Human Microbiome Project

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Human Microbiome Project (HMP)
Human Microbiome Project logo.jpg
OwnerUS National Institutes of Health
Established2007 (2007)
Disestablished2016 (2016)
Website hmpdacc.org

The Human Microbiome Project (HMP) was a United States National Institutes of Health (NIH) research initiative to improve understanding of the microbiota involved in human health and disease. Launched in 2007, [1] the first phase (HMP1) focused on identifying and characterizing human microbiota. The second phase, known as the Integrative Human Microbiome Project (iHMP) launched in 2014 with the aim of generating resources to characterize the microbiome and elucidating the roles of microbes in health and disease states. The program received $170 million in funding by the NIH Common Fund from 2007 to 2016. [2]

Contents

Important components of the HMP were culture-independent methods of microbial community characterization, such as metagenomics (which provides a broad genetic perspective on a single microbial community), as well as extensive whole genome sequencing (which provides a "deep" genetic perspective on certain aspects of a given microbial community, i.e. of individual bacterial species). The latter served as reference genomic sequences — 3000 such sequences of individual bacterial isolates are currently planned — for comparison purposes during subsequent metagenomic analysis. The project also financed deep sequencing of bacterial 16S rRNA sequences amplified by polymerase chain reaction from human subjects. [3]

Introduction

Depiction of prevalences of various classes of bacteria at selected sites on human skin Skin Microbiome20169-300.jpg
Depiction of prevalences of various classes of bacteria at selected sites on human skin

Prior to the HMP launch, it was often reported in popular media and scientific literature that there are about 10 times as many microbial cells and 100 times as many microbial genes in the human body as there are human cells; this figure was based on estimates that the human microbiome includes around 100 trillion bacterial cells and an adult human typically has around 10 trillion human cells. [4] In 2014 the American Academy of Microbiology published a FAQ that emphasized that the number of microbial cells and the number of human cells are both estimates, and noted that recent research had arrived at a new estimate of the number of human cells at around 37 trillion cells, meaning that the ratio of microbial to human cells is probably about 3:1. [4] [5] In 2016 another group published a new estimate of ratio as being roughly 1:1 (1.3:1, with "an uncertainty of 25% and a variation of 53% over the population of standard 70 kg males"). [6] [7]

Despite the staggering number of microbes in and on the human body, little was known about their roles in human health and disease. Many of the organisms that make up the microbiome have not been successfully cultured, identified, or otherwise characterized. Organisms thought to be found in the human microbiome, however, may generally be categorized as bacteria, members of domain Archaea, yeasts, and single-celled eukaryotes as well as various helminth parasites and viruses, the latter including viruses that infect the cellular microbiome organisms (e.g., bacteriophages). The HMP set out to discover and characterize the human microbiome, emphasizing oral, skin, vaginal, gastrointestinal, and respiratory sites.

The HMP will address some of the most inspiring, vexing and fundamental scientific questions today. Importantly, it also has the potential to break down the artificial barriers between medical microbiology and environmental microbiology. It is hoped that the HMP will not only identify new ways to determine health and predisposition to diseases but also define the parameters needed to design, implement and monitor strategies for intentionally manipulating the human microbiota, to optimize its performance in the context of an individual's physiology. [8]

The HMP has been described as "a logical conceptual and experimental extension of the Human Genome Project." [8] In 2007 the HMP was listed on the NIH Roadmap for Medical Research [9] as one of the New Pathways to Discovery. Organized characterization of the human microbiome is also being done internationally under the auspices of the International Human Microbiome Consortium. [10] The Canadian Institutes of Health Research, through the CIHR Institute of Infection and Immunity, is leading the Canadian Microbiome Initiative to develop a coordinated and focused research effort to analyze and characterize the microbes that colonize the human body and their potential alteration during chronic disease states. [11]

Contributing Institutions

The HMP involved participation from many research institutions, including Stanford University, the Broad Institute, Virginia Commonwealth University, Washington University, Northeastern University, MIT, the Baylor College of Medicine, and many others. Contributions included data evaluation, construction of reference sequence data sets, ethical and legal studies, technology development, and more.[ citation needed ]

Phase One (2007-2014)

The HMP1 included research efforts from many institutions. [12] The HMP1 set the following goals: [13]

Phase Two (2014-2016)

In 2014, the NIH launched the second phase of the project, known as the Integrative Human Microbiome Project (iHMP). The goal of the iHMP was to produce resources to create a complete characterization of the human microbiome, with a focus on understanding the presence of microbiota in health and disease states. [14] The project mission, as stated by the NIH, was as follows:

The iHMP will create integrated longitudinal datasets of biological properties from both the microbiome and host from three different cohort studies of microbiome-associated conditions using multiple "omics" technologies. [14]

