A Systems Approach to the Human Microbiome

“The trillions of microorganisms that reside in and on our bodies — our microbiome — represent a heretofore unrecognized organ, integral to our health and wellbeing. When the ecology of this organ is compromised, we become vulnerable to a range of complex diseases.”

-Dr. Sean Gibbons, ISB assistant professor


We see an accelerating loss of gut bacterial diversity in industrialized and developing countries. This loss of microbiome diversity is driven by a lack of exposure to maternal and environmental microbes, and also to shifts in diet and widespread use of antimicrobial compounds. This loss of biodiversity is alarming due to the importance of the microbiome for protecting us from disease, processing our food, and training our immune system.

The loss of gut microbial diversity is associated with the rise of modern plagues, like asthma, allergies, autoimmunity, diabetes, obesity, and other disorders arising from a dysregulated immune system. Loss of diversity is also associated with an increase risk of intestinal-related infections by pathogens like Clostridium difficile.

Over the last decade, emerging DNA sequencing technologies and computational tools have allowed us to peer directly into the complex ecology of the human microbiome. We have just begun to translate our scientific knowledge of the gut microbiome into ecological therapies for complex human diseases. From fecal transplants to individual-specific nutrition and pharmaceutical-grade probiotics, the human microbiome has emerged as a crucial component to personalized medicine.


ISB researchers, along with our external partners, are developing computational and wet-lab tools for engineering microbial communities. In particular, we are integrating multi-omics data from human blood and from the fecal microbiome to improve our understanding of how fluctuations in the gut microbiome are reflected in host physiology. By mining large multi-omic data sets, we will identify targets for experimental validation in in vitro and in vivo models of disease. We aim to understand the underlying eco-evolutionary rules governing microbial community assembly and resilience in individual people, in order to manipulate the gut ecosystem to improve human health.

To date, our researchers:

  • Integrating host metabolomic, proteomic, and genomic data with microbiome data to better define “microbiome health.”
  • Developing animal models for vertical transmission of the microbiota to better understand ecological community assembly.
  • Designing long-term evolution experiments to determine how our microbiota adapt to us as individuals over the course of our lifespans.
  • Running perturbation experiments to determine how antimicrobial and pre-biotic exposures alter the structure and resilience of microbial communities.
  • Building new bioinformatic and statistical tools for microbiome meta-analyses.




ISB and our partners have assembled the most comprehensive database to date on individual wellness, with genomic, blood proteomic, blood metabolomic, fecal microbiome, dietary, and behavioral data collected on more than 4,000 people. ISB researchers are also working with the Broad Institute and MIT to release a massive data resource containing multi-omic (16S amplicon sequences, metagenomics, and fecal metabolomics) time-series data on 90 healthy stool donors, including 10 long, dense time series (i.e. almost daily sampling for a year or more). This data resource is paired with an extensive, open-access isolate library containing more than 4,000 strains and more than 1,000 bacterial genomes from all the major genera in the gut.


ISB is developing bioinformatic tools for dealing with batch effects, which impede cross-study comparisons. In conjunction with tool development, ISB is working with external collaborators to assemble large, curated databases for large-scale meta-analyses. For example, there is a partnership between ISB and the Microboime Stress Project to assemble data on how various stressors impact microbial communities in environmental and host-associated environments. ISB researchers are also working with the infant probiotics company Commense to assemble all available infant gut time series data to carry out the first cross-study analysis of gut successional dynamics in early life.


