Our observations in gnotobiotic mice and unrelated adult obese and lean humans indicate that there is adynamic linkage between adiposity and gut microbial ecology. Project 1will test the hypothesis that thereisan identifiable shared set of organismal and gene lineages evident in the microbiota and microbiomes ofobese compared to lean adult individuals, and that these obesity-associated organismal genes havepredicted properties that could contribute to increased efficiency of energy harvest from a diet.
Aim 1 -Wewill perform comparative metagenomic (DNA-based) sequence analysis of fecal samples obtained fromyoung adult (25-35year old), vaginally delivered female MZtwin pairs who are obese (BMI^35 kg/m2), andMZ twin pairs who are lean (BMI 18.5-25kg/m2): five of the MZ twin pairs in each category (obese or lean)will be of European ancestry (total of 10 twin pairs). Five more twin pairs in each category will be African-American. Mothers of twin pairs will be used as reference controls since there is evidence for verticaltransmission of the gut microbiota from a mother to her offspring. Two fecal samples will initially becollected per individual over a one-month interval. Each fecal community DNA sample from each patientwill be subjected to 16S rRNA sequence-based enumeration using 'universal' bacterial, and archaeal primers.The two DNA samples from each individual will be pooled, and -40 Mb of DNA sequence will be generatedusing the GS20 pyrosequencer. We will compare communities using the UniFrac metric developed by theKnight lab, and employ existing algorithms, developed from our studies of obese and lean mice, to comparetheir microbiomes. The collection of both short-term (1-month) and longer-term followup fecal samples (at12, 24, 36, and 48 months) from MZ twin pairs and their mothers will allow us to examine the structureoftheir microbiotas and microbiomes over time relative to co-twin, mother, and BMI.To determine whethergenetic background of the host versus a shared mother plays a dominant role in selecting a microbiota andits microbiome, we will perform a comparable analysis of the microbiomes of obese and lean 25-35year-oldfemale European ancestry and African-American dizygotic twin pairs and their mothers.
Aim 2 - Therepresentation of KEGG and COG functional groups found in the fecal microbiomes of obese vs. lean MZtwin pairs will be correlated with fecal microbial community transcriptomes and metabolomes. cDNAlibraries prepared from RNAs isolated from the same fecal samples previously used for whole microbiomeshotgun DNA sequencing, will be characterized. Genes and transcripts identified in the fecalmicrobiome/transcriptome of obese vs. lean individuals will be placed onto KEGG metabolic pathways. The

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-6 (M1))
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Washington University
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