Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ between human populations when viewed from the perspective of component microbial lineages, encoded metabolic functions, stage of postnatal development, and environmental exposures, we characterized bacterial species present in fecal samples obtained from 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas, as well as the gene content of 110 of their microbiomes. This cohort encompassed infants, children, teenagers and adults, parents and offspring, and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the representation of genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial species assemblages and functional gene repertoires were noted between individuals residing in the USA compared to the other two countries. These distinctive features are evident in early infancy as well as adulthood. In addition, the similarity of fecal microbiomes among family members extends across cultures. These findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations, and the impact of Westernization.

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...

Alzheimer’s disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.

The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise indigestible dietary polysaccharides. The products of polysaccharide fermentation include shortchain fatty acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41؊/؊ and Gpr41؉/؉ mice that were either conventionally-raised with a complete gut microbiota or were reared germ-free and then cocolonized as young adults with two prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methanobrevibacter smithii. Both conventionallyraised and gnotobiotic Gpr41؊/؊ mice colonized with the model fermentative community are significantly leaner and weigh less than their WT (؉/؉) littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic studies of germ-free and cocolonized Gpr41؊/؊ and ؉/؉ littermates disclosed that Gpr41-deficiency is associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet. These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent upon the gut microbiota.host-microbial interactions ͉ energy balance ͉ enteroendocrine cells ͉ nutrient sensing ͉ polysaccharide fermentation O ur ability to effectively digest food reflects the combined activities of enzymes encoded in our primate genome and in the genomes of the trillions of microbes that reside in our distal guts. This microbial community, or microbiota, affects both sides of the energy-balance equation, influencing both the harvest of calories and the activity of host genes involved in the metabolism and storage of absorbed energy (e.g., ref.