A large National Institutes of Health initiative has published the most comprehensive catalogue yet of the microörganisms that live on and in the human body. By characterizing the ecology of the bacteria, viruses, fungi, and other microbes that inhabit healthy people, the researchers have established a baseline for the normal “human microbiome.” The work could accelerate research on development, obesity, infectious diseases, and more.
Most of the time we live in harmony with the microbes that inhabit our bodies, but sometimes that harmony breaks down, resulting in disease, says Eric Green, director of the National Human Genome Research Institute, one of the NIH institutions that has led the microbiome project. “We need to better understand what the normal microbiome is like and what happens to it when it changes to cause or influence disease,” he says. “This requires understanding the interaction of communities within our bodies, not just single microbes one at a time.”
At a microscopic level, the human body is a world of ecosystems as different as deserts and rainforests, each of which is occupied by its own unique community of microörganisms. Humans have co-evolved with these microörganisms, many of which are necessary for survival. While the medical and scientific community has known for some time that microbial cells outnumber human cells 10 to 1, little was known about the diversity and abundance of the species.
Traditionally, scientists study bacteria by growing them in single-species cultures in labs. However, many species of microbes are difficult to grow this way, in part because they depend on their fellow community members to survive. So the researchers in the Human Microbiome Project instead took mixed DNA samples from various parts of the study participants’ bodies and sequenced all of the genomes they found. They sampled parts of the body in 242 healthy adults—15 body habitats in men and 18 in women—from different locations within the mouth, nose, throat, elbow, ears, gut, and vagina.
The project would not have been possible without the cheaper and faster DNA sequencing technology that has come to market in the last few years, says Lita Proctor, who coördinated the effort for the NIH. The researchers used a machine from Roche to run a bacteria-specific form of DNA bar-coding to determine which species were present in more than 5,000 samples. The consortium then used Illumina’s technology to sequence the DNA in nearly 700 samples, creating so-called shotgun metagenomic sequences. The metagenomic sequences are a mixture of all the genes found in the microbial communities and give the researchers a “parts list” of the enzymes and other functional molecules each microbial community can make.
The study resulted in some 3.5 terabytes of genome sequence data. The team had to develop new computational methods to analyze it, says Proctor. With the metagenomic effort, the team was able to understand what biological functions the microbial communities were capable of performing. The healthy human microbiome contains at least 10,000 microbial species with some eight million different protein-encoding genes. In other words, 360 times more genes that what the human genome has to offer.
“The microbiome provides us with a lot more function than we would have without the organisms,” says George Weinstock, a genome scientist at the Genome Institute at Washington University in St. Louis and a leader in the Human Microbiome project. The organisms within the different communities have different metabolic capabilities (that is, they produce different enzymes and other molecules), some of which the human body depends on to digest certain foods, defend against invading pathogens, and more.
The researchers found that the microbial communities differed not only from site to site but also from person to person, with certain body sites being more consistent than others. For example, the mouth was particularly species-rich, and people living in the same community had similar kinds of microbes in their saliva (the study sampled people living around Houston and St. Louis). In contrast, bacteria living on the skin showed much greater variety between individuals.
However, although microbes differed from person to person, the functional potential of the microbes, as represented by the enzymes or other functional proteins encoded in their genomes, was similar from one person’s body part to another’s. So, while the species of bacteria in different individuals’ guts may vary, the suite of metabolic processes the communities can perform was largely the same.
Although the study subjects were all healthy (each was screened by multiple specialists), nearly all of them carried some pathogens, or microbes that can cause disease. These pathogens seemed to coexist peacefully in the participants, and future work will explore what happens to send these passengers into attack mode.
In a comment article published in the journal Nature, David Relman, a human microbe researcher at Stanford University, who was not involved in the study, noted that a recent study on populations living in less developed regions of the world have markedly different microbiomes from those living in the United States. He also points out that conditions that would have excluded participants from the Human Microbiome Project, such as gum disease or being overweight, are becoming more and more prevalent across the globe, and this should be considered in future studies.
Some of these concerns may be addressed in forthcoming reports from the NIH project. The 17 studies published today in Nature and the Public Library of Science journals are only the first results to come from the 200-scientist consortium. The next steps will be to move beyond studies of genetic potential to actual function by studying the gene products, such as proteins, that are produced by the human microbiome. Also, some groups within the Human Microbiome Project will examine how the microbiome changes with conditions such as Crohn’s disease or obesity.