Jeffrey I. Gordon, M.D.

Dr. Robert J. Glaser Distinguished University Professor
Pathology and Immunology
Director, The Edison Family Center for Genome Sciences & Systems Biology

Molecular Microbiology and Microbial Pathogenesis Program
Computational and Systems Biology Program
Molecular Cell Biology Program
Plant and Microbial Biosciences Program

  • 314-362-7243

  • 314-362-3963

  • 314-362-7047

  • 8510

  • 4515 McKinley, Room 4211A

  • jgordon@wustl.edu

  • http://gordonlab.wustl.edu

  • Gut microbiome; systems biology; postnatal development; childhood malnutrition; global health; gnotobiotic animal models; metabolic regulation; food webs; gut-brain axis; gut barrier/immune function; microbiome-targeted therapeutics

  • Role of the human gut microbiome in health and disease, notably childhood undernutrition and obesity

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 microbial genes in our body’s microbial communities is at least 100-fold greater than the number of genes in our human genome. The vast majority of these microbes live in our gut (tens of trillions, belonging to all three domains of life plus their viruses) 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 and genes, and our biological features as an amalgamation of human and microbial attributes.

We are interested in the following general questions: What are the genomic and metabolic foundations of our relationships with beneficial gut microbes? What mechanisms govern assembly of gut microbial strains into a community after birth; does this microbial ‘organ’ undergo an identifiable program of functional maturation in infancy and childhood that is shared across biologically unrelated individuals living in different parts of the world? How is this developmental program influenced by breast milk and by the types and order of presentation of complementary /weaning foods? What are the consequences of disruption of this postnatal program of gut microbiota development to the health status (physiologic, metabolic, immunologic and neurodevelopmental phenotypes) of children and adults? Can we intentionally and durably change the properties of our gut microbial communities (microbiota) to improve health?

A major focus of the lab is on the role of the gut microbiota in defining our nutritional status. This focus is based on the following considerations. First, dramatic changes in socioeconomic status, cultural traditions, population growth, and issues related to sustainable agriculture are affecting diets worldwide, placing great pressure to develop food systems that produce affordable more nutritious foods and to understand the factors that define the nutritional value of food. Second, diet has a great effect on the structural and functional configuration of the gut microbiota; the gut microbiota, in turn, serves as an adaptive microbial ‘metabolic’ organ to transform components of our diets in ways that determine their biologic effects on myriad cell populations. Third, undernutrition in infants and children, and obesity in children and adults are two pervasive, vexing and pressing global health challenges.

We are developing gut microbial community-targeted therapeutics to treat undernutrition in infants and children living in low-income countries, and obesity in Westernized countries. In one 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` gnotobiotic 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 gut microbial community in recipient mice that are reared under highly controlled environmental conditions allows us to (i) define the degree to which features of the human donor’s phenotype can be transmitted to the recipient animal via the microbiota, (ii) identify the metabolic and signaling networks that link various community members to one another through their syntropic (nutrient sharing) relationships, and to their host, and (iii) determine how dietary components affect these interactions. In cases where a transmissible phenotype is identified, we 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 and/or germ-free piglets to ascertain whether it too can transmit features of the donor’s phenotypes. If so, the contributions of the individual components or defined subsets of these culture collections are characterized in an effort to unravel the mechanisms involved in phenotypic transmission and determination of host biological ‘state’.

We apply and integrate a variety of experimental, computational and statistical methods to study human populations, notably twins as well as members of birth cohorts from several low-income countries (i.e., infants enrolled at birth and followed serially during their first several years of life). We generate gnotobiotic animal models using gut microbiota of selected members of these human populations. Our experimental approaches include (i) sequencing of gut microbial community DNA as well as the genomes of cultured microbial (primarily bacterial) members of the human gut community, (ii) forward genetic screens of cultured human gut bacterial strains to identify their fitness determinants in vitro and in gnotobiotic animal models, (iii) RNA-Seq plus targeted and non-targeted mass spectrometry-based analyses of the responses of members of the microbiota (and of the host) to dietary and other perturbations applied to our gnotobiotic animal models, and (iv) assays of metabolic flux, energy balance, innate and adaptive immune responses, bone biology, and CNS metabolism/function in these preclinical models. The results are used to guide targeted analyses of biospecimens and clinical/laboratory datasets obtained from the individuals and populations from whom microbial communities were obtained to create these gnotobiotic animal models.