  • Poyet, M., Groussin, M., Gibbons, S.M., Avila-Pacheco, J., Jiang, X., Kearney, S.M., Perrotta, A.R., Berdy, B., Zhao, S., Lieberman, T., Swanson, P.K., Smith, M., Roesemann, S., Alexander, J.E., Rich, S.A., Livny, J., Vlamakis, H., Clish, C., Bullock, K., Deik, A., Scott, J., Pierce, K.A., Xavier, R., and Alm, E.J. 2019. A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research. Nature Medicinehttps://doi.org/10.1038/s41591-019-0559-3
  • Wilmanski, T., Rappaport, N., Earls, J.C., Magis, A.T., Manor, O., Lovejoy, J., Omenn, G.S., Hood, L., Gibbons, S.M., Price, N.D. 2019. Blood metabolome signature predicts gut microbiome alpha-diversity in humans. Nature Biotechnology, https://doi.org/10.1038/s41587-019-0233-9
  • Shijie Zhao, Tami D. Lieberman, Mathilde Poyet, Kathryn M. Kauffman, Sean M. Gibbons, Mathieu Groussin, Ramnik J. Xavier, Eric J. Alm. 2019. “Adaptive evolution within gut microbiomes of healthy people.” Cell Host & Microbe. https://doi.org/10.1016/j.chom.2019.03.007
  • Otwell, A.E., García de Lomana, A.L., Gibbons, S.M., Orellana, M.V., Baliga, N.S. 2018. “Systems biology approaches towards predictive microbial ecology.” Environmental Microbiology. https://doi.org/10.1111/1462-2920.14378
  • Gurry, T., HST Microbiome Consortium, Gibbons, S.M., Nguyen, L.T.T., Kearney, S.M., Ananthakrishnan, A., Jiang, X., Duvallet, C., Kassam, Z., Alm, E.J. 2018. “Predictability and persistence of prebiotic dietary supplementation in a healthy human cohort.” Scientific Reports. https://doi.org/10.1038/s41598-018-30783-1
  • Gibbons, S.M., Duvallet, C., Alm, E.J. 2018. “Correcting for batch effects in case-control microbiome studies.” PloS Computational Biology, https://doi.org/10.1371/journal.pcbi.1006102
  • Kearney, S.M., Gibbons, S.M., Erdman, S., Alm, E.J. 2018. “Orthogonal dietary niche enables reversible engraftment of a gut bacterial commensal.” Cell Reports, https://doi.org/10.1016/j.celrep.2018.07.032
  • Price, Nathan D., Andrew T. Magis, John C. Earls, Gustavo Glusman, Roie Levy, Christopher Lausted, Daniel T. McDonald, et al. 2017. “A Wellness Study of 108 Individuals Using Personal, Dense, Dynamic Data Clouds.” Nature Biotechnology. https://doi.org/10.1038/nbt.3870
  • Thompson L.R., Sanders J.G., McDonald D., Ladau J., Locey K., Navas-Molina J.A., Prill R.J., Gibbons S.M., Gonzalez A., Amir A., et al. 2017. “A communal catalogue reveals Earth’s multiscale microbial diversity.” Nature, https://doi.org/10.1038/nature24621
  • Duvallet, C., Gibbons, S.M., Gurry, T., Irizarry, R. and Alm, E.J. 2017. “Meta-analysis of microbiome studies reveals disease-specific and shared responses.” Nature Communications, https://doi.org/10.1038/s41467-017-01973-8
  • Gibbons, S.M., Kearney, S.M., Smillie, C.S., and Alm, E.J. 2017. “Two dynamic regimes in the human gut microbiome.” PloS Computational Biology, http://dx.doi.org/10.1371/journal.pcbi.1005364



ISB’s multi-pronged and collaborative approach to the human microbiome is unique. We have made great strides in developing computational tools and experimental models targeted at engineering the gut microbiome.

However, our work is far from done. Your support is crucial to our quest to integrate the human microbiome into 21st Century medicine.

For more information, please contact:

Mark Cholvin | 206.732.1350 | mark.cholvin@isbscience.org

Featured Projects

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    Pioneer 100 Study Establishes Foundation for New Industry of Scientific Wellness

    Results from the Pioneer 100 Wellness Project, a nine-month study of 108 individuals, demonstrated that combining personal, dense, dynamic data clouds with tailored behavioral coaching can optimize wellness for individuals. These data clouds also can identify early transitions into disease states and facilitate the reversal of some disease states back to wellness.

  • Ötzi the Iceman: Helicobacter pylori Pathogen Found in Stomach Contents

    Institute for Systems Biology collaborates with researchers worldwide to study pathogens in the stomach content and microbiome of the 5300 year old European Copper Age glacier mummy “Ötzi” and discovers a Helicobacter pylori pathogen genome.
    Ötzi harbored a nearly pure Asian-origin bacterial population of H. pylori providing key information as to population migration into Europe over the last few thousand years.
    Supported by proteome information gathered at ISB, the Iceman’s stomach was found to be colonized by a cytotoxic strain of H. pylori that triggered host inflammation immune responses.