<p>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  Microbiome 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 non-obese subjects (BMI &#x3C; 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.</p>

Human Gut Microbiome in Amish Obesity