The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.

Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the Firmicutes. Here we show that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Our findings indicate that obesity has a microbial component, which might have potential therapeutic implications.

The human distal gut harbors a vast ensemble of microbes (the microbiota) that provide us with important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides1–6. Studies of a small number of unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes6–8, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is utilized and stored3–5. To address the question of how host genotype, environmental exposures, and host adiposity influence the gut microbiome, we have characterized the fecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person’s gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable ‘core microbiome’ at the gene, rather than at the organismal lineage level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity, and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiologic states (obese versus lean).

We have analyzed 5,088 bacterial 16S rRNA gene sequences from the distal intestinal (cecal) microbiota of genetically obese ob͞ob mice, lean ob͞؉ and wild-type siblings, and their ob͞؉ mothers, all fed the same polysaccharide-rich diet. Although the majority of mouse gut species are unique, the mouse and human microbiota(s) are similar at the division (superkingdom) level, with Firmicutes and Bacteroidetes dominating. Microbial-community composition is inherited from mothers. However, compared with lean mice and regardless of kinship, ob͞ob animals have a 50% reduction in the abundance of Bacteroidetes and a proportional increase in Firmicutes. These changes, which are division-wide, indicate that, in this model, obesity affects the diversity of the gut microbiota and suggest that intentional manipulation of community structure may be useful for regulating energy balance in obese individuals.energy balance͞obesity ͉ host-microbial interactions ͉ intestinal bacterial diversity ͉ ob͞ob mice ͉ phylogenetics T he 10 trillion to 100 trillion microorganisms that populate our adult intestines benefit us in a number of ways (1). One benefit is that they allow us to extract calories from otherwise indigestible common polysaccharides in our diet. This benefit occurs because components of the microbiota are able to adaptively deploy a large array of glycoside hydrolases and polysaccharide lysases that we humans do not encode in our genome (2, 3) (http:͞͞afmb.cnrs-mrs.fr͞CAZY͞). Furthermore, studies using germ-free and colonized normal and knockout mice fed a standard, polysaccharide-rich rodent-chow diet indicate that this mutualistic host-microbe relationship allows the extracted energy to be stored in adipocytes through a pathway that involves microbial regulation of the intestinal epithelial expression of fasting-induced adipocyte protein (Fiaf), a circulating inhibitor of lipoprotein lipase (LPL) (4). Microbial fermentation of dietary polysaccharides to monosaccharides and short-chain fatty acids in the distal gut and their subsequent absorption stimulate de novo synthesis of triglycerides in the liver. Microbial suppression of Fiaf in the gut epithelium results in reduced levels of this circulating LPL inhibitor, increased LPL activity in adipocytes, and enhanced storage of liver-derived triacyglycerols in fat cells (4).Although the root cause of obesity is excess caloric intake compared with expenditure, differences in gut microbial ecology between humans may be an important factor affecting energy homeostasis; i.e., individuals predisposed to obesity may have gut microbial communities that promote more efficient extraction and͞or storage of energy from a given diet, compared with these communities in lean individuals. This hypothesis raises a number of basic questions about gut microbial ecology in humans and mice. For example, how do the distal-gut microbiotas of the two hosts compare? Does kinship play an important role in the composition of the microbial community? Does adiposity affect community structure, and, ...

Our adult bodies harbor ~10 times more microbial than human cells. Their genomes (the microbiome) endow us with physiologic capacities that we have not had to evolve on our own and thus are both a manifestation of who we are genetically and metabolically, and a reflection of our state of well-being. Our distal gut is the highest density natural bacterial ecosystem known, the most comprehensively surveyed to date, and the most highly represented in pure culture. It contains more bacterial cells than all of our other microbial communities combined. To obtain a more comprehensive view of our biology, we propose a human gut microbiome initiative (HGMI) that will deliver deep draft whole genome sequences for 100 species representing the bacterial divisions (superkingdoms) known to comprise our distal gut microbiota: 15 of these genomes will be selected for finishing. A cost-effective strategy involves producing the bulk of the coverage by shotgun reads on a 454 Life Sciences pyrosequencer. Long-range linking information will be provided by paired end reads of fosmid subclones using a conventional ABI 3730xl capillary machine. The bulk of our sequencing will use human-derived strains, representing targeted phylotypes, from existing culture collections. The list will be augmented by in vivo culture of a human fecal microbiota in gnotobiotic mice. The latter approach will be used to obtain vastly simplified consortia, or pure cultures of previously uncultured representatives of important gutassociated bacteria. The deposited curated genome sequences will herald another phase of completion of the 'human' genome sequencing project, provide a key reference for metagenome projects, and serve as a model for future initiatives that seek to characterize our other extra-intestinal microbial communities.