Human microbiome

Lore & Background

The human microbiome includes both commensal and mutualistic microorganisms, though some non-pathogenic microbes can harm hosts via metabolites like trimethylamine. The role of most microbiota is not well understood. The Human Microbiome Project (HMP) sequenced the genome of human microbiota, focusing on skin, mouth, nose, digestive tract, and vagina, publishing initial results in 2012. From 242 healthy U.S. volunteers, over 5,000 samples were collected from 15–18 body sites, identifying 81–99% of genera.

Reader's Guide

The human microbiome represents a paradigm shift in understanding human biology, revealing that the body hosts a complex microbial ecosystem with a gene pool vastly exceeding human genes. The HMP's 2012 milestone provided a reference database of normal microbial variation, enabling future studies on disease associations. The concept challenges traditional definitions of 'self' and 'other,' as these microorganisms perform useful tasks, though many roles remain unknown. The field's significance lies in its potential to link microbiome composition to health and disease, though variability and technical challenges persist. The distinction between 'flora' (a misnomer) and 'microbiota' reflects evolving terminology. The HMP's work established boundaries of normal variation, a foundation for personalized medicine and ecological understanding of the human body.

Did You Know?

• The number of bacterial cells in the human body is estimated at around 38 trillion, comparable to the 30–40 trillion human cells.
• The term 'flora' is a misnomer for microbiota, as 'flora' pertains to plants, not microorganisms.
• More than 10,000 microbial species occupy the human ecosystem, with 81–99% of genera identified by the Human Microbiome Project.
• Some non-pathogenic microorganisms can harm human hosts via metabolites like trimethylamine, which is converted to trimethylamine N-oxide.

Origins and Ambitious Vision

The Human Microbiome Project emerged in 2007 as a landmark NIH initiative designed to deepen scientific understanding of the microbial communities that inhabit the human body and their connections to both wellness and illness. Backed by $170 million in funding from the NIH Common Fund over a nine-year span, the program was explicitly framed as a conceptual and experimental successor to the Human Genome Project, extending the same spirit of comprehensive cataloging to the trillions of organisms sharing our physiology. In its inaugural year, the HMP earned a place on the NIH Roadmap for Medical Research under the banner of New Pathways to Discovery. The project deliberately targeted five major body sites—oral cavity, skin, vaginal tract, gastrointestinal system, and respiratory passages—while also aiming to dissolve the traditional wall between medical and environmental microbiology. Beyond mere identification, its vision included establishing the parameters necessary to deliberately reshape an individual's microbial community so that it functions optimally within that person's unique physiology.

A Toolkit Beyond the Petri Dish

A defining feature of the HMP was its reliance on culture-independent approaches to microbial characterization, recognizing that the vast majority of organisms in the human microbiome had never been successfully grown in a laboratory, identified, or otherwise described. At the center of this methodological shift stood metagenomics, a technique that captures a broad genetic snapshot of an entire microbial community in a single sample. Complementing this wide-angle view, the project invested heavily in whole-genome sequencing of individual bacterial isolates, yielding what researchers called a deep genetic perspective on specific species. Approximately three thousand such reference sequences were planned to serve as benchmarks for later metagenomic comparisons. The HMP also funded deep sequencing of bacterial 16S rRNA gene fragments amplified through polymerase chain reaction from human subjects. When the second phase, the iHMP, arrived in 2014, the technical palette expanded further to include whole metagenome shotgun sequencing, metatranscriptomics, metabolomics and lipidomics, and immunoproteomics, creating a multi-omic framework for studying host-microbe interactions.

Rewriting the Numbers

Before the HMP era, a widely repeated claim held that the human body harbored roughly ten times as many microbial cells and a hundred times as many microbial genes as its own cells, a figure rooted in estimates of 100 trillion bacteria versus 10 trillion human cells. That narrative began to shift in 2014 when the American Academy of Microbiology published a public FAQ acknowledging that both figures were rough estimates and highlighting newer research placing the human cell count closer to 37 trillion, which would push the microbial-to-human ratio down to approximately three to one. By 2016, yet another group proposed an even more balanced picture, estimating the ratio at roughly one to one—specifically 1.3 to 1, with a stated uncertainty of 25 percent and a population-level variation of 53 percent among standard 70-kilogram males. Despite these staggering microbial populations, the HMP's launch revealed that scientists knew remarkably little about what these organisms actually did for human health. The microbial world encompassed not just bacteria but also members of the domain Archaea, yeasts, single-celled eukaryotes, helminth parasites, and viruses including bacteriophages that prey on the bacterial residents themselves.

Two Phases, Many Partners

The HMP unfolded in two distinct phases. The first, running from 2007 to 2014, set five broad goals: assembling a reference set of microbial genome sequences, exploring how disease correlates with shifts in the microbiome, building new computational tools, creating a shared resource repository, and examining the ethical, legal, and social implications of the research. In 2014 the NIH launched the Integrative Human Microbiome Project, which aimed to produce integrated longitudinal datasets pairing microbiome data with host biological properties across three cohort studies of microbiome-associated conditions. The iHMP's key findings were published in 2019. The collaborative network behind both phases was remarkably wide, drawing in Stanford University, the Broad Institute, Virginia Commonwealth University, Washington University, Northeastern University, MIT, and Baylor College of Medicine, among others, with contributions spanning data evaluation, reference sequence construction, technology development, and ethical inquiry. Internationally, the International Human Microbiome Consortium coordinated parallel efforts, while in Canada the CIHR Institute of Infection and Immunity led the Canadian Microbiome Initiative to study microbial colonization and its alteration during chronic disease.

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