The project encompassed three sub-projects carried out at multiple institutions. Study methods included 16S rRNA gene profiling, whole metagenome shotgun sequencing, whole genome sequencing, metatranscriptomics, metabolomics/lipidomics, and immunoproteomics. The key findings of the iHMP were published in 2019. [15]

Pregnancy & Preterm Birth

The Vaginal Microbiome Consortium team at Virginia Commonwealth University led research on the Pregnancy & Preterm Birth project with a goal of understanding how the microbiome changes during the gestational period and influences the neonatal microbiome. The project was also concerned with the role of the microbiome in the occurrence of preterm births, which, according to the CDC, account for nearly 10% of all births [16] and constitutes the second leading cause of neonatal death. [17] The project received $7.44 million in NIH funding. [18]

Onset of Inflammatory Bowel Disease (IBD)

The Inflammatory Bowel Disease Multi'omics Data (IBDMDB) team was a multi-institution group of researchers focused on understanding how the gut microbiome changes longitudinally in adults and children suffering from IBD. IBD is an inflammatory autoimmune disorder that manifests as either Crohn's disease or ulcerative colitis and affects about one million Americans. [19] Research participants included cohorts from Massachusetts General Hospital, Emory University Hospital/Cincinnati Children's Hospital, and Cedars-Sinai Medical Center. [20]

Onset of Type 2 Diabetes (T2D)

Researchers from Stanford University and the Jackson Laboratory of Genomic Medicine worked together to perform a longitudinal analysis on the biological processes that occur in the microbiome of patients at risk for Type 2 Diabetes. T2D affects nearly 20 million Americans with at least 79 million pre-diabetic patients, [21] and is partially characterized by marked shifts in the microbiome compared to healthy individuals. The project aimed to identify molecules and signaling pathways that play a role in the etiology of the disease. [22]

Achievements

The impact to date of the HMP may be partially assessed by examination of research sponsored by the HMP. Over 650 peer-reviewed publications were listed on the HMP website from June 2009 to the end of 2017, and had been cited over 70,000 times. [23] At this point the website was archived and is no longer updated, although datasets do continue to be available. [24]

Major categories of work funded by HMP included:

Developments funded by HMP included:

Milestones

Reference database established

On 13 June 2012, a major milestone of the HMP was announced by the NIH director Francis Collins. [51] The announcement was accompanied with a series of coordinated articles published in Nature [52] [53] and several journals including the Public Library of Science (PLoS) on the same day. [54] [55] [56] By mapping the normal microbial make-up of healthy humans using genome sequencing techniques, the researchers of the HMP have created a reference database and the boundaries of normal microbial variation in humans. [57]

From 242 healthy U.S. volunteers, more than 5,000 samples were collected from tissues from 15 (men) to 18 (women) body sites such as mouth, nose, skin, lower intestine (stool) and vagina. All the DNA, human and microbial, were analyzed with DNA sequencing machines. The microbial genome data were extracted by identifying the bacterial specific ribosomal RNA, 16S rRNA. The researchers calculated that more than 10,000 microbial species occupy the human ecosystem and they have identified 81 – 99% of the genera. In addition to establishing the human microbiome reference database, the HMP project also discovered several "surprises", which include:[ citation needed ]

Clinical application

Among the first clinical applications utilizing the HMP data, as reported in several PLoS papers, the researchers found a shift to less species diversity in vaginal microbiome of pregnant women in preparation for birth, and high viral DNA load in the nasal microbiome of children with unexplained fevers. Other studies using the HMP data and techniques include role of microbiome in various diseases in the digestive tract, skin, reproductive organs and childhood disorders. [51]

Pharmaceutical application

Pharmaceutical microbiologists have considered the implications of the HMP data in relation to the presence / absence of 'objectionable' microorganisms in non-sterile pharmaceutical products and in relation to the monitoring of microorganisms within the controlled environments in which products are manufactured. The latter also has implications for media selection and disinfectant efficacy studies. [58]

See also

Related Research Articles

<span class="mw-page-title-main">Human microbiome</span> Microorganisms in or on human skin and biofluids

The human microbiome is the aggregate of all microbiota that reside on or within human tissues and biofluids along with the corresponding anatomical sites in which they reside, including the gastrointestinal tract, skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, and the biliary tract. Types of human microbiota include bacteria, archaea, fungi, protists, and viruses. Though micro-animals can also live on the human body, they are typically excluded from this definition. In the context of genomics, the term human microbiome is sometimes used to refer to the collective genomes of resident microorganisms; however, the term human metagenome has the same meaning.

<span class="mw-page-title-main">Metagenomics</span> Study of genes found in the environment

Metagenomics is the study of genetic material recovered directly from environmental or clinical samples by a method called sequencing. The broad field may also be referred to as environmental genomics, ecogenomics, community genomics or microbiomics.

