Intestinal bacterial metagenome in pediatric NAFLD

描述（由申请方提供）：在美国成人和儿童人群中，非酒精性脂肪性肝病（NAFLD）及其重度表型非酒精性脂肪性肝炎（NASH）的患病率显著增加。NAFLD与肥胖和代谢综合征相关，其患病率与肥胖和2型糖尿病的患病率平行增加。NAFLD的发展，其不同的表型和疾病进展的异质性尚未完全了解。最近的证据表明，在人类和动物模型中，肠道微生物定植（肠道微生物组）与肥胖之间存在关联。此外，有证据表明细菌定植异常，以及肠道细菌产物诱导的与NAFLD相关的炎症和进展为NASH。该提案的目的是调查肥胖和肥胖加NAFLD儿科患者的肠道微生物组的组成，并确定肠道微生物组，免疫激活和NAFLD发展之间的关系。我们假设肠道微生物组的改变与免疫激活增加和NAFLD的发展有关。目标1的重点是确定具有NAFLD的良好表型的儿科受试者和良好表征的儿科肥胖对照组，并评估其临床状态和全身炎症的程度。将与Jeffrey博士合作招募患有NAFLD的儿科受试者 Schwimmer和现有的NIDDK赞助的多中心NASH临床研究网络（NASH CRN）以及UCSD的青少年肥胖计划。将通过磁共振波谱（MRS）评价肥胖对照的肝脏脂肪变性。目的2重点研究NAFLD儿童和肥胖对照儿童的肠道微生物组。将使用从粪便标本中分离的细菌基因组DNA/RNA的高通量16 S rDNA分析、鸟枪测序、宏基因组/宏转录组分析来鉴定2个不同研究组中每个个体的特征性微生物组。目的3将重点分析NAFLD，全身性炎症和肠道微生物组之间的关系。指示NAFLD发展的肠道微生物组的特征将导致对疾病过程的更多理解。更好地理解肠道微生物组在NAFLD的发展和进展中的作用可以导致鉴定新的生物标志物来预测肥胖人群对NAFLD的易感性，并且还可以通过使用益生元、益生菌、抗生素、抗生或通过其他新发现的机制。

DESCRIPTION (provided by applicant): The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe phenotype, non-alcoholic steatohepatitis (NASH), are increasing significantly in the United States in the adult and pediatric population. NAFLD is associated with obesity and metabolic syndrome and its prevalence has increased in parallel to the prevalence of obesity and type-2 diabetes. The development of NAFLD, its different phenotypes, and the heterogeneity of disease progression are not completely understood. Recent evidence suggests that there is an association between intestinal microbial colonization (the intestinal microbiome) and obesity in humans and in animal models. In addition, there is evidence of abnormalities of bacterial colonization, and intestinal bacterial product induced inflammation associated with NAFLD and progression to NASH. The goal of this proposal is to investigate the composition of the intestinal microbiome in pediatric patients with obesity and obesity plus NAFLD, and determine the relationship between alterations in the intestinal microbiome, immune activation, and the development of NAFLD. We hypothesize that alterations in the intestinal microbiome are associated with increased immune activation and the development of NAFLD. The focus of aim 1 is to ascertain well-phenotyped pediatric subjects with NAFLD and a well-characterized pediatric obese control group, and evaluate their clinical status, and extent of systemic inflammation. Pediatric participants with NAFLD will be recruited in collaboration with Dr. Jeffrey Schwimmer and the existing NIDDK-sponsored multicenter NASH Clinical Research Network (NASH CRN) and through the adolescent obesity program at UCSD. Obese controls will be evaluated for liver steatosis by magnetic resonance spectroscopy (MRS). Aim 2 focuses on the study of the intestinal microbiome of children with NAFLD and in obese controls. High through put 16S rDNA analysis, shotgun sequencing, metagenome/metatranscriptome analysis of bacterial genomic DNA/RNA isolated from fecal specimens will be used to identify the characteristic microbiome of each individual within the 2 different study groups. Aim 3 will focus on the analysis of the relationship between NAFLD, systemic inflammation, and the intestinal microbiome. Characteristics of the intestinal microbiome indicative of the development of NAFLD will lead to an increased understanding of the disease process. Greater understanding of the role of the intestinal microbiome in the development and progression of NAFLD could lead to the identification of novel biomarkers to predict susceptibility to NAFLD in populations with obesity, and also to novel interventions in the prevention and treatment of this disease through the manipulation and modulation of the intestinal microbiome or its functional metabolic capacity through the use of prebiotics, probiotics, antibiotics, or via other newly revealed mechanisms.