My NCBI Sign In
Jump to: Authorized Access | Attribution | Authorized Requests

Study 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 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 < 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.

  • Study Type: Longitudinal
  • Number of study subjects that have individual level data available through Authorized Access: 404

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

We have identified at least 1,300 subjects who are potentially eligible for follow-up. Inclusion criteria for this study are: (1) age > 20 years of age; (2) previously participated in a research study five or more years previously in which weight and MetS-defining traits were measured; and (3) was not on any medications that alter MetS traits at the time of initial study. (Note that MetS is not required for inclusion since we seek to obtain data from individuals across a full spectrum of each MetS trait.

We will not include currently pregnant or post-partum < 6 months, breast feeding; took antibiotics within the previous 6 months; history of intestinal surgery including cholecystectemy, inflammatory bowel disease, celiac disease, lactose intolerance, chronic pancreatitis, or other malabsorption disorder, current use of anti-inflammatory agents, glucocorticoids or other immune modulating medications.

Subjects will be eligible if they are diagnosed with a MetS trait even if they are currently being treated. We will not require that they discontinue their medications, but rather will account for the confounding influence of medications in our analysis.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
16S rRNA Sequencing Roche 454 GS FLX Titanium N/A N/A
Study History

The obesity epidemic has stimulated a number of studies that have explored host and environmental factors that affect energy balance. Excessive fat tissue, especially in and around the abdomen is associated with metabolic syndrome (MetS) and its attendant features of dyslipidemia, elevated blood pressure, insulin resistance, abnormalities in blood clotting, and elevated circulating levels of pro-inflammatory cytokines. Great inter-individual variation is apparent in propensity toward obesity, location where excess fat is deposited, and the extent to which this results in adverse health outcomes. Comparison of gut microbiota in obese and lean mice and humans, suggest that the gut microbial communities may contribute to overall energy balance in man. To explore the possible dysbiosis of gut microbiota in obesity and its metabolic complications, we will study obese and non-obese Old Order Amish subjects. Using a number of approaches we will characterize the genomic architecture of the gut microbiota at baseline, and after manipulation with antibiotics, to access its role in energy homeostasis, inflammation, and MetS traits.

Selected publications
Diseases/Traits Related to Study (MESH terms)
Authorized Data Access Requests
Study Attribution