Metagenomic studies of the obese and lean gut microbiome

The human 'metagenome' is a composite of Homo sapiens genes and genes present in the genomes of the trillions of microbes that colonize our adult bodies (the 'microbiome'). In this thesis, we use culture-independent methods to characterize the lean and obese, human and mouse distal gut microbiome, testing the hypothesis that the distal gut microbiome is a key component in the human and mouse energy balance equation. 16S rRNA gene sequencing and shotgun sequencing of total community DNA and cDNA were used to survey gut microbial community structure and gene content. These methods were complemented with biochemical studies of gnotobiotic mice colonized with microbiotas harvested from lean or obese mouse donors, as well as a human donor. Studies of mice with genetic-induced obesity (caused by a mutation in the leptin gene), mice with diet-induced obesity (caused by consumption of a high-fat/high-sugar 'Western' diet), and obese and lean human twins have shown that obesity is linked to shifts in gut community structure and altered representation of bacterial genes and metabolic pathways. Experiments in germ-free animals and mice colonized with microbes isolated from obese or lean donors have demonstrated that the obesity-associated microbiome promotes host adiposity. Furthermore, our results provide an initial description of the organismal and genetic diversity in humans and mice, leading the way for further studies of the interplay between diet, the gut microbiome, and host adiposity.