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

描述：新出现的证据表明，肠道微生物群可能以重要的方式对人类健康和疾病做出贡献，这使我们和其他人假设肠道微生物与其宿主之间的共生和病理关系可能是肥胖和肥胖代谢并发症的关键因素。我们的“节俭微生物假说”提出肠道微生物群在人体能量稳态中起关键作用。具体而言，肠道微生物群落的成分可能在营养匮乏时为其宿主带来生存优势，通过提高营养吸收效率、提高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，可能导致脂肪增加和肥胖，在遗传易感个体中，脂肪量增加可能导致首选腹部肥胖、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，导致细菌产物渗漏到肠淋巴和门静脉循环，从而诱发炎症状态，进一步加重代谢综合征特征，加速动脉粥样硬化。这种病理转变以及抗菌药物泄漏发生的程度以及引起炎症和其他肥胖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，我们将通过在有意操纵肠道微生物组之前和之后对密集表型和基因分型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，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名肥胖受试者（BMI > 30 kg/m2）伴有代谢综合征，（ii） 50名肥胖受试者（BMI > 30 kg/m2）无代谢综合征，（iii） 50名非肥胖受试者（BMI < 25 kg/m2）无代谢综合征，并通过16S rRNA基因的高通量测序来表征本研究入组受试者肠道微生物群的结构；(2)表征基因含量（宏基因组），以评估75名受试者肠道微生物群的代谢潜力，以确定特定基因或途径是否与疾病表型相关；(3)表征75名受试者的转录组，以确定肠道微生物群基因表达差异是否与疾病表型相关；(4)确定抗生素对50名肥胖代谢综合征受试者的能量稳态、炎症标志物和代谢综合征特征的影响；(5)研究肠道微生物群与代谢和心血管疾病特征、体重变化的关系；以及1000名阿米什人的宿主基因组学，这些阿米什人已经具有这些特征，并且已经完成了500K Affymetrix SNP芯片。这些研究将为我们提供迄今为止对肠道微生物作用的最深刻理解，比如“谁在那里？”，“他们在做什么？”以及“它们如何影响宿主能量稳态、肥胖及其代谢并发症？”公共卫生相关性：本研究旨在揭示通常居住在人类胃肠道中的细菌对肥胖发展的贡献，以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。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Old Order Amish患者肠道微生物群落结构和功能的变化：肥胖患者，肥胖合并代谢综合征患者和非肥胖个体。旧秩序阿米什人是中欧血统的一个基因封闭的同质高加索人群，是基因研究的理想选择。这些工作有可能为肠道菌群在肥胖和代谢综合征中的作用提供新的机制见解，这是一种在成年人中导致显著发病率的疾病，并可能最终导致预防和治疗这种疾病的新方法。

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.