<span class="mw-page-title-main">Integrated Microbial Genomes System</span> Genome browsing and annotation platform

The Integrated Microbial Genomes system is a genome browsing and annotation platform developed by the U.S. Department of Energy (DOE)-Joint Genome Institute. IMG contains all the draft and complete microbial genomes sequenced by the DOE-JGI integrated with other publicly available genomes. IMG provides users a set of tools for comparative analysis of microbial genomes along three dimensions: genes, genomes and functions. Users can select and transfer them in the comparative analysis carts based upon a variety of criteria. IMG also includes a genome annotation pipeline that integrates information from several tools, including KEGG, Pfam, InterPro, and the Gene Ontology, among others. Users can also type or upload their own gene annotations and the IMG system will allow them to generate Genbank or EMBL format files containing these annotations.

Jeffrey Ivan Gordon is a biologist and the Dr. Robert J. Glaser Distinguished University Professor and Director of the Center for Genome Sciences and Systems Biology at Washington University in St. Louis. He is internationally known for his research on gastrointestinal development and how gut microbial communities affect normal intestinal function, shape various aspects of human physiology including our nutritional status, and affect predisposition to diseases. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine of the National Academies, and the American Philosophical Society.

<span class="mw-page-title-main">Microbiota</span> Community of microorganisms

Microbiota are the range of microorganisms that may be commensal, mutualistic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to be crucial for immunologic, hormonal, and metabolic homeostasis of their host.

Pathogenomics is a field which uses high-throughput screening technology and bioinformatics to study encoded microbe resistance, as well as virulence factors (VFs), which enable a microorganism to infect a host and possibly cause disease. This includes studying genomes of pathogens which cannot be cultured outside of a host. In the past, researchers and medical professionals found it difficult to study and understand pathogenic traits of infectious organisms. With newer technology, pathogen genomes can be identified and sequenced in a much shorter time and at a lower cost, thus improving the ability to diagnose, treat, and even predict and prevent pathogenic infections and disease. It has also allowed researchers to better understand genome evolution events - gene loss, gain, duplication, rearrangement - and how those events impact pathogen resistance and ability to cause disease. This influx of information has created a need for bioinformatics tools and databases to analyze and make the vast amounts of data accessible to researchers, and it has raised ethical questions about the wisdom of reconstructing previously extinct and deadly pathogens in order to better understand virulence.

<span class="mw-page-title-main">Earth Microbiome Project</span>

The Earth Microbiome Project (EMP) was an initiative founded by Janet Jansson, Jack Gilbert and Rob Knight in 2010 to collect natural samples and analyze microbial life around the globe.

Biological dark matter is an informal term for unclassified or poorly understood genetic material. This genetic material may refer to genetic material produced by unclassified microorganisms. By extension, biological dark matter may also refer to the un-isolated microorganisms whose existence can only be inferred from the genetic material that they produce. Some of the genetic material may not fall under the three existing domains of life: Bacteria, Archaea and Eukaryota; thus, it has been suggested that a possible fourth domain of life may yet be discovered, although other explanations are also probable. Alternatively, the genetic material may refer to non-coding DNA and non-coding RNA produced by known organisms.

<span class="mw-page-title-main">Viral metagenomics</span>

Viral metagenomics uses metagenomic technologies to detect viral genomic material from diverse environmental and clinical samples. Viruses are the most abundant biological entity and are extremely diverse; however, only a small fraction of viruses have been sequenced and only an even smaller fraction have been isolated and cultured. Sequencing viruses can be challenging because viruses lack a universally conserved marker gene so gene-based approaches are limited. Metagenomics can be used to study and analyze unculturable viruses and has been an important tool in understanding viral diversity and abundance and in the discovery of novel viruses. For example, metagenomics methods have been used to describe viruses associated with cancerous tumors and in terrestrial ecosystems.

Mark J. Pallen is a research leader at the Quadram Institute and Professor of Microbial Genomics at the University of East Anglia. In recent years, he has been at the forefront of efforts to apply next-generation sequencing to problems in microbiology and ancient DNA research.

<span class="mw-page-title-main">Karen E. Nelson</span> Jamaican-born American microbiologist

Karen Nelson is a Jamaican-born American microbiologist who was formerly president of the J. Craig Venter Institute (JCVI). On July 6, 2021 she joined Thermo Fisher Scientific as Chief Scientific Officer.

<span class="mw-page-title-main">Microbiome</span> Microbial community assemblage and activity

A microbiome is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps et al. as "a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The term thus not only refers to the microorganisms involved but also encompasses their theatre of activity". In 2020, an international panel of experts published the outcome of their discussions on the definition of the microbiome. They proposed a definition of the microbiome based on a revival of the "compact, clear, and comprehensive description of the term" as originally provided by Whipps et al., but supplemented with two explanatory paragraphs. The first explanatory paragraph pronounces the dynamic character of the microbiome, and the second explanatory paragraph clearly separates the term microbiota from the term microbiome.

