The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice

Abstract

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...

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