Intestinal bacterial metagenome in pediatric NAFLD

小儿 NAFLD 中的肠道细菌宏基因组

• 批准号: 8909121
• 负责人: Ingrid Bernadette Borecki
• 金额: $ 139.94万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909121
• 关键词: Adolescent; Adult; Animal Model; Antibiotics; Attention; Bacteria; Biological Markers; California; Characteristics; Child; Childhood; Choline; Clinical; Clinical Research; Collaborations; Complementary DNA; Control Groups; DNA; Development; Disease; Disease Progression; Ecosystem; Enrollment; Epithelial; Evaluation; Fatty Liver; Gastrointestinal tract structure; Genetic Transcription; Genome; Genomic DNA; Goals; Harvest; Health; Heterogeneity; High-Throughput Nucleotide Sequencing; Histology; Human; Incidence; Individual; Inflammation; Inflammatory disease of the intestine; Intervention; Intestines; Lead; Liver; Liver Failure; Liver diseases; Magnetic Resonance Spectroscopy; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Metagenomics; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathology; Pediatric Hospitals; Phenotype; Population; Population Control; Predisposition; Prevalence; Prevention; Principal Investigator; Probiotics; Process; Public Health; RNA; Recombinant DNA; Recruitment Activity; Research Personnel; Resources; Role; Sampling; Severities; Shotgun Sequencing; Specimen; Techniques; Testing; United States; United States National Institutes of Health; Universities; Viral; Washington; Wisconsin; case control; effective therapy; immune activation; inflammatory marker; liver biopsy; liver inflammation; liver transplantation; medical schools; metagenome; microbial colonization; microbiome; new technology; next generation sequencing; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel strategies; obesity in children; pediatric patients; prebiotics; programs

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.

描述（由申请人提供）：在美国成人和儿童群体中，非酒精性脂肪肝病 (NAFLD) 及其严重表型非酒精性脂肪性肝炎 (NASH) 的患病率正在显着增加。 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增加。 NAFLD 的发展、其不同表型以及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以及肠道细菌产物诱导与 NAFLD 相关的炎症以及进展为 NASH。该提案的目标是调查肥胖和肥胖合并 NAFLD 儿童患者肠道微生物组的组成，并确定肠道微生物组变化、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 的重点是确定表型良好的 NAFLD 儿科受试者和特征明确的儿科肥胖对照组，并评估他们的临床状态和全身炎症程度。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) 以及加州大学圣地亚哥分校的青少年肥胖项目。肥胖对照者将通过磁共振波谱（MRS）评估肝脏脂肪变性。目标 2 重点研究 NAFLD 儿童和肥胖对照者的肠道微生物组。对从粪便样本中分离的细菌基因组 DNA/RNA 进行高通量 16S rDNA 分析、鸟枪法测序、宏基因组/宏转录组分析将用于识别 2 个不同研究组中每个个体的特征微生物组。目标 3 将重点分析 NAFLD、全身炎症和肠道微生物组之间的关系。表明 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。更好地了解肠道微生物组在 NAFLD 发生和进展中的作用，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，也可能导致通过操纵来预防和治疗这种疾病的新干预措施通过使用益生元、益生菌、抗生素或通过其他新发现的机制来调节肠道微生物组或其功能代谢能力。