<span class="mw-page-title-main">Curtis Huttenhower</span> American biologist (born 1981)

Curtis Huttenhower is a Professor of Computational Biology and Bioinformatics in the Department of Biostatistics, School of Public Health, Harvard University.

Microbial dark matter (MDM) comprises the vast majority of microbial organisms that microbiologists are unable to culture in the laboratory, due to lack of knowledge or ability to supply the required growth conditions. Microbial dark matter is analogous to the dark matter of physics and cosmology due to its elusiveness in research and importance to our understanding of biological diversity. Microbial dark matter can be found ubiquitously and abundantly across multiple ecosystems, but remains difficult to study due to difficulties in detecting and culturing these species, posing challenges to research efforts. It is difficult to estimate its relative magnitude, but the accepted gross estimate is that as little as one percent of microbial species in a given ecological niche are culturable. In recent years, more effort has been directed towards deciphering microbial dark matter by means of recovering genome DNA sequences from environmental samples via culture independent methods such as single cell genomics and metagenomics. These studies have enabled insights into the evolutionary history and the metabolism of the sequenced genomes, providing valuable knowledge required for the cultivation of microbial dark matter lineages. However, microbial dark matter research remains comparatively undeveloped and is hypothesized to provide insight into processes radically different from known biology, new understandings of microbial communities, and increasing understanding of how life survives in extreme environments.

Metatranscriptomics is the set of techniques used to study gene expression of microbes within natural environments, i.e., the metatranscriptome.

Hologenomics is the omics study of hologenomes. A hologenome is the whole set of genomes of a holobiont, an organism together with all co-habitating microbes, other life forms, and viruses. While the term hologenome originated from the hologenome theory of evolution, which postulates that natural selection occurs on the holobiont level, hologenomics uses an integrative framework to investigate interactions between the host and its associated species. Examples include gut microbe or viral genomes linked to human or animal genomes for host-microbe interaction research. Hologenomics approaches have also been used to explain genetic diversity in the microbial communities of marine sponges.

<span class="mw-page-title-main">Pharmacomicrobiomics</span>

Pharmacomicrobiomics, proposed by Prof. Marco Candela for the ERC-2009-StG project call, and publicly coined for the first time in 2010 by Rizkallah et al., is defined as the effect of microbiome variations on drug disposition, action, and toxicity. Pharmacomicrobiomics is concerned with the interaction between xenobiotics, or foreign compounds, and the gut microbiome. It is estimated that over 100 trillion prokaryotes representing more than 1000 species reside in the gut. Within the gut, microbes help modulate developmental, immunological and nutrition host functions. The aggregate genome of microbes extends the metabolic capabilities of humans, allowing them to capture nutrients from diverse sources. Namely, through the secretion of enzymes that assist in the metabolism of chemicals foreign to the body, modification of liver and intestinal enzymes, and modulation of the expression of human metabolic genes, microbes can significantly impact the ingestion of xenobiotics.

Nikos Kyrpides is a Greek-American bioscientist who has worked on the origins of life, information processing, bioinformatics, microbiology, metagenomics and microbiome data science. He is a senior staff scientist at the Berkeley National Laboratory, head of the Prokaryote Super Program and leads the Microbiome Data Science program at the US Department of Energy Joint Genome Institute.

Clinical metagenomic next-generation sequencing (mNGS) is the comprehensive analysis of microbial and host genetic material in clinical samples from patients by next-generation sequencing. It uses the techniques of metagenomics to identify and characterize the genome of bacteria, fungi, parasites, and viruses without the need for a prior knowledge of a specific pathogen directly from clinical specimens. The capacity to detect all the potential pathogens in a sample makes metagenomic next generation sequencing a potent tool in the diagnosis of infectious disease especially when other more directed assays, such as PCR, fail. Its limitations include clinical utility, laboratory validity, sense and sensitivity, cost and regulatory considerations.

Culturomics is the high-throughput cell culture of bacteria that aims to comprehensively identify strains or species in samples obtained from tissues such as the human gut or from the environment. This approach was conceived as an alternative, complementary method to metagenomics, which relies on the presence of homologous sequences to identify new bacteria. Due to the limited phylogenetic information available on bacteria, metagenomic data generally contains large amounts of "microbial dark matter", sequences of unknown origin. Culturomics provides some of the missing gaps with the added advantage of enabling the functional study of the generated cultures. Its main drawback is that many bacterial species remain effectively uncultivable until their growth conditions are better understood. Therefore, optimization of the culturomics approach has been done by improving culture conditions.

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