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Overview

Microscopic study of the healthy human body has demonstrated that microbial cells outnumber human cells by about ten to one. Until recently though, this abundant community of human-associated microbes remained largely unstudied, leaving their influence upon human development, physiology, immunity, and nutrition almost entirely unknown. The NIH Common Fund Human Microbiome Project (HMP) was established with the mission of generating research resources enabling comprehensive characterization of the human microbiota and analysis of their role in human health and disease.

HMP logoTraditionally, microorganisms have been studied as cultures in the laboratory. However the vast majority of human-associated microbial species have never been successfully isolated in the laboratory, presumably because their growth is dependent upon specific conditions or substances which have not been duplicated in the laboratory. Advances in DNA sequencing technologies have created a new field of research, called metagenomics, allowing comprehensive examination of microbial communities without the need for cultivation. Instead of examining the genomes of individual bacterial strains that have been grown in the laboratory and then trying to reassemble the community of microbes, the metagenomic approach allows analysis of genetic material harvested directly from microbial communities without the need to culture the microbes. In the HMP, this approach is complementing genetic analyses of available reference strains, providing unprecedented information about the complexity of human-associated microbial communities. Other advanced ‘omics technologies like transcriptomics, proteomics and metabolomics, which measure the biological properties of whole microbial communities, are being used to provide insights into how the microbiome and human host interact to support health or to trigger disease.

The NIH Human Microbiome Project is one of several international efforts designed to take advantage of large scale, high through multi ‘omics analyses to study the microbiome in human health. As a community resource program, the HMP is a partner in an international collaboration to generate rich, comprehensive, and publicly available datasets of the microbiome. This information will be available worldwide for use by investigators and others in efforts to understand and improve human health. For more information on the Human Microbiome Project, please e-mail HMPinformation@mail.nih.gov.

The first phase of HMP (FY2007-2012) had the following six Initiatives which focused on the development of metagenomics datasets and computational tools for characterizing the microbiome in healthy adults and in cohorts of specific microbiome-associated diseases.  An Ethical, Legal and Societal Implications (ELSI) program was also created to address the new and unexplored issues which arise from human microbiome research.

Development of a reference set of microbial genome sequences and preliminary characterization of the human microbiome

Elucidation of the relationship between disease and changes in the human microbiome Development of new technologies for computational analysis

Development of new tools for computational analysis

The second phase of HMP (FY2013-2015) is focused on one Initiative which will create the first ever integrated datasets of biological properties from both the microbiome and the host using multi ‘omics technologies.

Evaluation of Multi-‘omic Data in Understanding the Human Microbiome’s Role in Health and Disease

 

The long-term objective of this initiative is to develop datasets and tools that the community can use to evaluate which biological properties of the microbiome and host will yield important new insights in understanding human health and disease. This initiative is also designed to stimulate the collection of multi ‘omics properties of the microbiome and the host by the research community.

There are thee research projects funded under this initiative:

A Multi-omic Analysis of the Vaginal Microbiome during Pregnancy

Gregory Buck, Jerry Strauss, and Kimberly Ferguson (Virginia Commonwealth University)

In the U.S., the annual cost of health care for newborns with complications approaches $26 billion, and worldwide, preterm birth is the leading cause of morbidity and mortality among neonates. Despite improved survival rates, the past few decades have seen no significant decrease in preterm births. It is becoming more clear that the billions of bacteria that colonize the human body play important roles in the health of the individual. However, the role of the millions of bacteria and other microbes that colonize the human female urogenital tract in prenatal health and birth of a healthy baby remains obscure. Previous to the recent development of 'omics' technologies; i.e., genomics, transcriptomics, proteomics, metabolomics, interactomics, etc., it was not possible to study these microbial populations in any in depth or highly efficient way. Many of these organisms have never been characterized and a fairly large fraction have not been successfully cultured. The Gregory Buck team (Virginia Commonwealth University) will be conducting a longitudinal study of the vaginal and related microbiomes of a very large, ethnically and racially diverse cohort (~2000 subjects) of pregnant adult and adolescent (15-17 year old) women with normal or with preterm births. Buck and colleagues plan to collect and analyze microbiome taxonomic, metagenomic,  and metatranscriptomic data, and to study, in parallel, host immunoproteomic and lipidomic data from vaginal, rectal, buccal, and skin samples from this cohorts. Neonate samples, including buccal, meconium and stool samples for multi ‘omic analysis. These multiple data types will form the integrated dataset for the Buck project and will be made publically available through the Multi’omic Microbiome Study-Pregnancy Initiative (MOMS-PI) database. This resource will allow the community to examine properties or combinations of properties of the microbiome and host and lead to new insights into the roles of the vaginal and related microbiota in preterm birth and other adverse outcomes of pregnancy. An understanding of the roles these organisms play in the health of the female urogenital tract will lead to better, more efficient prenatal and postnatal care, likely leading to diminished levels of preterm birth and infant morbidity and mortality.

