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Center for Genome Sciences & Systems Biology
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St. Louis, MO  63108

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Office Phone:  314-362-7243
Lab Phone:  314-362-3963
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Research Abstract:

Mutually beneficial relationships between microbes and animals are a pervasive feature of life in our microbe-dominated planet. We are no exception: the total number of microbes that colonize our body habitats exceeds our total number of H. sapiens cells by 10-fold and the total number of microbial genes in our aggregate microbial communities vastly exceed the number of genes in our human genome. The majority of these microbes live in our gut (tens of trillions, belonging to all three domains of life, and their viruses). Thus, we should view ourselves as a composite of microbial and human cells, our genetic landscape as a summation of the genes embedded in our H. sapiens genome, and in the collective genomes of our microbial partners (‘the microbiome’), and our metabolic features as an amalgamation of human and microbial attributes.

We are interested in the following questions: What are the genomic and metabolic foundations of our mutually beneficial relationships with gut microbes? How do gut communities (microbiota) assemble after birth? Does the gut microbiota/microbiome undergo an identifiable program of functional maturation in infancy and childhood and what are the consequences of disruption of this program? How is the human gut microbiome evolving as a function of our changing lifestyles? How does it contribute to our physiologic variations and predispositions to various diseases? Can we intentionally manipulate the functional properties of our gut microbial communities to improve human health?

Dramatic changes in socioeconomic status, cultural traditions, population growth, and agriculture are affecting diets worldwide. Our comparative metagenomic studies of a large number of mammalian species, including humans, have underscored the dominant role played by diet in shaping the configuration and function of gut microbiomes. To understand how diet influences the composition and dynamic operations of our gut microbial communities, and how the gut microbiome in turn influences our nutritional status, we are characterizing the gut microbiomes of twins, concordant or discordant for obesity, or for severe forms of childhood undernutrition. Our studies of undernutrition involve infants and children living in a number of economically less developed countries.

We are developing a translational research pipeline for identifying next generation prebiotics, probiotics- and synbiotics (combinations of pre- and probiotics) to prevent or treat metabolic dysfunction and nutritional deficiencies. In one experimental approach, we transplant intact gut microbial communities directly from human donors sharing characteristics of interest into germ-free mice that harbor no microbes of their own.  The resulting 'humanized' mice are then fed the diets consumed by their corresponding human microbiota donors, or systematically manipulated derivatives of those diets.  Our ability to replicate an individual’s microbiota in multiple recipient mice who are reared under highly controlled environmental conditions, allows us to (i) define the degree to which features of the donor’s phenotype can be transmitted to the recipient via the gut microbiota/microbiome, (ii) identify the metabolic and signaling networks that link various microbial community activities to host biology, and  (iii) determine how dietary context affects these interactions. In cases where a transmissible phenotype is identified, we can subsequently generate sequenced collections of cultured gut bacteria that represent the majority of diversity present in the donor's microbiota.  His or her 'personal culture collection' is then transplanted into germ-free mice to ascertain whether it too can transmit features of the donor’s phenotype. If so, the contributions of the individual components of these culture collections are subsequently characterized in an effort to unravel the mechanisms involved in phenotypic transmission.

We use a variety of experimental and computational approaches in the lab. They include, for example, characterizing assembly of the gut microbiota and its responses to various factors by shotgun sequencing of microbial community DNA (to define gene content), RNA-Seq (digital profiling of mRNAs expressed by the microbiome), targeted and non-targeted mass spec-based metabolomics (to characterize the activity of a variety of metabolic pathways), plus whole genome transposon mutagenesis (to identify fitness determinants in different community and dietary contexts, plus the underpinnings of nutrient sharing relationships among community members). We also quantify the effects of gut microbial communities on various features of host biology (e.g., facets of energy balance, innate and adaptive immunity, metabolism, neurodevelopment, and bone biology). The insights gleaned from gnotobiotic mouse models complement and inform our human studies in several countries; these studies are designed to better understand the pathogenesis of complex diseases and to develop new gut microbiome-directed therapeutics that improve health.

Publications:

Subramanian, S., Yatsunenko, T., Huq, S., Haque, R., Mahfuz, M., Alam, M.A., Benezra, A., DeStefano, J., Meier, M.F., Muegge, B.D., Barratt, M.J., Zhang, Q., Province, M.A., Petri, W.A., Ahmed, T., and Gordon, J.I. Persistent gut microbiota immaturity in malnourished Bangladeshi children.  Nature 509: 417-421 DOI: 10.1038/nature13421 (2014)

Faith, J.J., Ahern, P.P., Ridaura, V.K., Cheng, J., and Gordon, J.I. Identifying gut microbiome-host phenotype relationships using combinatorial communities in gnotobiotic mice, Science Translational Medicine 6: 220ra11 (2014)

Smith, M.I., Yatsunenko, T., Manary, M.J., Trehan, I., Mkakosya, R., Cheng, J., Kau, A.,
Rich, S.S., Concannon, P., Mychaleckyj, J.C., Liu, J., Houpt, E., Li, J.V., Holmes, E., Nicholson, J., Knights, D., Ursell, L.K., Knight, R., and Gordon, J.I. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor.  Science 339: 548-554 (2013)

McNulty, N.P., Wu, M., Erickson, A.R., Martens, E.C., Pudlo, N.A., Muegge, B., Henrissat, B., Hettich, R.L., and Gordon, J.I. Effects of diet on resource utilization by a defined model human gut microbiota containing Bacteroides cellulosilyticus WH2, a symbiont with an extensive glycobiome, PLoS Biology 11: e1001637 (2013)

Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., Duncan, A.E., Kau, A.L., Lombard, V., Henrissat, B., Bain, J.R., Muehlbauer, M.J., Ilkayeva, O., Ursell, L.K., Clemente, J.C., Van Treuren, W., Walters, W.A., Newgard, C.B., Knight, R., Heath, A.C., and Gordon, J.I. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341: 1241214 doi: 10.1126/science.1241214 (2013)

Faith, J.J., Guruge, J.L., Charbonneau, M., Subramanian, S., Seedorf, H., Goodman, A.L., Clemente, J.C., Knight, R., Heath, A.C., Leibel, R.L., Rosenbaum, M., and Gordon, J.I. The long-term stability of the human gut microbiota. Science 341: 1237439 doi: 10.1126/science.1237439 (2013)

Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G., Contreras,

M., Magris, M., Hidalgo, G., Baldassano, R.N., Anokhin, A.P., Heath, A.C., Warner, B., Reeder, J., Kuczynski, J., Caporaso, J.G., Lozupone, C.A., Lauber, C., Clemente, J.C., Knights, D., Knight, R., and Gordon, J.I. Human gut microbiome viewed across age and geography.  Nature 486: 222-227 (2012)

Keywords: human microbiome; host-microbial symbioses in the gut; ecology; systems biology; metabolism; obesity; childhood undernutrition; immunology; global health; prebiotics/probiotics/synbiotics; anthropology of microbes

Short Research Description: We study the human gut microbiome and its impact on health and nutritional status