Although the ’omics era has accelerated all aspects of biological research, its effects have been particularly apparent in studies of microbial communities and the human microbiome. In the 18 years since the publication of the first human genome, studies of the microbiome have grown from culture-based surveys of the oral cavity and gut to molecular profiles of microbial biochemistry in all ecological niches of the human body1,2,3. Epidemiology and model systems have been used to identify associations between changes in the microbiome and conditions ranging from autism4 to cancer5,6,7, and microbial and immunological mechanisms have been identified that affect, for example, the efficacy of drugs used to treat cardiac conditions8 or survival during graft-versus-host disease9.

Contemporary studies of the human microbiome have also been a source of basic biological and translational surprises, exposing a compelling range of novel findings and open questions. Every human being appears to carry their own, largely individual, suite of microbial strains10,11, which are acquired early in life12,13,14, differ between environments and populations15,16, and can persist for years17 or undergo relatively rapid transitions18. Microbial diversity manifests differently in different ecological niches of the body; for example, greater diversity is generally expected in the gut, but can be associated with dysbiotic states and risk of adverse events in the female reproductive tract. The microbiome can be perturbed by conditions such as inflammatory bowel disease and diabetes, but a variety of microbiome-linked health states, and the underpinnings of these links, remain unexplored. How dynamic is the microbiome during processes such as pregnancy or viral infection? Which changes in the microbiome represent causes rather than effects of changes in health? Which molecular elements of a personalized microbiome might be responsible for health outcomes, and how do they integrate with and maintain physiological processes such as the immune system and metabolism? And what ecological elements dictate the success of a microbiota transplant, and why are they successful in treating some individuals and conditions, but not others?

The National Institutes of Health Human Microbiome Project was one of the first large-scale initiatives to address a subset of these questions19 (Fig. 1). Launched in 200720, the first phase of the program sought to determine whether there were common elements to ‘healthy’ microbiomes, in the absence of overt disease. Studies of both a baseline adult population21,22,23 and ‘demonstration’ populations with specific disease states established typical ranges (for some populations) of microbial membership and enzymatic repertoires across the body, combinations of metabolic functions that were either prevalent or strain-specific, and some of the host factors (such as race or ethnicity) that determine this variation. Studies of targeted populations identified ecological states of niches such as the vagina24,25, skin26,27,28, and gut29,30,31,32,33, among many others (https://www.hmpdacc.org/health/projectdemos.php). This first phase of the HMP (HMP1) thus yielded a wealth of community resources: nucleotide sequences of microorganisms and communities from a large number of isolates, individuals, and populations (http://hmpdacc.org)34,35,36,37; protocols to support reproducible body-wide microbiome sampling and data generation38,39,40; and computational methods for microbiome analysis and epidemiology41,42,43,44,45,46,47.

Fig. 1: The first and second phases of the NIH Human Microbiome Project. The ten-year NIH Human Microbiome Project (HMP) program, organized into two phases (HMP1 and HMP2), developed reference sequences, multi-omic data sets, computational and statistical tools, and analytical and clinical protocols as resources for the broader research community. The HMP1 focused on the characterization of microbial communities from numerous body sites (oral, nasal, vaginal, gut, and skin) in a baseline study of healthy adult subjects, and included a set of demonstration projects that focused on specific diseases or disorders. The HMP2 expanded the repertoire of biological properties analysed for both host and microbiome in three longitudinal cohort studies of representative microbiome-associated conditions: pregnancy and preterm birth (vaginal microbiomes of pregnant women), inflammatory bowel diseases (gut microbiome) and prediabetes (gut and nasal microbiomes). These studies followed the dynamics of these conditions through multi-omic analyses of multiple measurement types over time, including changes in microbial community composition, viromics, metabolomic profiles, gene expression and protein profiles from both host and microbiome, and host-specific properties such as genetic, epigenomic, antibody, and cytokine profiles, along with other study-specific features. All sequences and multi-omic data, clinical information, and tools from both HMP1 and HMP2 are housed in the HMP Data Coordination Center (DCC) or referenced public or controlled-access repositories to serve as a central resource for the research community. Full size image

One of the main findings of the HMP1 was that the taxonomic composition of the microbiome alone was often not a good correlate with host phenotype—this tended to be better predicted by prevalent microbial molecular function or personalized strain-specific makeup21. This finding served as the foundation for the development of the second phase of the HMP, the Integrative HMP (iHMP or HMP2)48, which was designed to explore host–microbiome interplay, including immunity, metabolism, and dynamic molecular activity, to gain a more holistic view of host–microbe interactions over time. This multi-omic program sought to expand the resource base available to the microbiome research community, to begin to address the relationship between host and microbiome mechanistically, and to address the questions introduced above. Disease-targeted projects within the HMP2 were therefore encouraged to use multiple complementary approaches in order to assess the mechanisms of human and microbial activity longitudinally and to provide protocols, data, and biospecimens for future work. These projects included three studies that followed the dynamics of human health and disease during conditions with known microbiome interactions, thus addressing important health outcomes directly while also serving as models of ‘typical’ microbiome-associated conditions of broad interest to the research community. These comprised pregnancy and preterm birth (PTB); inflammatory bowel diseases (IBD); and stressors that affect individuals with prediabetes. These studies, which have now reached the first stage of completion49,50,51, together provide a wealth of information and insights about not only microbial dynamics, but also associated human host responses and microbial inter-relationships. A collection of more than 20 manuscripts to date describe some of these results at https://www.nature.com/collections/fiabfcjbfj, and together they provide a rich multi-omic data resource to be mined by future work (http://www.ihmpdcc.org).