Longitudinal Multiomics Microbial Profiling in Healthy and Disease Individuals

Michael Snyder (Stanford University) and George Weinstock (Washington University)

The complex relationship between humans and their microbiome and the changes of the microbiome during onset of human disease are poorly understood. The Michael Snyder (Stanford University)/George Weinstock (Washington University at St Louis) team has formed a multiomics Center for the detailed longitudinal analysis of both the microbiome, its activity, and its interconnected relationship with the host during healthy and disease states by omics profiling. The team is conducting a closely-spaced longitudinal study of the microbiomes of a small cohort (~40-50 subjects) of prediabetic subjects with the goal of evaluating immunological triggers for diabetes. This team is testing the hypothesis that typical colds or flu or other stressors (trauma, antibiotics, etc) can induce the onset of type 2 diabetes in prediabetic patients. Building upon their broad expertise, this team will analyze human microbiomes (fecal, nasal, and exogenous viral) in conjunction with host blood and urine components. Samples will be collected and analyzed during healthy and viral infections from the same individuals over the course of at least three years. Through analysis of the microbiome and host biological activities as measured through a variety of ‘omics approaches (metagenome, genome, transcriptome, proteome, metabolome), they will follow the dynamic changes in the microbiome and host pathways that occur during viral infections and other potential stresses, and obtain an unprecedented view of the molecular pathways that change during this period. They will focus on subjects at risk for diabetes, and will correlate the molecular changes in microbiome (endogenous and viral) activity with changes in host glucose levels and diabetes onset. Overall, more than 1000 different physiological states will be analyzed in ‘omic detail and the microbiome and corresponding host information will be deposited in a public repository and serve as an invaluable resource to the scientific community. These multiple data types will form the integrated dataset for the Snyder/Weinstock project and will be made publically available.

Characterizing the gut microbial ecosystem for diagnosis and therapy in IBD

Ramnik Xavier (Massachusetts General Hospital, Broad Institute) and Curtis Huttenhower (Harvard School of Public Health, Broad Institute)

Inflammatory bowel diseases (IBD) comprise both Crohn's disease (CD) and ulcerative colitis (UC) and affect some 1.5 million Americans. 25% of cases occur in children, and overall incidence has increased >400% in the past 50 years. CD and UC are both complex diseases that can manifest and proceed differently among patients, and recent studies have found that their genetic risk is likewise complex. Studies of environmental associations with IBD have not yet resulted in simple diagnostic markers or treatable points of intervention. Instead, IBD has emerged as one of the most important human conditions linked to the gut microbiota, the complex mixture of bacterial, viral, archaeal, and fungal organisms normally resident in the gut. The association of IBD with gut microbes is again complex, with no single microbe or pathogen appearing to be causal. Instead, IBD has been repeatedly linked to the overall ecology of entire gut microbial ecosystem. This suggests that the disease may be best studied by integrating many different types of measurements of gut microbes as they change within IBD patients and non-IBD controls over time. The Ramnik Xavier (Massachusetts General Hospital, Broad Institute)/Curtis Huttenhower (Harvard School of Public Health, Broad Institute) team is conducting a closely-spaced longitudinal study of the gut microbiomes of three different cohorts (90 subjects total, including both children and adults) of healthy and IBD patients. This team will collect several data types to form an integrated dataset provided by an IBD multi'omic database (IBDMDB). This will produce a resource enabling the gut microbial ecosystem as a target for diagnosis, therapy, and mechanistic understanding of IBD. It will leverage existing, well-phenotyped cohorts to provide longitudinal taxonomic, metagenomic, metatranscriptomic, metaproteomic, and metabolomic profiling of the gut microbiome. To further provide data on host interaction mechanisms as well, the team will profile host genetics, epigenetics, and transcriptional activity. Both sample collection and bioinformatic protocols will be validated and distributed, and the study will result in forward-looking platforms for single-cell and host-focused meta'omic assays. This team includes leaders in the study of the human microbiome, IBD, microbial community ecology and function, and meta'omic data integration, together providing the expertise and resources necessary to construct a definitive multi'omic data resource to understand the gut microbiome's role in IBD.

 

 

 

 

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