Jeffrey I. Gordon, M.D.
Dr. Robert J. Glaser Distinguished University Professor
Director, Center for Genome Sciences
Molecular Microbiology and Microbial Pathogenesis Program
Developmental Biology Program
Molecular Cell Biology Program
Office: 314-362-7243 Fax: 314-362-7047
5th Floor, Center for Genome Sciences, 4444 Forest Park Box 8510
Symbiotic relationships between bacteria and animals are a dominant theme of life on Earth. The total number of bacteria that colonize our body surfaces is estimated to exceed our total number of somatic and germ cells by an order of magnitude. The majority of our bacterial symbionts reside in the intestine where they provide metabolic traits that we have not had to evolve on our own. In this sense, we should view ourselves as a composite of species, and our genetic landscape as a summation of the genes embedded in our own genome and in the genomes of our microbial partners. The number of genes in this microbiome may exceed those in our human genome by 100-fold. Members of the gut microbiota have endured a stringent selection to become ‘master physiologic chemists’: i.e., they have developed chemical strategies for regulating host gene expression in ways that benefit themselves and us. Identifying these host genes and the microbial effectors of their expression/function should provide new molecular targets and new chemical strategies for promoting health (energy balance, proper nutrition), or treating diseases in susceptible hosts (e.g., obesity, certain immunopathologic states and cancers).
To identify the molecular foundations of these symbiotic relationships, their contributions to our post-natal development and adult physiology, and their effects on microbial genome evolution and function, we use germ-free model organisms (normal and genetically-engineered mice and zebrafish), colonized with bacterial and archaeal species that normally reside in the human gut. We are employing a variety of methods (e.g., functional genomics/proteomics/mass-spec-based metabolomics) to monitor host and microbial responses to colonization. For example, we have sequenced the 6.3 Mb genome of Bacteroides thetaiotaomicron, a prominent member of the distal intestinal microbial community of mice and humans that modulates a number of essential host functions (including processing of otherwise indigestible polysaccharides). 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 in silico reconstructions of bacterial physiology, ex vivo studies of bacterial responses to defined environmental perturbations, and in vivo studies involving isogenic wild type and mutant bacterial strains introduced into gnotobiotic mice and fish. Other approaches involve comparative microbial genomics involving other Bacteroides strains and species, other genera represented in the human gut microbiota, as well as mesophilic methanogenic archeaons (e.g. Methanobrevibacter smithii). Studies of biodiversity involve 16S rRNA sequence-based enumerations of communities recovered from defined mouse and human gut habitats, as well as whole genome sequencing of strains recovered from these locales. The latter studies are currently focused on the CFB Division.
We also use germ-free normal and genetically engineered mice to identify host and microbial factors that allow Helicobacter pylori, a bacterium that colonizes the stomachs of 50% of humans, to operate along the continuum between mutualism and pathogenicity (ulcers, cancer). This project is directed towards an analysis of the interactions between H. pylori isolates and gastric stem cells, as well as comparative studies of the genomes of clinical isolates recovered from patients with gastric cancer and its precursor states.
Finally, we study the features of multipotent gut stem cells. These cells fuel the rapid renewal of the GI epithelium that occurs continuously throughout life. We utilize mice with genetically engineered increases in stem cell census to retrieve these progenitors and define their molecular properties (e.g., by sequencing normalized cDNA libraries produced from laser capture microdissected (LCM) cells and by performing metabolomic studies of the LCM cell populations).
Keywords: functional and comparative genomics, genome analysis (microbial), ecology (symbiosis, ecogenomics), computational biology, systems biology, gut development, gut stem cells