Disease development in diabetes-prone BB rats is modified by the type of diet fed after weaning. The aim of this investigation was to determine whether exposure during the first week of life to antigens from a known diabetes-promoting diet (NIH-07) could modify diabetes incidence and, if so, to what extent this occurs via alterations in systemic T-cell reactivity, gut cytokines, or islet infiltration. Diabetes-prone BB (BBdp) rats were hand-fed twice daily between age 4 and 7 days with vehicle, a hydrolyzed casein (HC)-based infant formula, Pregestimil (PG), PG ؉ cereal-based NIH-07 diet, PG ؉ lipopolysaccharides (LPS) or PG ؉ LPS ؉ silica. After weaning, they were fed either an NIH-07 diet or a semipurified HC (diabetes-retardant) diet until 150 days. In separate studies, 5-day-old BBdp rat pups were administered the aforementioned treatments, and expression of intestinal mRNA for ␥-interferon (IFN-␥) or transforming growth factor-␤ (TGF-␤) was quantified using reverse transcriptase-polymerase chain reaction. The effect of early oral treatment with NIH-07 or PG on systemic T-cell reactivity was evaluated using footpad swelling delayed-type hypersensitivity (DTH) and the popliteal lymph node assay. Oral exposure of neonates to a complex mixture of antigens from the diabetespromoting diet delayed onset of diabetes (79 vs. 88 days) and prevented disease in approximately one-third of animals. A similar protective effect was seen for neonatal exposure to wheat gluten in animals subsequently weaned onto a semipurified wheat gluten diet. By contrast, LPS-treated neonates displayed more severe insulitis and developed diabetes at an increased rate, which was significantly suppressed by co-administration of silica particles. The protective effect of early exposure to diabetogenic diets was not associated with significant reduction of islet infiltration, and there was no impact on the DTH response to food antigens. However, whereas diabetes-resistant BBc rats developed systemic tolerance to NIH-07 antigens fed chronically, BBdp rats did not. The lack of effect of the early oral antigen regimen on the DTH reaction in the footpad, a classic Th1-mediated reaction, suggests little effect on systemic T-cell reactivity. However, local effects were observed in the small intestine. Oral exposure to diabetes-promoting food antigens or LPS downregulated the Th1 cytokine IFN-␥ and decreased the IFN-␥/TGF-␤ ratio. Thus, oral exposure to diabetes-promoting food antigens and immune modulators in neonates can modify diabetes expression in association with changes in local cytokine balance in the gut. Diabetes 51:73-78, 2002

Current listing indications used for intestinal transplantation (IT) were proposed in 2001. We undertook the present single center study to see if these criteria are still valid. The 2001 criteria (advanced cholestasis, loss of >50% central venous catheter (CVC) sites, !2 sepsis/year, ultrashort bowel) were compared in children with intestinal failure in old era-1998-2005 (N ¼ 99) to current era-2006-2012 (N ¼ 91) to predict the need for IT using sensitivity, specificity, NPV and PPV. Two 2001 criteria had poorer predictive value in the current era: Advanced cholestasis (PPV 64% old vs. 40% current era; sensitivity 84% vs. 65%, respectively) and ultrashort bowel (PPV 100% old vs. 9% current era; sensitivity 10% vs. 4%, respectively). Three newly proposed criteria had high predictive value: !2 ICU admissions (p ¼ 0.0001, OR 23.6, 95% CI 2.7-209.8), persistent bilirubin >75 mmol/L despite lipid strategies (p ¼ 0.0005, OR 24.0, 95% CI 3.2-177.4), and loss of !3 CVC sites (p ¼ 0.0003, OR 33.3,).There was 98% probability of needing IT when two of these new criteria were present. The 2001 IT criteria have limited predictive ability in the current era and should be revised. A multicenter study is required to validate the findings of this single center experience.

Treatment by IRP, coupled with recent advances in the medical management of intestinal failure, is associated with improved survival and outcome of patients waiting for IT, and may lead to overall reduction in the number of IT in the future.

BackgroundNecrotizing 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.MethodsDeep 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.ResultsData 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.ConclusionsGene 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0166-9) contains supplementary material, which is available to authorized users.

The development of autoimmune type 1 diabetes involves complex interactions among several genes and environmental agents. Human patients with type 1 diabetes show an unusually high frequency of wheat gluten-sensitive enteropathy; T-cell response to wheat proteins is increased in some patients, and high concentrations of wheat antibodies in blood have been reported. In both major models of spontaneous type 1 diabetes, the BioBreeding (BB) rat and non-obese diabetic mouse, at least half of the cases are diet-related. In studies of BB rats fed defined semipurified diets, wheat gluten was the most potent diabetes-inducing protein source. A major limitation in understanding how wheat or other dietary antigens affect type 1 diabetes has been the difficulty in identifying specific diabetes-related dietary proteins. To address this issue, we probed a wheat cDNA expression library with polyclonal IgG antibodies from diabetic BB rats. Three clones were identified, and the intensity of antibody binding to one of them, WP5212, was strongly associated with pancreatic islet inflammation and damage. The WP5212 putative protein has high amino acid sequence homology with a wheat storage globulin, Glb1. Serum IgG antibodies from diabetic rats and humans recognized low molecular mass (33-46 kDa) wheat proteins. Furthermore, antibodies to Glb1 protein were found in serum from diabetic patients but not in age-, sex-, and HLA-DQ-matched controls. This study raises the possibility that in some individuals, type 1 diabetes may be induced by wheat proteins. Also, it provides a first candidate wheat protein that is not only antigenic in diabetic rats and human patients but is also closely linked with the autoimmune attack in the pancreas.

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These results suggest that the protective effect of EGF and the deleterious influence of INDO on the immature intestine could be mediated via regulation of NOS2. Pathways downstream of NOS2 involved with these effects include metabolism linked to NO production, epithelial barrier permeability and antioxidant expression. These results suggest that NOS2 is a likely regulator of the inflammatory response in the immature human gut and may provide a mechanistic basis for the protective effect of EGF and the deleterious effects of INDO.

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