When researchers at NIH and Celera published the first complete draft sequences of the human genome in 2001, many people assumed that the genetic foundation for a new and complete understanding of the human body and its functions had been achieved.
As it turned out this was far from the complete story, since it turns out that our bodies are, well… not completely human.
In the culmination of a multi-year effort directed by NIH, the Human Microbiome Project (HMP) has announced first genomic compilation of the generalized biome of microbes in the human body that complement the human genome. In a sprawling series of coordinated scientific reports published on June 14, 2012, in Nature and several journals in the Public Library of Science (PLoS), some 200 members of the HMP Consortium from nearly 80 multidisciplinary research institutions report on five years of research. HMP received $153 million from the NIH Common Fund, a trans-NIH initiative that finances high-impact, large-scale research.
"Like 15th century explorers describing the outline of a new continent, HMP researchers employed a new technological strategy to comprehensively define, for the first time, the normal microbial makeup of the human body," said NIH Director Francis S. Collins, M.D., Ph.D. "HMP created a remarkable reference database by using genome sequencing techniques to directly detect microbes in healthy volunteers. This lays the foundation for accelerating infectious disease research previously impossible without this community resource."
The human body contains trillions of microorganisms—outnumbering human cells by 10 to one. Because of their small size, however, microorganisms make up only about one to three percent of the body's mass, but play a vital role in human health.
HMP researchers reported that this plethora of microbes contribute more genes responsible for human survival than humans themselves. Where the human genome carries some 22,000 protein-coding genes that carry out metabolic activities, researchers estimate that the microbiome contributes some 8 million unique protein-coding genes or 360-times more bacterial genes than human genes.
In addition, the bacterial genomic contribution is critical for human survival. Genes carried by bacteria in the gastro-intestinal track, for example, allow humans to digest foods and absorb nutrients that otherwise would be unavailable.
"Humans don't have all the enzymes we need to digest our own diet," said Lita Proctor, Ph.D., HMP program manager. "Microbes in the gut breakdown much of the proteins, lipids and carbohydrates in our diet into nutrients that we can then absorb. Moreover, the microbes produce beneficial compounds, like vitamins and anti-inflammatories (compounds that suppress inflammation in the gut) that our genome cannot produce."
To define the normal human microbiome, HMP researchers sampled 242 healthy U.S. volunteers (129 male, 113 female), collecting tissues from 15 body sites in men and 18 body sites in women (including three vaginal sites). Researchers collected up to three samples from each volunteer at sites such as the mouth, nose, skin (two behind each ear and each inner elbow),and lower intestine (stool).
Where doctors had previously isolated only a few hundred bacterial species from the body, HMP researchers now calculate that more than 10,000 species occupy the human ecosystem. Moreover, researchers calculate that they have found between 81 and 99 percent of all the genuses of microorganisms in healthy adults.
Defining "a" human biome, however, can be difficult, as HMP researchers found immense variation in bacterial communities, both in bacterial diversity and in bacterial group abundances -- variation that includes population differences both between areas in each body and between similar areas in different bodies.
Each body site can be inhabited by organisms as different as those in the Amazon Rainforest and the Sahara Desert. Further, these sites on different individuals are populated with different assemblages of bacteria, or with some of the same bacteria, but in markedly different proportions.
In one companion paper, researchers asked the question of whether there were particular types of bacteria that were common, or "core", across all the human subjects in the HMP cohort. Defining a core bacteria as one present in 95% of all subjects, an analysis performed by Sue Huse and colleagues published in PLoS ONE ("A Core Human Microbiome as Viewed Through 16S rRNA Sequences Clusters," SM Hulse, Y Ye, Y Zhou, A Fodor) found that the nine sample sites from the mouth had the highest numbers of shared core bacteria, with the number of core varieties shared between stool samples being somewhat lower and very few core bacteria found at the skin and vagina sample sites.
Anthony Fodor, a co-author on the paper and an associate professor in bioinformatics at UNC Charlotte, notes however that, while there are a small core of commonly shared bacteria found at some body sites, he and his colleagues found the abundances of the "core" taxa at the sample sites could vary by several orders of magnitude between individuals.
"Consider stool samples," he said. "There's one sample where a particular type of bacteria represents about 90% of the sequences that we saw. But then there are other samples where it represents not 90% but .01% -- and there's everything in between. And this kind of variation is not just true of this type of bacteria but of essentially every type of bacteria within the HMP.
"Since all of the volunteers within the HMP were healthy, this tells us that there do not appear to be particular bacteria that are required to be present in high numbers to maintain health," Fodor noted.
Interestingly, this high level of variation in bacterial populations does not mean that the combined metabolic functions those populations perform are similarly different.
"The microbiome doesn't work that way," Fodor said. "You and I can both be perfectly healthy and one taxa can represent 95% of my gut, and be .01% of your gut. Maybe that is explained by the analysis in the Nature paper that shows that even though the types of bacteria are different, the function of genes within the genomes of these different bacteria appear to be very similar." From these data, it appears that different bacteria within the body can perform similar ecological functions, according to Fodor.
"It remains an open question how individual variation in the types of bacteria within healthy people influences disease development," Fodor continued. "It will be really interesting to see how this question is resolved as the field continues to mature and we learn more about the contribution of the microbiome to specific diseases such as obesity, cancer, fatty liver and inflammatory bowel disease."
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