Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity: Potential M

描述（由申请人提供）：拟制的机制配方喂养研究规定：(i)确定广泛水解酪蛋白配方能够保护1型糖尿病（T1D）风险儿童免受β细胞自身免疫的机制；（ii）评估部分或广泛水解乳清配方是否具有与酪蛋白配方共同的机制特征。基于临床和实验观察，本研究将重点确定四种不同配方对肠道通透性、IL-17免疫、血清代谢组和肠道菌群的影响。该研究将基于一项随机先导干预试验，目的是进行统计学分析，以比较四个治疗组之间的肠通透性。我们假设，与传统的牛奶配方相比，高度水解的酪蛋白配方降低了肠道通透性，下调了IL-17免疫和促炎溶血磷脂酰胆碱，并稳定了肠道微生物群中的乳酸杆菌水平，而乳清配方对肠道通透性、IL-17免疫、血清代谢组或肠道微生物群的影响更为温和。研究人群包括200名具有hla致T1D易感性的新生儿。这些母亲将被鼓励尽可能长时间地纯母乳喂养婴儿。断奶的时间和配方奶粉的引入将留给母亲。这些婴儿被随机分配给四种研究配方之一断奶：i)标准牛奶配方；部分水解乳清配方；（iii）广泛水解的乳清配方；（iv）广泛水解酪蛋白配方。目标是让婴儿在270天之前至少接触他/她的研究配方奶粉90天。研究婴儿在1、3、6、9和12个月大时的3天饮食记录。为了估计配方奶粉的用量，将在每次配方奶粉喂养前后测量婴儿的体重。HLA基因型将从脐带血中进行分析，结果将在出生后10天内得出。当孩子1个月、3个月、6个月、9个月和12个月大的时候，家人会去学习中心。每次就诊时将采集血液样本。此外，在研究期间，这些家庭被要求每月在家中收集一次粪便样本。将在3、6、9和12个月大时通过乳果糖/甘露醇试验评估肠通透性。肠道菌群将采用高通量、不依赖培养的方法进行分析，血清代谢组学将采用已建立的代谢组学平台进行分析。利用外周血单核细胞研究Il-17免疫。该提案广泛涉及自身免疫，这是目前《自由贸易法》征求申请的领域之一。这项工作将通过研究广泛水解酪蛋白配方对β细胞自身免疫的保护作用的潜在机制，产生导致显性T1D的疾病过程的新知识。查明这种机制将极有可能有助于在改变早期婴儿营养的基础上改进有效的预防措施。

DESCRIPTION (provided by applicant): The proposed mechanistic formula feeding study sets out (i) to identify the mechanism(s) by which an extensively hydrolyzed casein formula is able to protect children at risk for type 1 diabetes (T1D) from beta-cell autoimmunity and (ii) to assess whether partly or extensively hydrolyzed whey formulas have mechanistic characteristics common with the casein formula. Based on clinical and experimental observations the study will focus on defining the effects of four different formulas on intestinal permeability, IL-17 immunity, serum metabolome, and gut microflora. The study will be based on a randomized pilot intervention trial using an intention to treat statistical analysis to compare e.g. gut permeability between the four treatment groups. We hypothesize that the highly hydrolyzed casein formula decreases intestinal permeability, down-regulates IL- 17 immunity and proinflammatory lysophoshatidylcholines, and stabilize Lactobacilli levels in the gut micro- flora when compared to the conventional cow's milk formula, whereas the whey formulas have more modest, if any, effects on gut permeability, IL-17 immunity, serum metabolome or intestinal microbiota. The study population comprises 200 newborn infants with HLA-conferred susceptibility to T1D. The mothers will be encouraged to exclusively breast-feed their infants as long as possible. The timing of weaning and introduction of study formula will be left to the mother. The infants are randomized to be weaned to one of four study formulas: i) standard cow's milk formula; (ii) a partially hydrolyzed whey formula; (iii) an extensively hydrolyzed whey formula; and (iv) an extensively hydrolyzed casein formula. The target will be that the infant should be exposed to his/her study formula for at least 90 days before the age of 270 days. The diet of the infant will be studied with 3-day food records at the age of 1, 3, 6, 9, and 12 months of age. To estimate the amount of formula used the weight of the infant will be measured just before and after each formula feed. The HLA genotype will be analyzed from cord blood, and the result will be available within 10 days after birth. The family will visit the Study Center when the infant is 1, 3, 6, 9, and 12-month-old. Blood samples will be obtained on each visit. In addition the families are asked to collect stool samples at home once a month during the study. Intestinal permeability will be assessed with the lactulose/mannitol test at the age of 3, 6, 9, and 12 months. Gut microflora will be analyzed with high-throughput, culture-independent methods and serum metabolome with established metabolomics platforms. Il-17 immunity will be studied using peripheral blood mononuclear cells. This proposal addresses broadly autoimmunity, one of the areas the current FOA solicits applications for. This work will generate novel knowledge of the disease process leading to overt T1D by studying potential mechanism(s) mediating the protective effect conferred by an extensively hydrolyzed casein formula against beta-cell autoimmunity. The identification of such mechanism(s) will most likely facilitate the refinement of effective preventive measures based on modifications of early infant nutrition. PUBLIC HEALTH RELEVANCE: Weaning to an extensively hydrolyzed casein formula has been shown to reduce the appearance of diabetes-predictive autoantibodies by half by the age of 10 years in children at risk for type 1 diabetes. Our study sets out to identify those mechanism(s) which mediate such a protective effect. Learning about the mediating mechanisms will generate novel knowledge of the disease process leading to clinical type 1 diabetes and facilitate the refinement of effective preventive measures based in modifications of early infant nutrition - a safe and relatively simple intervention.