Early Childhood Diet, Growth, Gut Microbiome and Lung Health in Cystic Fibrosis

 描述（申请人提供）：囊性纤维化（CF）是最常见的缩短寿命的遗传性疾病之一。它的特点是胰腺功能不全，导致营养不良和生长迟缓，即使在婴儿早期诊断通过新生儿筛查。阻塞性肺病合并反复呼吸道感染是不可避免的。2008年，中位生存年龄提高到38岁，但仍有20%的死亡发生在20岁之前。 该补助金的总体目标是评估纯母乳喂养和学龄前饮食对CF儿童在生命的前6年生长，营养状况和肺部健康的影响，并确定这些影响是否与母乳中必需脂肪酸摄入不足和肠道微生物群的变化有关。这将通过扩大自2012年以来在4个州（UT、WI、IN和MA）的5个CF中心网络中进行的一项高效、强有力的多中心前瞻性观察性研究（称为FIRSTage 0 -2研究）的随访来完成。 具体目标是：1）调查160名2 - 6岁CF儿童纯母乳喂养（exBF）的潜在益处和风险（称为FIRSTage 2 -6研究），并检验以下假设：a）exBF在生命最初2年的抗假单胞菌感染益处导致6岁时肺功能更好，以及B）早期生长-通过在2-6岁期间强化母乳和丰富学龄前饮食，在6岁时减少exBF的蹒跚效应; 2）检验母乳中必需脂肪酸浓度低是由于母亲摄入量低，使患有CF的暴露BF婴儿易患必需脂肪酸缺乏症的假设，导致了低增长（母乳研究）; 3）使用16 S rRNA基因测序表征粪便微生物群，并测试以下假设：a）母乳喂养和配方奶粉喂养的CF婴儿之间的肠道微生物群不同，并且与抗生素暴露的频率和质子泵抑制剂的使用有关，和B）肠道微生物群的差异与不良生长/营养状态和肺部疾病的严重程度有关（肠道微生物群研究）。这项拨款中提出的研究是及时的，非常重要的，因为截至2010年，CF的NBS在美国和许多欧洲国家都是普遍的。然而，最佳喂养是未知的，在这个非常早期诊断的CF婴儿群体。目标#1将确定纯母乳喂养是否确实是许多CF临床医生认为的CF婴儿的首选喂养方法。目的2将阐明CF中母亲饮食、母乳脂肪酸含量和婴儿必需脂肪酸状态之间的联系，为解决CF婴儿补充必需脂肪酸的长期争议提供所需的证据。利用目标1和2产生的丰富临床数据，目标3不仅将促进我们对CF肠道微生物组的理解，还将描述其对CF临床结局的影响。实现这一赠款的目标将导致CF婴儿护理的创新变化。

 DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is one of the most common life-shortening genetic diseases. It is characterized by pancreatic insufficiency, resulting in malnutrition and growth faltering even in infants diagnosed early through newborn screening. Obstructive lung disease with recurrent respiratory infections is inevitable. Median age of survival has improved to 38 years in 2008, but 20% of deaths still occur before age 20 years. The overall objective of this grant is to assess the effects of exclusive breastfeeding and preschool diet on growth, nutritional status and pulmonary health in CF children through the first 6 years of life and determine if these effects are related to an insufficient essential fatty acid intake from breast milk and variations in gut microbiota. This will be done by expanding the follow-up of a highly productive, strong multi-center prospective observational study being conducted in a network of 5 CF Centers in 4 states (UT, WI, IN and MA) since 2012, referred to as FIRSTage0-2 study. Specific Aims are: 1) to investigate the potential benefits and risks of exclusive breastfeeding (exBF) in 160 children with CF from age 2 to 6 years (referred to as FIRSTage2-6 study) and test the hypotheses that a) the anti-Pseudomonas infection benefit of exBF in the first 2 years of life results in better lung function at age 6 years and b) the early growth-faltering effect of exBF is reduced at 6 years by fortifying human milk and enriching the preschool diet during age 2-6 years; 2) to test the hypothesis that low essential fatty acid concentration of breast milk results from low maternal intake, predisposes exBF infants with CF to essential fatty acid deficiencies, and contributes to poor growth (Breast Milk study); 3) to characterize fecal microbiota using 16S rRNA gene sequencing and testing the hypotheses that a) the gut microbiota differs between breastfed and formula-fed CF infants and is related to the frequency of antibiotic exposure and use of proton pump inhibitor, and b) differences in gut microbiota are related to poor growth/nutritional status and the severity of lung disease (Gut Microbiome study). Research proposed in this grant is timely and highly significant, because as of 2010, NBS for CF is universal in the US as well as in many European countries. However, optimal feeding is unknown in this very early diagnosed population of CF infants. Aim #1 will determine if exclusive breastfeeding is indeed the preferred method of feeding infants with CF as perceived by many CF clinicians. Aim 2 will elucidate the links between maternal diet, breast milk fatty acid content and infant essential fatty acid status in CF, generating the needed evidence to resolve the long-standing controversy of essential fatty acid supplementation for CF infants. Utilizing the wealth of clinical data generated from Aims 1 and 2, Aim 3 will not only advance our understanding of gut microbiome in CF but delineate its impact on clinical outcomes of CF. Accomplishing the aims of this grant will lead to innovative changes in the care of infants with CF.