Necrotizing Enterocolitis: Prevention and Prediction

描述(申请人提供)：坏死性小肠结肠炎(NEC)是早产儿的一种常见和毁灭性的疾病。有效的预防药物和预测高危婴儿的生物标志物是重要的临床需求。预防NEC最有希望的干预措施是母乳喂养和益生菌，尽管作用机制尚不清楚。我们的建议来自加州大学戴维斯分校的综合、多学科牛奶生物活性物质联盟，并包括令人兴奋的初步数据：两种益生菌产品在早产儿中的临床试验、人类乳寡糖选择性刺激特定双歧杆菌生长的证据，以及一种新的潜在的婴儿易感性生物标记物。我们假设，益生菌低聚糖和/或益生菌的方案，增加双歧杆菌的定植，以模拟健康的足月母乳喂养的婴儿，将促进婴儿生长，并导致一个有吸引力的方案，用于预防NEC的更大规模的试验。我们进一步假设，防御素基因拷贝数低的多态使一些早产儿容易发展出低双歧杆菌的肠道微生物区系，从而导致正常菌群保护的缺陷增加了他们对NEC的易感性。特定目标1将进行第一阶段和第二阶段临床试验，以确定和评估首选的饮食补充方案，以实现早产儿粪便微生物群中双歧杆菌的优势。具体目标2将进行一系列体外实验，以(A)分析接受益生素低聚糖和/或益生菌的婴儿粪便中双歧杆菌的生化和遗传特性，以及(B)分析母乳成分的益生菌特性。具体目标3将分析一种新的遗传生物标记物对NEC易感性的潜力：防御素基因拷贝数。拟议的临床试验和体外实验旨在回答有关肠道微生物区系发育的重要问题，母乳成分对发育中的肠道微生物区系的影响，以及肠道微生物区系的变化对早产儿健康和生长的影响。公共卫生相关性：肠道中有更多健康的细菌可能会促进早产儿的生长并防止感染。通过给早产儿服用不同剂量和组合的健康活细菌(益生元)和纤维(益生元)，我们旨在找到最好的方法来改变肠道中的细菌，使其更像健康的母乳喂养的足月儿。患有肠道感染的早产儿的基因可能与没有感染的早产儿略有不同；我们将测试一组特别有希望的基因，看看这是否属实。

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Effective preventive agents and biomarkers predictive of high-risk infants are significant clinical needs. The most promising interventions shown to prevent NEC are breast milk feedings and probiotic microorganisms, although the mechanisms of action are unknown. Our proposal draws from the integrated, multi-disciplinary Milk Bioactives Consortium at the University of California Davis and includes exciting preliminary data: a clinical trial of two probiotic products in premature infants, evidence that human milk oligosaccharides selectively stimulate growth of specific bifidobacteria, and a novel potential biomarker of infant susceptibility. We hypothesize that a regimen of prebiotic oligosaccharides and/or probiotic microbes, which increases bifidobacteria colonization to mimic that of healthy term breast-fed infants, will improve infant growth and lead to an attractive regimen for larger trials of prevention of NEC. We further hypothesize that a low ¿-defensin gene copy number polymorphism predisposes some premature infants to development of an intestinal microbiota low in bifidobacteria and the consequent deficit in normal microflora protection increases their susceptibility to NEC. Specific Aim 1 will conduct Phase 1 and Phase 2 clinical trials to identify and evaluate a preferred dietary supplement regimen to achieve a predominance of bifidobacteria in the fecal microbiota of preterm infants. Specific Aim 2 will conduct a series of in vitro experiments to (a) analyze biochemical and genetic properties of the bifidobacteria in the feces of infants receiving prebiotic oligosaccharides and/or probiotic microbes and (b) analyze the prebiotic properties of components of human milk. Specific Aim 3 will analyze the potential of a novel genetic biomarker for susceptibility to NEC: ¿-defensin gene copy number. The proposed clinical trials and in vitro experiments are designed to answer important questions regarding the development of the intestinal microbiota, the effect of breast milk components on the developing intestinal microbiota, and the effect of changes in the intestinal microbiota on the health and growth of the premature infant. PUBLIC HEALTH RELEVANCE: Having more healthy bacteria in the intestines may improve growth and prevent infections in premature infants. By giving different doses and combinations of live healthy bacteria (probiotics) and fiber (prebiotics) to premature infants, we aim to find the best way to change the bacteria in the intestines to be more like those of healthy breast-fed term infants. The genes of premature infants who get intestinal infections may be slightly different from those who don't; we will test one group of particularly promising genes to see if that is true.