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The Human Microbiome Project enabled sequencing of communities terizing the baseline state of the micro-
(HMP) [1,2] is a concept that was long across the human body, and immunolo- biota is a critical first step in determining
in the making. After the Human Ge- gists began exploring the fundamental how altered microbial states contribute
nome Project, interest grew in sequenc- role of microorganisms in the maturation to disease (e.g., [13,2023]). Previous
ing the other genome of microbes of the innate and adaptive immune work showed wide inter- and intra-
carried in and on the human body systems. Initial metagenomic studies of personal diversity of human-associated
[3,4]. Microbial ecologists, realizing that human-associated microbial communi- microbes [24], necessitating analysis of a
.99% of environmental microbes could ties were performed using the traditional large number of subjects and character-
not be easily cultured, developed ap- Sanger platform [13,14]. Upon intro- ization of many reference bacterial
proaches to study microorganisms in situ duction of pyrosequencing [15], the genomes [25] to assist in interpretation
[5], primarily by sequencing the 16S number of 16S-based data sets increased of metagenomic data. The scope of the
ribosomal RNA gene (16S) as a phylo- dramatically [16,17]. The time was right HMP thus required a particularly diverse
genetic and taxonomic marker to identify to invest in a concerted study of the consortium (Figure 2A), and collabora-
members of microbial communities [6]. microbial communities associated with tion among these teams ultimately stim-
The need to develop corresponding new the human body and the metabolic ulated research growth throughout the
methods for culture-independent studies capabilities they providethe human field and produced a study including the
[7,8] in turn precipitated a sea change in microbiome (Figure 1) [18]. first consistent sampling of many clini-
the study of microbes and human health, To coordinate these efforts relating the cally relevant body habitats, within a
inspiring the new term metagenomics microbiome to human health, the NIH large population, with paired 16S profil-
[9] both to describe a technological Common Fund launched the HMP as a ing and deep metagenomic sequencing
approachsequencing and analysis of community resource program (http:// coverage for hundreds of microbial
the genes from whole communities rath- commonfund.nih.gov/hmp/) [19]. One communities.
er than from individual genomesand of its main goals was to create a baseline The HMP required careful consider-
to emphasize that microbes function view of the healthy human microbiome ation of ethical, legal, and social impli-
within communities rather than as indi- in five major areas (airways, skin, oral cations (ELSI) unique to the study of the
vidual species. This shift from a focus on cavity, gastrointestinal tract, and vagina) microbiome [26]. Such research raises
individual organisms to microbial inter- and to make this resource available to questions regarding traditional distinc-
actions [10] culminated in a National the broad scientific community. Charac- tions between self and non-self, human
Academy of Science report [11], which
outlined challenges and promises for Citation: Gevers D, Knight R, Petrosino JF, Huang K, McGuire AL, et al. (2012) The Human Microbiome Project:
metagenomics as a way of understanding A Community Resource for the Healthy Human Microbiome. PLoS Biol 10(8): e1001377. doi:10.1371/
the foundational role of microbial com- journal.pbio.1001377
munities both in the environment and in Published August 14, 2012
human health. Copyright: 2012 Gevers et al. This is an open-access article distributed under the terms of the Creative
Pioneering medical microbiologists Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
applied these approaches, finding far
more microbial diversity than expected Funding: This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.,
D.G. and K.H.; U54HG004973 to J.F.P.; U54AI084844 to B.A.M and K.E.N.; U01HG004866 to O.R.W.; R01HG005969
even in well-studied body site habitats to C.H.; R01HG004872 to R.K.; Army Research Office grant W911NF-11-1-0473 and National Science Foundation
[12]. Technological advances further grants NSF DBI-1053486 to C.H.; R.K. is an HHMI Early Career Scientist. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
The Community Page is a forum for organizations
and societies to highlight their efforts to enhance Abbreviations: 16S, 16S ribosomal RNA gene; DACC, HMP Data Analysis Coordination Center; ELSI, Ethical
the dissemination and value of scientific knowledge. Legal and Social Implications; HMP, Human Microbiome Project
* E-mail: chuttenh@hsph.harvard.edu (CH); bmethe@jcvi.org (BAM)
and non-human, genetics and environ- Planning for Human Finally, quality data generation from
ment, and health and disease. The Microbiome Studies: Tools, appropriately designed microbiome stud-
prospect of manipulating the microbiota Techniques, and Design ies enables a variety of subsequent com-
in ways that could permanently alter an putational analyses (Figure 2B). While we
individuals biological identity requires Any study of human populations must refer the reader to existing broader reviews
the development of new ethical para- put both subject protection and study of human microbiome bioinformatics [35
digms analogous to, but not identical to, design first, and the HMP was no excep- 37], here we highlight numerous recent
those already considered for gene thera- tion. Power calculations for microbiome approaches specifically developed during
py. Likewise, just as gene patents have studies in human cohorts are particularly the HMP. Several of these focused on
