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

描述(申请人提供)：拟议的机械性配方喂养研究提出(I)确定广泛水解酪蛋白配方能够保护患有1型糖尿病(T1D)的儿童免受β细胞自身免疫的机制(S)，以及(Ii)评估部分或广泛水解乳清配方是否具有与酪蛋白配方相同的机械特性。在临床和实验观察的基础上，这项研究将重点确定四种不同配方对肠道通透性、IL-17免疫、血清代谢物和肠道菌群的影响。这项研究将基于一项随机试点干预试验，使用意向处理统计分析来比较四个处理组之间的肠道通透性。我们假设，与传统的牛奶配方相比，高水解酪蛋白配方降低了肠道通透性，下调了IL-17免疫和促炎溶磷脂胆碱，并稳定了肠道微生物群中的乳杆菌水平，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区系的影响较小。研究人群包括200名具有人类白细胞抗原-T1D易感性的新生儿。将鼓励母亲尽可能长时间地纯母乳喂养婴儿。断奶的时间和学习配方的引入将留给母亲。婴儿被随机分成四种研究配方中的一种断奶：i)标准牛奶配方；(Ii)部分水解型乳清配方；(Iii)广泛水解型乳清配方；以及(Iv)广泛水解型酪蛋白配方。目标将是婴儿在270天大之前至少接触他/她的学习配方奶粉90天。在婴儿1、3、6、9和12个月时，将通过3天的食物记录来研究婴儿的饮食。为了估计配方奶粉的使用量，婴儿的体重将在每次配方奶喂养之前和之后测量。将对脐带血进行人类白细胞抗原基因分析，结果将在出生后10天内得出。家人将在婴儿1、3、6、9和12个月大的时候访问学习中心。每次探视都会采集血液样本。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个月龄时用乳果糖/甘露醇试验评估肠道通透性。肠道微生物区系将用高通量、不依赖于培养的方法和已建立的代谢组学平台分析血清代谢组。IL-17免疫将使用外周血单核细胞进行研究。这项提案涉及广泛的自动豁免，这是目前《外国投资法》征集申请的领域之一。这项工作将通过研究广泛水解的酪蛋白配方对β细胞自身免疫的保护作用的潜在机制(S)，产生导致显性T1D的疾病过程的新知识。这种机制的确定(S)很可能有助于在修改婴儿早期营养的基础上完善有效的预防措施。 公共卫生相关性：已有证据表明，在有1型糖尿病风险的儿童中，在10岁之前，断奶服用广泛水解的酪蛋白配方可以将预测糖尿病的自身抗体的出现减少一半。我们的研究旨在确定那些调节这种保护作用的机制(S)。了解调节机制将产生导致临床1型糖尿病的疾病过程的新知识，并有助于完善基于修改早期婴儿营养的有效预防措施--一种安全和相对简单的干预措施。

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.