The Thrifty Microbiome: The Role of the Gut Microbiota in Obesity in the Amish

节俭的微生物群：肠道微生物群在阿米什人肥胖中的作用

• 批准号: 8147922
• 负责人: CLAIRE M. FRASER
• 金额: $ 25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-24 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147922
• 关键词: Abdomen; Address; Adult; Affect; Age; Amish; Anthropometry; Anti-Bacterial Agents; Antibiotics; Architecture; Atherosclerosis; Bacteria; Blood Circulation; Blood Clot; Blood Pressure; Blood coagulation; Body Composition; Body Weight; Body Weight Changes; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Central obesity; Classification; Communities; DNA; DNA Sequence; Deposition; Development; Disease; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Enrollment; Environmental Risk Factor; Epidemic; European; Extravasation; Fatty acid glycerol esters; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Genotype; Health; Homeostasis; Human; Hyperlipidemia; Hypertension; Individual; Inflammation; Inflammatory; Insulin Resistance; Integration Host Factors; Intestines; Lead; Liver; Location; Lymphatic; Magnetic Resonance Imaging; Matched Group; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Metadata; Metagenomics; Methods; Microbe; Morbidity - disease rate; Mus; Muscle; Neomycin; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Pathway interactions; Patients; Pennsylvania; Phenotype; Play; Population; Predisposition; Prevention; Property; Relative (related person); Role; Sampling; Structure; Testing; Time; Tissues; Variant; Visceral; Weight Gain; Work; absorption; antimicrobial; clinical phenotype; cytokine; disease phenotype; energy balance; functional genomics; genome wide association study; gut microbiota; gut microflora; human subject; improved; inflammatory marker; insight; interdisciplinary approach; man; microbial; microbial community; microbiome; novel strategies; public health relevance; rRNA Genes; sex; trait

DESCRIPTION: Emerging evidence that the gut microbiota may contribute in important ways to human health and disease has led us and others to hypothesize that both symbiotic and pathological relationships between gut microbes and their host may be key contributors to obesity and the metabolic complications of obesity. Our "Thrifty Microbiome Hypothesis" poses that gut microbiota play a key role in human energy homeostasis. Specifically, constituents of the gut microbial community may introduce a survival advantage to its host in times of nutrient scarcity, promoting positive energy balance by increasing efficiency of nutrient absorption and improving metabolic efficiency and energy storage. However, in the presence of excess nutrients, fat accretion and obesity may result, and in genetically predisposed individuals, increased fat mass may result in preferential abdominal obesity, ectopic fat deposition (liver, muscle), and metabolic complications of obesity (insulin resistance, hypertension, hyperlipidemia). Furthermore, in the presence of excess nutrients, a pathological transition of the gut microbial community may occur, causing leakage of bacterial products into the intestinal lymphatics and portal circulation, thereby inducing an inflammatory state, further aggravating metabolic syndrome traits and accelerating atherosclerosis. This pathological transition and the extent to which antimicrobial leakage occurs and causes inflammatory and other maladaptive sequelae of obesity may also be influenced by host factors, including genetics. In the proposed study, we will directly test the Thrifty Mirobiome Hypothesis by performing detailed genomic and functional assessment of gut microbial communities in intensively phenotyped and genotyped human subjects before and after intentional manipulation of the gut microbiome. To address these hypotheses, five specific aims are proposed: (1) enroll three age- and sex-matched groups from the Old Order Amish: (i) 50 obese subjects (BMI > 30 kg/m2) with metabolic syndrome, (ii) 50 obese subjects (BMI > 30 kg/m2) without metabolic syndrome, and (iii) 50 nonobese subjects (BMI < 25 kg/m2) without metabolic syndrome and characterize the architecture of the gut microbiota from the subjects enrolled in this study by high-throughput sequencing of 16S rRNA genes; (2) characterize the gene content (metagenome) to assess the metabolic potential of the gut microbiota in 75 subjects to determine whether particular genes or pathways are correlated with disease phenotype; (3) characterize the transcriptome in 75 subjects to determine whether differences in gene expression in the gut microbiota are correlated with disease phenotype, (4) determine the effect of manipulation of the gut microbiota with antibiotics on energy homeostasis, inflammation markers, and metabolic syndrome traits in 50 obese subjects with metabolic syndrome and (5) study the relationship between gut microbiota and metabolic and cardiovascular disease traits, weight change, and host genomics in 1,000 Amish already characterized for these traits and in whom 500K Affymetrix SNP chips have already been completed. These studies will provide our deepest understanding to date of the role of gut microbes in terms of 'who's there?', 'what are they doing?', and 'how are they influencing host energy homeostasis, obesity and its metabolic complications? PUBLIC HEALTH RELEVANCE: This study aims to unravel the contribution of the bacteria that normally inhabit the human gastrointestinal tract to the development of obesity, and its more severe metabolic consequences including cardiovascular disease, insulin resistance and Type II diabetes. We will take a multidisciplinary approach to study changes in the structure and function of gut microbial communities in three sets of Old Order Amish patients from Lancaster Pennsylvania: obese patients, obese patients with metabolic syndrome and non-obese individuals. The Old Order Amish are a genetically closed homogeneous Caucasian population of Central European ancestry ideal for genetic studies. These works have the potential to provide new mechanistic insights into the role of gut microflora in obesity and metabolic syndrome, a disease that is responsible for significant morbidity in the adult population, and may ultimately lead to novel approaches for prevention and treatment of this disorder.

