The relationship of fecal microbiomes and nutritional status in CF

CF患者粪便微生物群与营养状况的关系

• 批准号: 9349480
• 负责人: Lucas R Hoffman
• 金额: $ 61.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349480
• 关键词: Address; Ancillary Study; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Genes; Bacteroides; Bioinformatics; Body mass index; Breast Feeding; Carbohydrates; Caring; Characteristics; Child; Chronic Disease; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Computing Methodologies; Cystic Fibrosis; DNA analysis; DNA sequencing; Data; Dietary Intervention; Dietary intake; Disease; Early Diagnosis; Early Intervention; Enrollment; Escherichia coli; Evolution; Exocrine pancreatic insufficiency; Failure; Fat-Soluble Vitamin; Fatty Acids; Fatty acid glycerol esters; Feces; Foundations; Functional disorder; Funding; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Genes; Goals; Growth; Harvest; Health; Height; Hereditary Disease; Human; Immune system; Infant; Inflammation; Inflammatory disease of the intestine; Intake; Intervention; Intestinal Diseases; Intestinal Obstruction; Intestines; Leukocyte L1 Antigen Complex; Life; Life Expectancy; Link; Lipids; Longevity; Lung; Lung diseases; Machine Learning; Malabsorption Syndromes; Malnutrition; Massive Parallel Sequencing; Measures; Metabolic; Metagenomics; Methods; Microbe; Microbiology; Micronutrients; Minerals; Morbidity - disease rate; Multicenter Studies; Neonatal Screening; Nutrient; Nutritional; Nutritional Study; Nutritional status; Observational Study; Obstruction; Outcome; Pancreatic enzyme; Parents; Pathway interactions; Pharmaceutical Preparations; Phylogenetic Analysis; Play; Proteins; Proteobacteria; Research; Resources; Rest; Role; Sampling; Serum; Severities; Specimen; Study models; Systems Biology; Techniques; Testing; United States National Institutes of Health; Visit; Vitamins; Volatile Fatty Acids; Weight; absorption; analytical method; aqueous; candidate marker; children with cystic fibrosis; design; dosage; early cystic fibrosis; enzyme replacement therapy; experience; gastrointestinal; gastrointestinal sign; gastrointestinal symptom; gene complementation; gut microbiome; gut microbiota; improved; infancy; infant nutrition; metabolomics; metagenome; microbial; microbiome; microbiota; mortality; next generation; novel; nutrient absorption; nutrient metabolism; nutrition; public health relevance; routine care; uptake

 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.

 描述（由申请人提供）：肠道疾病是导致遗传性疾病囊性纤维化（CF）患者发病率和死亡率的主要原因。CF肠道疾病的表现经常发生在婴儿期，并且由胰腺外分泌不足（PI）引起，导致严重的营养吸收不良和营养不良，并因此导致生长衰竭和肠梗阻。尽管积极的，早期营养干预与胰腺酶替代和其他治疗，早期生长衰竭仍然常见于CF婴儿，这表明PI以外的特征有助于CF婴儿的生长和营养衰竭。因此，确定CF儿童的生长和营养决定因素仍然是CF护理的关键研究目标。最近，对胃肠道中存在的微生物-肠道微生物群的研究中出现了一条线索，揭示了儿童营养和能量摄取的潜在关键因素。研究已经确定了肠道微生物群，营养摄入，营养吸收和其他健康措施之间的复杂关系。已知胃肠道微生物对人类营养代谢和能量收获有显著贡献，并且它们在许多疾病状态下发生改变。因此，婴儿胃肠道微生物可能是CF营养结果的重要决定因素，这反过来又会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GI微生物群与没有CF的儿童的GI微生物群明显不同，并且这种生态失调与GI功能障碍的严重程度相关。然而，CF GI微生物群与生长和其他临床重要结果之间的关系尚未研究。我们假设CF儿童的肠道微生物组与吸收不良、肠道炎症、胃肠道体征和症状、维生素和矿物质缺乏以及营养状况的严重程度相关。为了检验这些假设，这项辅助研究将使用超高通量、不依赖于培养物的测序方法，确定250名CF婴儿的粪便微生物组，这些婴儿正在参加一项正在进行的婴儿营养多中心研究（婴儿观察性营养研究（BONUS），由囊性纤维化基金会和美国国立卫生研究院资助）。有了这些资源，我们将（1）定义粪便微生物组，由微生物群组成（存在的微生物种类）和宏基因组（存在的微生物基因，反映了微生物群的代谢能力）每个受试者在生命的第一年至少四个粪便样本，以及（2）确定粪便微生物组的关系及其在一年中的演变研究，与营养和临床参数（包括体重、身高、体重指数、受试者中这些参数中的每一个的生长速率、血清维生素水平、粪便营养物和代谢物含量、GI症状和炎症的测量）。我们将使用大规模并行的下一代DNA测序方法，结合先进的生物信息学分析方法，我们在这方面拥有丰富的经验。我们的目标是确定婴儿CF GI微生物组在生长和营养中的作用，希望确定改善CF早期生长的干预措施，从而改善CF的长期结局。