The intestinal microbiota: a frontier within
There are 10-100 trillion microbes that reside in our gastrointestinal tract representing thousands of species. This gut microbiota elicits host responses that impact fundamental and diverse aspects of our biology including the development and maintenance of innate and adaptive immune systems, and energy harvest and obesity. Many of the metabolic activities that the microbiota encodes in its collective genome (microbiome) are complementary to our own genome suggesting humans are composite organisms having both microbial and human parts.
Microbiota composition varies considerably between individuals, yet little is known about how factors like variation in host genotype and dietary change impact community membership and function. Similar to genetic polymorphisms, polymorphisms within our microbiome are likely to differentially influence aspects of host biology (e.g., immune function) and may explain aspects of phenotypic variation within and between human populations (e.g., pathogen susceptibility). The potential plasticity of the microbiota suggests that it may be a viable therapeutic target, and necessitates the pursuit of a fundamental understanding of how extrinsic and intrinsic factors alter its composition, function, and interaction with the host.
What do we want to learn?
Our research program aims to elucidate the basic principles that govern interactions within the intestinal microbiota and between the microbiota and the host. Specifically, we are exploring how perturbations in the intestinal environment, such as changes in host diet, microbial community composition, pathogen exposure, host genotype, and microbiota-targeted small molecules alter microbiota structure and function, and how these changes, in turn, influence host biology. To pursue these aims, we study germ-free (gnotobiotic) mice colonized with simplified, model microbial communities, apply systems approaches (e.g. functional genomics) and use genetic tools for the host and microbes to gain mechanistic insight into emergent properties of the host-microbial superorganism.
Germ-free mice as model hosts
One major challenge in obtaining a basic and mechanistic understanding of the microbiota is teasing apart relationships within this excessively complex community. Germ-free mice serve as an ideal platform for creating a defined community of microbial species amenable to controlled experimental investigation using tools emerging from the ongoing genomic revolution. Recent molecular enumerations of the human microbiota have established that greater than 90% of bacterial cells in the distal gut microbiota are members of one of two dominant divisions (phyla): the Bacteroidetes and the Firmicutes. Therefore, the microbiota can be reasonably modeled in the intestines of gnotobiotic (ex-germ-free; gnoto = known, bios = life) mice using a simplified community composed of species that represent the prevalent microbial taxa.