描述：越来越多的证据表明肠道微生物区系对人类健康和疾病有重要作用，这使得我们和其他人假设肠道微生物与宿主之间的共生和病理关系可能是肥胖和肥胖的代谢并发症的关键因素。我们的“节俭微生物群假说”认为肠道微生物区系在人体能量平衡中起着关键作用。具体地说，肠道微生物群落的组成可能会在营养匮乏的时候为宿主带来生存优势，通过提高养分吸收效率、改善代谢效率和能量储存来促进正能量平衡。然而，在营养过剩的情况下，可能会导致脂肪堆积和肥胖，在遗传易感性的个体中，增加的脂肪质量可能会导致特发性腹型肥胖、异位脂肪沉积(肝脏、肌肉)和肥胖的代谢并发症(胰岛素抵抗、高血压、高脂血症)。此外，在营养过剩的情况下，肠道微生物群落可能发生病理转变，导致细菌产物泄漏到肠道淋巴管和门静脉循环，从而诱导炎症状态，进一步加重代谢综合征的特征，加速动脉粥样硬化。这种病理转变和抗菌素渗漏发生的程度以及导致炎症和其他肥胖适应不良后遗症的程度也可能受到宿主因素的影响，包括遗传因素。在拟议的研究中，我们将通过对肠道微生物组进行详细的基因组和功能评估，在有意识地操纵肠道微生物组之前和之后，对表型和基因分型密集的人类受试者的肠道微生物群落进行详细的基因组和功能评估，从而直接测试节俭微生物组假说。为了解决这些假设，提出了五个具体目标：(1)从Old Order Amish中招募三个年龄和性别匹配的组：(I)50名患有代谢综合征的肥胖者(BMI和Gt；30 kg/m2)，(Ii)50名没有代谢综合征的肥胖者(BMI和Gt；30 kg/m2)，以及(Iii)50名没有代谢综合征的非肥胖者(BMI和lt；25 kg/m2)，并通过16S rRNA基因的高通量测序描述参与研究的受试者的肠道微生物区系的结构；(2)表征基因含量(元基因组)以评估75名受试者肠道微生物区系的代谢潜力，以确定特定的基因或途径是否与疾病表型相关；(3)研究75名受试者的转录组，以确定肠道微生物区系中的基因表达差异是否与疾病表型相关；(4)确定抗生素操纵肠道微生物区系对50名患有代谢综合征的肥胖患者能量稳态、炎症标志物和代谢综合征性状的影响；以及(5)研究肠道微生物区系与代谢和心血管疾病特征、体重变化和宿主基因组学之间的关系，其中1,000名阿米什人已经对这些特征进行了表征，其中500K Affymetrix SNP芯片已经完成。这些研究将使我们对肠道微生物的作用有了最深入的了解，比如“谁在那里？”“它们在做什么？”以及“它们如何影响宿主能量平衡、肥胖及其代谢并发症？”公共卫生相关性：这项研究旨在揭示通常生活在人类胃肠道的细菌对肥胖的发展及其更严重的代谢后果(包括心血管疾病、胰岛素抵抗和II型糖尿病)的贡献。我们将采用多学科方法研究来自宾夕法尼亚州兰开斯特的三组旧秩序阿米什患者的肠道微生物群落结构和功能的变化：肥胖患者、肥胖伴代谢综合征患者和非肥胖者。古老的亚米希人是一个基因封闭的中欧血统的同种高加索人群体，非常适合进行遗传学研究。这些工作有可能为肠道微生物区系在肥胖和代谢综合征中的作用提供新的机械性见解，肥胖和代谢综合征是一种导致成人人口显著发病率的疾病，并最终可能导致预防和治疗这种疾病的新方法。