Intestinal bacterial metagenome in pediatric NAFLD

描述(申请人提供)：在美国成人和儿童人群中，非酒精性脂肪性肝病(NAFLD)及其严重表型--非酒精性脂肪性肝炎(NASH)的患病率正在显著增加。非酒精性脂肪肝与肥胖和代谢综合征有关，其患病率与肥胖症和2型糖尿病的患病率同步增加。NAFLD的发展，其不同的表型，以及疾病进展的异质性还没有完全了解。最近的证据表明，在人类和动物模型中，肠道微生物定植(肠道微生物群)与肥胖之间存在关联。此外，有证据表明细菌定植异常，肠道细菌产物引起与NAFLD相关的炎症并进展为NASH。本研究的目的是调查肥胖及肥胖合并NAFLD患儿肠道微生物群的组成，确定肠道微生物群变化、免疫激活与NAFLD发生发展的关系。我们假设肠道微生物组的改变与免疫活性的增强和NAFLD的发展有关。目标1的重点是确定患有NAFLD的表型良好的儿童受试者和具有良好特征的儿童肥胖对照组，并评估他们的临床状况和全身炎症的程度。将与Jeffrey博士合作招募患有NAFLD的儿科参与者 Schwimmer和现有的NIDDK赞助的多中心NASH临床研究网络(NASH CRN)和加州大学圣迭戈分校的青少年肥胖计划。肥胖对照将通过磁共振波谱(MRS)对肝脏脂肪变性进行评估。目的研究非酒精性脂肪肝(NAFLD)患儿和肥胖对照儿童的肠道菌群。高通量16S rDNA分析、鸟枪测序、从粪便标本中分离的细菌基因组DNA/RNA的元基因组/元转录组分析将被用来识别两个不同研究小组中每个人的特征微生物组。目的3重点分析非酒精性脂肪肝、全身炎症和肠道微生物群之间的关系。指示NAFLD发展的肠道微生物组特征将有助于加深对疾病过程的了解。更深入地了解肠道微生物组在NAFLD的发生发展中的作用，可能会导致识别新的生物标志物来预测肥胖人群对NAFLD的易感性，并通过使用益生菌、益生菌、抗生素或通过其他新发现的机制来操纵和调节肠道微生物组或其功能代谢能力，从而在预防和治疗这种疾病方面找到新的干预措施。

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.