Necrotizing Enterocolitis: Prevention and Prediction

描述（申请人提供）：坏死性小肠结肠炎（NEC）是早产儿常见的破坏性疾病。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微生物，尽管其作用机制尚不清楚。我们的提案来自于加州大学戴维斯分校整合的、多学科的牛奶生物活性联盟，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，人类牛奶低聚糖选择性地刺激特定双歧杆菌生长的证据，以及一种新的潜在婴儿易感性生物标志物。我们假设益生元低聚糖和/或益生菌微生物的方案，增加双歧杆菌定植，以模仿健康足月母乳喂养的婴儿，将改善婴儿的生长，并为预防NEC的更大规模试验提供有吸引力的方案。我们进一步假设，低防御素基因拷贝数多态性使一些早产儿易患双歧杆菌肠道菌群低，由此导致的正常菌群保护缺陷增加了他们对NEC的易感性。Specific Aim 1将进行1期和2期临床试验，以确定和评估首选的膳食补充剂方案，以实现双歧杆菌在早产儿粪便微生物群中的优势。Specific Aim 2将进行一系列体外实验，以(a)分析接受益生元寡糖和/或益生菌微生物的婴儿粪便中双歧杆菌的生化和遗传特性，以及(b)分析人乳成分的益生元特性。特异性目标3将分析一种新的遗传生物标志物对NEC易感性的潜力：防御蛋白基因拷贝数。拟建的临床试验和体外实验旨在回答有关肠道菌群发育、母乳成分对肠道菌群发育的影响以及肠道菌群变化对早产儿健康和生长的影响等重要问题。公共卫生相关性：肠道中有更多的健康细菌可以促进早产儿的生长和预防感染。通过给早产儿不同剂量和组合的健康活菌（益生菌）和纤维（益生元），我们的目标是找到改变肠道细菌的最佳方法，使其更像健康的母乳喂养的足月婴儿。患有肠道感染的早产儿的基因可能与没有肠道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.