The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the USA. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes were transmissible with uncultured fecal communities, and with their corresponding fecal bacterial culture collections. Co-housing mice harboring an obese twin’s microbiota (Ob) with mice containing the lean co-twin’s microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cagemates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota, and was diet-dependent. These findings reveal transmissible, rapid and modifiable effects of diet-by-microbiota interactions.

Diet and nutritional status are among the most important modifiable determinants of human health. The nutritional value of food is influenced in part by a person's gut microbial community (microbiota) and its component genes (microbiome). Unraveling the interrelations among diet, the structure and operations of the gut microbiota, and nutrient and energy harvest is confounded by variations in human environmental exposures, microbial ecology, and genotype. To help overcome these problems, we created a well-defined, representative animal model of the human gut ecosystem by transplanting fresh or frozen adult human fecal microbial communities into germ-free C57BL/6J mice. Culture-independent metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these humanized mice were stably and heritably colonized and reproduced much of the bacterial diversity of the donor's microbiota. Switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar "Western" diet shifted the structure of the microbiota within a single day, changed the representation of metabolic pathways in the microbiome, and altered microbiome gene expression. Reciprocal transplants involving various combinations of donor and recipient diets revealed that colonization history influences the initial structure of the microbial community but that these effects can be rapidly altered by diet. Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle "clinical trials" that test the effects of environmental and genetic factors on the gut microbiota and host physiology. INTRODUCTIONAdvances in "next-generation" DNA sequencing have dramatically reduced costs and markedly increased capacity, allowing cultureindependent metagenomic methods to be readily deployed to characterize microbial communities (microbiota) associated with human body habitats at various stages of the human life cycle and in various populations (1-5). These metagenomic surveys not only capture the microbial organismal and genetic diversity associated with humans but also have begun to investigate the functional contributions that our microbes make to our physiologic phenotypes, our health, and our disease predispositions. The distal gut is home to our largest number of microbes. A recent study of the fecal microbiota of adult monozygotic and dizygotic pairs of twins and their mothers revealed that no single identifiable abundant (defined as representing >0.5% of the microbiota) bacterial species was shared by all 154 individuals surveyed. Nonetheless, family members had a more similar community structure than unrelated individuals. In addition, the degree of relatedness of the fecal microbiota of adult monozygotic twin pairs was not greater than that of dizygotic twin pairs (5), suggesting that early environmental exposures are important determinants of community structure. Despite...

Identifying a scalable, unbiased method for discovering which members of the human gut microbiota influence specific physiologic, metabolic and immunologic phenotypes remains a challenge. Here we describe a method in which a clonally-arrayed collection of cultured, sequenced bacteria was generated from one of several human fecal microbiota samples found to transmit a particular phenotype to recipient germ-free mice. Ninety-four bacterial consortia, of diverse size, randomly drawn from the culture collection, were introduced into germ-free animals. We identified an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells (Tregs) and expansion of Nrp1lo/− peripheral Tregs, as well as strains that modulated mouse adiposity and cecal metabolite concentrations using feature selection algorithms and follow-up mono-colonization. This combinatorial approach enabled a systems-level understanding of some of the microbial contributions to human biology.

SUMMARY To study how microbes establish themselves in a mammalian gut environment, we colonized germ-free mice with microbial communities from human, zebrafish and termite guts, human skin and tongue, soil, and estuarine microbial mats. Bacteria from these foreign environments colonized and persisted in the mouse gut; their capacity to metabolize dietary and host carbohydrates, and bile acids, correlated with colonization success. Co-housing mice harboring these xenomicrobiota with one another, with mice harboring native gut microbiota, and germ-free ‘bystanders’ revealed the success of particular bacterial taxa in colonizing an empty gut habitat and guts with established communities. Unanticipated patterns of ecological succession were observed; for example, a soil-derived bacterium dominated even in the presence of bacteria from other gut communities (zebrafish and termite), and human-derived bacteria colonized germ-free mice before mouse-derived organisms. This approach generalizes to address a variety of mechanistic questions about succession, including succession in the context of microbiota-directed therapeutics.

Chronic inflammatory diseases are the most important causes of mortality in the world today and are on the rise. We now know that immune-driven inflammation is critical in the etiology of these diseases, though the environmental triggers and cellular mechanisms that lead to their development are still mysterious. Many chronic inflammatory diseases are associated with significant shifts in the microbiota towards inflammatory configurations, which can affect the host both by inducing local and systemic inflammation and by alterations in microbiota-derived metabolites. This review discusses recent findings suggesting that shifts in the microbiota may contribute to chronic disease via effects on the immune system.