Results from three long-term studies following host and microbiome characteristics during pregnancy and preterm birth, inflammatory bowel disease, and prediabetes have expanded our understanding of how humans and microbes interact and the resulting consequences for our health. The studies were funded as part of a second phase of the National Institutes of Health’s Human Microbiome Project (HMP). Key findings, datasets and new techniques developed over the course of this phase were published in a series of research articles in the Nature family of journals.

The NIH Common Fund launched the HMP in 2007 to develop resources for characterizing the microbiome in healthy adults and in people with specific microbiome-associated diseases. The second phase of the HMP, the integrative HMP or iHMP, emphasized human and microbiome interactions and analyzed the temporal trends in many biological properties of them both. Three known microbiome-associated conditions served as models for the iHMP to develop new approaches and tools for microbiome research.

“The first phase of the HMP revolutionized our understanding of the healthy human microbiome and gave us clues to its role in a few human diseases,” said James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives, which oversees the Common Fund. “Research now shows that just identifying the microbes that make up a person’s microbiome is not enough to understand the microbes’ health consequences. The function of a microbial community is different from the sum of the individual microbes’ behavior.” 

An iHMP project at Virginia Commonwealth University, Richmond, focused on the vaginal microbiome and the host immune system in women who give birth preterm versus those who give birth at term. The team of researchers followed more than 1,500 women over the course of pregnancy, and identified specific microbes present early in pregnancy in women who experienced preterm birth. The researchers also discovered a profile of inflammatory molecular signals in the women who experienced preterm birth together with a distinct metabolic profile in their microbiomes. These profiles were observed very early in pregnancy, which may provide new clinical biomarkers to predict women at risk of preterm birth.

A second iHMP project at the Broad Institute of MIT and Harvard, Cambridge, and Massachusetts General Hospital, Boston, followed host and gut microbiome interactions in 132 study participants with and without inflammatory bowel disease (IBD). Researchers took measurements and samples over a year for all participants during both IBD flares and remission, capturing microbial and host responses to these episodes. Compared to people without IBD, study results showed that the gut microbiome was much more unstable over time in people with IBD. This study also identified a previously unclassified group of bacteria whose levels were drastically lower in people with IBD, and saw different genes turned on and off in the bacteria Clostridia between the groups.

A third iHMP project by Stanford University, Palo Alto, California, and the Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, followed the dynamic interplay of the host with gut and nasal microbiomes in the development of type 2 diabetes. The study team followed 106 participants for nearly four years. When the study began, 51 participants had prediabetes and a portion of the participants had insulin resistance. Many specimens were collected from the participants over time and analyzed for changes in the microbiome as well as several other molecular processes in the body. Particular attention was dedicated to changes that could have been caused by challenges to the immune system like viral respiratory infections. Extensive differences were identified in molecular pathway changes in participants with respiratory infections. Some pathways involved in the immune response seemed abnormal during respiratory infections in insulin resistant participants versus insulin sensitive. While the study is small, it highlights the complex and dynamic interaction between host and microbes during health and immune disruptions.

Though each iHMP project had a different health outcome focus, they all evaluated the intimate interplay between microbial and host biological properties, particularly for immune properties. Together, they provide a framework for future studies of the role of the microbiome in health and disease. All project information, and those data not restricted by the Institutional Review Board, as well as software tools, and protocols from both phases of the HMP, have been collected and curated by the HMP Data Coordination Center, which has been organized and integrated by the Institute for Genome Sciences at the University of Maryland School of Medicine: https://www.hmpdacc.org(link is external), for use by the broader research community.

“The tools and data generated by the first phase of the HMP were used in hundreds of subsequent studies by other researchers, which greatly advanced human microbiome research,” said Lita Proctor, Ph.D., who directed the HMP program. “With the more complex iHMP datasets now available, the potential for a similar burst of innovation exists.”

The iHMP was managed by a trans-NIH working group and funded by the NIH Common Fund, the National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Integrative Health, the Office of Dietary Supplements, and the Office of Research on Women’s Health.