weight 1.98kg (interquartile range 1.17-2.50). Twenty-nine (88%) infants had abnormal General Movements. More than half had suspect or abnormal scores on the Alberta Infant Motor Scale and medium to high-risk scores for future neuromotor delay on the Movement Assessment of Infants. Delays were seen across all Mullen subscales, most notably in gross motor skills. Factors significantly associated with poorer outcomes at 12-15months included: prematurity, low birth weight, central nervous system co-morbidity, longer neonatal intensive care admission, necrotizing enterocolitis diagnosis, number of operations and conjugated hyperbilirubinemia. CONCLUSION: Multiple risk factors contribute to early developmental delay in children with intestinal failure, highlighting the importance of close developmental follow-up.

Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn's disease.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units. The challenge for neonatologists is to detect early clinical manifestations of NEC. One strategy would be to identify specific markers that could be used as early diagnostic tools to identify preterm infants most at risk of developing NEC or in the event of a diagnostic dilemma of suspected disease. As a first step in this direction, we sought to determine the specific gene expression profile of NEC. METHODS: Deep sequencing (RNA-Seq) was used to establish the gene expression profiles in ileal samples obtained from preterm infants diagnosed with NEC and non-NEC conditions. Data were analyzed with Ingenuity Pathway Analysis and ToppCluster softwares. RESULTS: Data analysis indicated that the most significant functional pathways over-represented in NEC neonates were associated with immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors for bacteria and viruses. Among the genes that were strongly modulated in neonates with NEC, we observed a significant degree of similarity when compared with those reported in Crohn's disease, a chronic inflammatory bowel disease. CONCLUSIONS: Gene expression profile analysis revealed a predominantly altered immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn's disease gene expression repertoires revealed a surprisingly high degree of similarity between these two conditions suggesting a new avenue for identifying NEC biomarkers.

A CARD9 polymorphism is associated with decreased likelihood of persistent conjugated hyperbilirubinemia in intestinal failure.

Recently, genetic associations have been described in intestinal transplants. Namely, Crohn's disease susceptibility gene NOD2 polymorphisms have been reported to be more prevalent in patients with graft failure following intestinal transplantation (IT). Therefore, we sought to determine if polymorphisms in the NOD2 signaling cascade, including NOD2, CARD9, RAC1 and ATG16L1 are associated with intestinal failure (IF) or its complications. We carried out a cross-sectional study of 59 children with IF and 500 healthy Caucasian controls. Using the Taqman platform we determined the prevalence of NOD2 as well as ATG16L1, RAC1 and CARD9 SNPs. NOD2 pathway polymorphisms were evaluated in relation to outcomes of episodes of sepsis, ICU admissions, hyperbilirubinemia and need for IT. We found that the minor allele of a CARD9 SNP was associated with protection from developing IF when compared to healthy controls and was also associated with decreased odds of sustained conjugated hyperbilirubinemia. Therefore, IF patients with CARD9 polymorphism are less likely to develop progressive liver disease and suggests that host innate immunity may play a role in IF associated liver disease.