proven controversial, defining who challenging, as they must simultaneously microbial interactions, such as ecological
owns a microbiome raises difficult address assay types (e.g., 16S versus shot- network reconstruction [38,39]. Other
questions of intellectual property. The gun), depth of sequencing, taxon detection, computational methods dealt with meta-
ELSI team helped to develop an appro- and fold abundance changes in clades, genomic sequences, including both assem-
priate sample collection protocol, to draft genes, or pathways of interest [2831]. bly-based [40,41] and assembly-free anal-
a template for informed consent, and After study design, as the HMP spanned yses of microbial community membership
consulted on ethical issues arising during multiple sequencing centers over a pro- [42] and metabolic function [43]. Both
the study, such as the possibility that longed duration, the group established data types enable taxonomic and phylo-
unique human microbiome signatures standardized and benchmarked protocols genetic profiling [44,45], and ecological
[27] might compromise participant pri- for sample collection [2], handling, and metrics proved to associate microbial,
vacy. A portion of the HMPs dedicated subsequent 16S profiling [32]. Metage- gene, and pathway diversity on an un-
research budget continues to be commit- nomic library construction was likewise precedented scale [2]. The HMP Data
ted to integrating multidisciplinary ap- standardized among centers, and stringent Analysis Coordination Center (DACC,
proaches (including philosophical, social quality control was aided by the optimiza- http://hmpdacc.org) hosts all available
science, and legal methods) to study these tion of 16S read processing [33] and by HMP data and many tools, focusing the
issues and involve stakeholders including improved taxonomic frameworks for clas- tremendous quantity of raw data through
study participants, scientists, policy mak- sification of microbial sequences prior to lenses such as SitePainter [46]; IMG/
ers, patients, and indigenous populations. biological interpretation [34]. HMP, an HMP-specific version of the
Integrated Microbial Genomes (IMG [47]) Additionally, the large HMP cohort shows tal factors such as diet, and a lifetime of
system; METAREP [48]; and MG-RAST that the composition of the gut micro- pharmaceutical and immunological expo-
[49], and efforts are ongoing to provide biome rarely clusters subjects into discrete sures [41].
these data for meta-analysis alongside types, as was suggested before on more
other human microbiome studies in the limited data [61]; although other habitats The Healthy Microbiome
cloud. such as the vagina can exhibit such
Informs Studies of Disease
clustering [20], the gut was most often
Community Structure, Function, characterized by smooth abundance gra- Data from individuals without overt
and a Core Human dients of key organisms [2]. signs of disease serve as an excellent
Microbiome A potentially more universal core reference for disease-associated micro-
human microbiome emerged during the biome studies, while also providing a
The HMP was designed in part to consideration of microbial genes and comprehensive baseline for comparison
address a key question about our microbial pathways carried throughout communi- of Western populations with disparate
selves: do all humans have an identifiable ties metagenomes. While microbial or- geographic, ethnic, and genetic cohorts
core microbiome of shared components ganisms varied among subjects as de- [63]. The adoption of uniform sampling,
comparable to our shared genome [50]? scribed above, metabolic pathways nucleic acid extraction, sequencing, and
Several definitions of core have been necessary for human-associated microbial analysis protocols is an important step in
proposed, recently unified in one concep- life were consistently present, forming a such integration, with some success al-
tual framework [51]. Earlier studies re- functional core to the microbiome at all ready realized in, for example, several
ported that different people shared few body sites [2,43,53]. Although the path- aspects of autoimmune disease. The in-
microbes in their gut and skin microbiota ways and processes of this core were flammatory bowel diseases have long been
[17,5256], a greater fraction of their oral consistent, the particular genes that im- linked to the human gut microbiome [22],
microbiota [56,57], or might be classifi- plemented them again varied. Microbial with integration of host genotype, gene
able into multiple core microbiomes based sugar utilization, for example, was en- expression, and microbial membership
on vaginal [20] and gut communities [58]. riched for metabolism of simple sugars in now suggesting mediation of specific
The HMP provides a comprehensive the oral cavity, complex carbohydrates in host-microbial interactions by human gene
picture of the human microbiome cover- the gut, and glycogen/peptidoglycan deg- products as well as by host environment
ing multiple body sites and thus an in- radation in the vaginal microbiome [62]. [64,65]. Bacteria are of course not the only
depth exploration of these concepts. The The healthy microbiome may thus achieve mediators of dysbiotic disease, and meta-
study confirmed high inter-individual var- a consistent balance of function and genomic approaches can also be used to
iation [59] and showed that even rare metabolism that is maintained in health, identify potential viral etiologies (e.g., in
organisms in these communities are im- but with fine-grained details personalized pediatric fever of undefined origin [66]).
portant reservoirs of genetic diversity [60]. by genetics, early life events, environmen- Likewise the healthy microbiome pro-
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