These studies are providing new mechanistic insights about how components of the microbiota interact with one another and with various host biological processes, as well as new therapeutic candidates; notably (i) microbiota-directed therapeutic foods and human gut-derived bacterial strains (next generation probiotics) designed to repair the developmental abnormalities we have documented in the gut communities of children with undernutrition, and (ii) diet ingredients (including those recovered from otherwise discarded components of current food manufacturing processes) and consortia of human gut-derived microbes to rectify the perturbed functioning of the microbiota in individuals with obesity and its related metabolic abnormalities.

The effects of our microbiota-directed food prototypes have been are currently being examined in children with acute undernutrition living in Bangladesh and in obese individuals with and without metabolic dysfunction living in the USA.

Selected Publications:

Chen, R.Y., Kung, V.L., Das, S., Hossain, M.S., Hibberd, M.C., Guruge, J., Mahfuz, M., Begum, S.M.K.N., Rahman, M.M., Fahim, S.M., Gazi, M. A., Haque, R., Sarker, S.A., Mazunder, R.N., Di Luccia, B., Ahsan, K., Kennedy, E., Santiago-Borges, J., Rodionov, D.A., Leyn, S.A., Osterman, A.L., Barratt, M.J., Ahmed, T., and Gordon, J.I. Duodenal microbiota in stunted undernourished children with enteropathy. New Engl. J. Med. 283, 321-333 (2020).

Di Luccia B., Ahern, P.P., Griffin N.W., Cheng, J., Guruge, J.L., Byrne, A.E., Rodionov, D.A., Leyn, S.A., Osterman, A.L., Ahmed T., Colonna, M., Barratt, M.J., Delahaye, N.F., and Gordon, J.I., Oral cholera vaccination response to a combined prebiotic and microbial intervention in a gnotobiotic mouse model of childhood undernutrition. Cell Host Microbe 27, 899-908 (2020).

Feng, L., Raman, A.S., Hibberd, M.C., Cheng, J., Griffin, N.W., Peng, Y., Leyn, S.A., Rodionov, D.A., Osterman, A.L., and Gordon, J.I. Identifying determinants of bacterial fitness in a model of human gut microbial succession. Proc. Natl. Acad. Sci USA, 117, 2622-2633 (2020).

Gehrig, J.L., Venkatesh, S Chang, H-W., Hibberd, M.C., Kung, V.L., Cheng, J., Chen, R.Y., Subramanian, S., Cowardin, C.A., Meier, M., O’Donnell, D., Talcott, M., Spears, L.D., Semenkovich, C.F., Henrissat, B., Giannone, R.J., Hettich, R.L., Ilkayeva, O., Muehlbauer, M., Newgard, C.B., Sawyer, C., Head, R., Rodionov, D.A., Arzamosov, A.A., Leyn, S.A., Osterman, A.L., Hossain, I., Islam, M., Choudhury, N., Sarker, S., Huq, S., Mahmud, I., Mostafa, I., Mahfuz, M., Barratt, M.J., Ahmed, T., and Gordon, J.I., Effects of microbiota-directed foods in gnotobiotic animals and undernourished children, Science 365, eaau4732 (2019).

Raman, A.S., Gehrig, J.L., Subramanian, S., Venkatesh, M.C. Hibberd, S., Kang, G., Bessong, P.O., Lima, A.A.M., Kosek, M.N., Petri, W.A., Huq, S., Mostafa, I., Islam, M., Mahfuz, M., Haque, R., Ahmed, T., Barratt, M.J., and Gordon, J.I. A sparse covarying unit that describes healthy and impaired human gut microbiota development, Science 364, eaau4735 (2019).

Patnode, M.L., Beller, Z.W., Han, N.D., Cheng, J., Peters, S.L., Terrapon, N., Henrisssat, B., Le Gall, S., Saulnier, L., Hayashi, D.K., Meynier, A., Vinoy, S., Giannone, R.J., Hettich, R.L., and Gordon, J.I., Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans. Cell 179, 59-73 (2019).

Cowardin, C.A., Ahern, P.P., Kung, V.L., Hibberd, M.C., Cheng, J., Guruge, J.L., Sundaresan, V., Head, R.D., Barile, D., Mills, D.A., Barratt, M.J., Huq, S., Ahmed, T., and Gordon, J.I. Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition, Proc. Natl. Acad. Sci USA 116, 11988-11996 (2019).

Last Updated: 8/11/2020 2:36:49 PM

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