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Center for Genome Sciences & Systems Biology
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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 surfaces exceeds our total number of H. sapiens cells by 10-fold and the total number of microbial genes in our aggregate microbial communities is at least 100-fold greater than the number of genes in our human genome. The vast majority of these microbes, and their viruses, live in our gut (tens of trillions, belonging to all three domains of life) where they provide us with traits we have not had to evolve on our own. 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 the collective genomes (‘microbiome’) of our body habitat-associated microbial communities, 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 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 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 malnutrition. Our studies of malnutrition 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 microbiome donors, or systematically manipulated derivatives of those diets. Our ability to replicate an individual’s microbiome 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 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 metagenomics (e.g., shotgun sequencing of microbial community DNA to define gene content), RNA-Seq (digital profiling of mRNAs expressed by the microbiome and host), mass-spec-based proteomics and metabolomics, and a variety of tools to quantify host physiological parameters (e.g., energy balance, facets of innate and adaptive immunity). The insights gleaned from gnotobiotic mouse models complement past, and inform future human studies designed to better understand the pathogenesis of complex diseases, and to develop new gut microbiome-directed therapeutics that improve health.
Faith, J.J., McNulty, N.P., Rey, F.E., and Gordon, J.I. Predicting a human gut microbiota’s response to diet in gnotobiotic mice. Science 333, 101-104 (2011)
Muegge, B., Kuczynski, J., Knights, D., Clemente, J.C., Gonzalez, A., Fontana, L., Henrissat, B., Knight, R., and Gordon, J.I., Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970-974 (2011)
Gordon, J.I., Honor thy gut symbionts redux. Science 336:1251-1253 (2012)
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)
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)
Keywords: human microbiome; host-microbial symbioses in the gut; metagenomics; ecology; systems biology; metabolism; obesity/malnutrition; 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