The relationship of fecal microbiomes and nutritional status in CF

 描述(申请人提供)：肠道疾病是遗传性疾病囊性纤维化(CF)患者的相当大一部分发病率和死亡率的原因。CF型肠病多见于婴儿期，多见于胰腺外分泌功能不全(PI)，导致严重的营养不良和营养不良，进而导致生长衰竭和肠梗阻。尽管积极的早期营养干预和胰酶替代及其他治疗，早期生长障碍在CF婴儿中仍然很常见，这表明PI以外的其他特征与CF婴儿的生长和营养衰竭有关。因此，确定儿童CF的生长和营养决定因素仍然是CF护理中的一个关键研究目标。最近，对胃肠道中存在的微生物--肠道微生物区系--的研究，为儿童营养和能量吸收的一个潜在关键贡献者提供了线索。研究已经确定了肠道微生物区系、营养摄入、营养吸收和其他健康措施之间的复杂关系。众所周知，胃肠道微生物对人类的营养新陈代谢和能量获取有重要贡献，在许多疾病状态下，它们都会发生变化。因此，婴儿胃肠道微生物可能是CF营养结局的重要决定因素，这反过来又可以显著影响肺部疾病的严重程度和总体寿命。我们最近发现，患有CF的婴儿和儿童的胃肠道微生物区系明显不同于没有CF的儿童，并且这种生态失调与GI功能障碍的严重程度相关。然而，CFGI微生物区系与生长和其他临床重要结果之间的关系尚未被研究。我们假设CF患儿的肠道微生物群与吸收不良的严重程度、肠道炎症、胃肠道症状和体征、维生素和矿物质缺乏以及营养状况有关。为了验证这些假设，这项辅助研究将使用超高通量、独立于培养的测序方法，定义正在进行的婴儿营养多中心研究(婴儿观察营养研究(BONUS)，由囊性纤维化基金会和美国国立卫生研究院资助)中250名患有CF的婴儿的粪便微生物群。有了这些资源，我们将(1)定义粪便微生物群，由微生物群(存在的微生物种类)和元基因组(存在的微生物基因，反映微生物群的代谢能力)组成，每个受试者在出生后第一年至少有四个粪便样本，(2)确定粪便微生物群及其在研究一年中的演变与营养和临床参数(包括体重、身高、体重指数、每个参数在受试者中的增长率、血清维生素水平、粪便营养和代谢物含量、胃肠道症状和炎症指标)的关系。我们将使用大规模并行的下一代DNA测序方法，结合我们拥有丰富经验的先进生物信息学分析方法。我们的目标是确定婴儿CFGI微生物群在生长和营养中的作用，希望确定能够改善CFGI早期生长的干预措施，从而改善CFGI的长期结果。

 DESCRIPTION (provided by applicant): Intestinal tract disease is responsible for a substantial amount of the morbidity and mortality among people with the genetic disease cystic fibrosis (CF). The manifestations of CF intestinal disease frequently occur during infancy and result from pancreatic exocrine insufficiency (PI), resulting in profound nutrient malabsorption and malnutrition, and consequently in growth failure and intestinal obstruction. Despite aggressive, early nutritional intervention with pancreatic enzyme replacement and other therapies, early growth failure remains common among infants with CF, suggesting that characteristics other than PI contribute to growth and nutritional failure in infants with CF. The identification of thes growth and nutritional determinants in children with CF therefore remains a key research goal in CF care. Recently, a clue to a potentially critical contributor to nutrient and energy uptake in children has emerged from the study of the microbes present in the gastrointestinal tract- the gut microbiota. Research has identified a complex relationship between gut microbiota, nutritional intake, nutrient absorption, and other health measures. GI tract microbes are known to contribute significantly to human nutrient metabolism and energy harvest, and they are altered in many disease states. Therefore, infant GI tract microbes may represent important determinants of CF nutritional outcomes, which in turn can significantly impact severity of lung disease and overall longevity. We recently showed that infants and children with CF had GI microbiota that differ markedly from those of children without CF, and that this dysbiosis correlated with severity of GI dysfunction. However, the relationships between CF GI microbiota with growth and other clinically important outcomes have not been studied. We hypothesize that the intestinal microbiomes among children with CF correlate with severity of malabsorption, intestinal inflammation, gastrointestinal signs and symptoms, vitamin and mineral deficiency, and nutritional status. To test these hypotheses, this ancillary study will define the fecal microbiomes of 250 infants with CF being enrolled in an ongoing multicenter study of infant nutrition (the Baby Observational NUtrition Study (BONUS), funded by the Cystic Fibrosis Foundation and the National Institutes of Health) using ultra high-throughput, culture-independent sequencing methods. With these resources, we will (1) define the fecal microbiomes, composed of the microbiota (the species of microbes present) and metagenomes (the microbial genes present, which reflects the metabolic capacity of the microbiota) of at least four stool samples per subject over the first year of life, and (2) determine the relationship of fecal microbiomes, and their evolution over the year of study, with nutritional and clinical parameters (including weight, height, body mass index, growth rate of each of these parameters among subjects, serum vitamin levels, fecal nutrient and metabolite content, GI symptoms, and measures of inflammation). We will use massively parallel next- generation DNA sequencing methods, combined with advanced bioinformatic analytical methods, with which we have extensive experience. Our goal is to define the role of the infant CF GI microbiome in growth and nutrition, with the hope of identifying interventions that will improve early growth, and thus long-term outcomes, in CF.