Senior Scholar Award in Global Infectious Disease
Jeffrey I Gordon, M.D.
Washington University School of Medicine

A Gnotobiotic Zebrafish Model for Analyzing Symbiotic Host-bacterial Interactions in the Mammalian Gut

Mutually beneficial (symbiotic) relationships between bacteria and animals are a dominant feature of life on Earth. We are no exception. Our bodies are home to a vast nation of friendly bacteria: the total number exceeds the total number of our own human cells. Our largest collection of microbes resides in the intestine (~100 trillion organisms). The number of bacterial genes embedded in the genomes of this community of 500-1000 species is ~100 times greater than the number of genes in our genome. The products of these bacterial genes provide essential metabolic capabilities that we have not evolved in our genome, including the ability to break down otherwise indigestible nutrients. The current revolution in genomics provides an unprecedented opportunity to define how gut symbionts modulate features of our postnatal development and adult physiology. One assumption prompting this analysis is that our bacterial partners have developed the capacity to synthesize novel chemical entities that help establish and sustain their symbiotic relationships, and that prospecting for these chemicals, and characterizing how they operate will provide new ways for manipulating our biology to enforce health, and to prevent, ameliorate, or cure various disease states (e.g., infectious diarrheas, inflammatory bowel disease). In a dynamic, densely populated ecosystem like the gut, exchange of genes between bacterial species can have profound effects on bacterial evolution and physiology. Therefore, studying the genomes of gut bacteria provides an opportunity to address general questions related to how the environment affects development of species, the definition and meaning of their extinction within a community, and the mechanisms by which they sense/define resource availability and cooperate to process otherwise inaccessible nutrients.

Our lab has studied the molecular foundations of the human-bacterial symbioses in the gut by colonizing germ-free mice with bacterial species that normally reside in the human intestine and then monitoring host and bacterial responses to colonization using genomic and computational tools. We have recently sequenced the genome of Bacteroides thetaiotaomicron, a prominent member of the distal intestinal microbial community of mice and humans, to obtain insights about how organisms have evolved to become successful symbionts. The roles of specified bacterial and host genes in establishing and maintaining the human-Bacteroides symbiosis are being analyzed through genetic and biochemical tests, guided in part by genome-based computer reconstructions/predictions of host and bacterial physiology, in part by profiling of changes in B. thetaiotaomicron gene expression in response to defined environmental perturbations, and in part by embarking on other microbial genome sequencing projects involving other Bacteroides species, as well as other groups of bacteria represented in the human intestinal microbial community.

Support from the Ellison Foundation is being used to develop the means to identify microbial signals that regulate our physiology. The zebrafish (Danio rerio) is very well suited for genetic and chemical screens: animals can be conveniently propagated; there is a wealth of genetic information about this organism; and they are transparent following hatching, allowing for direct observation of their developing gut and its microbial inhabitants. We are devising methods for raising zebrafish under germ-free conditions, for colonizing them with single or multiple bacterial species, and for identifying responses to colonization that are conserved between fish and mice. Fish genetically engineered to allow rapid monitoring of these conserved responses will be used as ‘living test tubes’ to identify chemical entities, produced by our gut inhabitants, that mediate such effects.

Contact Dr. Gordon.