Intestinal bacterial metagenome in pediatric NAFLD

描述（由申请人提供）：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）的患病率在美国成人和儿童人群中显著增加。NAFLD与肥胖和代谢综合征相关，其患病率与肥胖和2型糖尿病的患病率同步上升。NAFLD的发展、其不同的表型和疾病进展的异质性尚不完全清楚。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，肠道细菌产物诱导的炎症与NAFLD和进展为NASH相关。本课题的目的是研究肥胖和肥胖合并NAFLD儿童患者肠道微生物组的组成，并确定肠道微生物组改变、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。目的1的重点是确定表型良好的儿童NAFLD患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态和全身性炎症的程度。患有NAFLD的儿童参与者将与Jeffrey博士合作招募

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.