The Rare Biosphere of the Human Body
Intestinal section from a gnotobiotic mouse model inoculated with selected bacterial species found in the human gut. Blue=Bacteroides WH2, green=Bacteroides thetaiotamicron, pink=Bacteroides vulgatus, yellow=Collinsella aerofaciens, red=Ruminococcus torques. Credit: Yuko Hasegawa/MBL Woods Hole
The landmark publication of a "map" of the bacterial make-up of healthy humans has deep roots in an unexpected place: the ocean.
Microbial communities that live on and in the human body, known collectively as the microbiome, are thought to have a critical role in human health and disease. Five years ago, the National Institutes of Health launched the ambitious Human Microbiome Project (HMP) to define the boundaries of bacterial variation found in 242 healthy human beings.
"In order to understand what sick is, it’s helpful to define the healthy microbiome first," says MBL scientist Susan M. Huse, lead author of one of the HMP reports published this week.
The project’s 200 scientists from 80 institutions, including Huse and Mitchell Sogin from the MBL, faced the daunting task of making sense of more than 5,000 samples of human and bacterial DNA and 3.5 terabases of genomic data.
The solution? The HMP adopted several, state-of-the-art genetic sequencing and analysis methods, many of which were originally developed by the MBL for the International Census of Marine Microbes—a massive, ten-year project that yielded the first inventory of microbial diversity in the world’s oceans.
And, perhaps not surprisingly, the HMP discovered that microbial distributions in the human body are not so different from those in ocean ecosystems.
Whether in the human gut, mouth, or vagina, the Pacific Ocean or the Sargasso Sea, microbial communities contain a few highly abundant bacterial types plus many, many more low-abundance types (the so-called "rare biosphere," a phenomenon first discovered in ocean samples by Sogin and his MBL colleagues).
"The more closely we look, the more bacterial diversity we find," Huse says. "We can’t even name all these kinds of bacteria we are discovering in human and environmental habitats. It’s like trying to name all the stars." HMP researchers concluded that an estimated 10,000 bacterial species occupy the human microbiome.
This illustration shows the body sites that were sampled from volunteers for the Human Microbiome Project, part of the National Institutes of Health’s Roadmap for Medical Research. Credit: Courtesy of NIH Medical Arts and Printing
The HMP also confirmed that in people, like in the ocean, which bacteria are abundant and which are rare varies from site to site. The common bacterium Bacteroides, for instance, can comprise nearly 100% of the microbes in one person’s gut, yet be barely present in another’s.
"What this means is, there is not just one way to be healthy, " says Huse. "There doesn’t have to be one or two ‘just right’ gut communities, but rather a range of ‘just fine’ communities."
Another key finding of the HMP is that nearly everyone carries pathogens—microbes known to cause illness. In healthy individuals, however, pathogens cause no disease; they simply co-exist with the rest of the rare and abundant microbes in the person’s microbiome. Researchers now must figure out why some pathogens turn deadly and under what conditions, likely revising current concepts of how microorganisms cause disease.
"It’s really important to understand how and why these rare organisms ‘swing,’" Huse says. "And one of the problems we have is people take antibiotics, which really change the microbiome. Antibiotics can kill the abundant bacteria, which then allows the rare bacteria to flourish in a gut environment full of food. If the rare bacteria include a pathogen, then you can get sick."
The HMP employed two major strategies to characterize the microbes in 18 different sites in the mouth, nose, skin, vagina, and stool of the volunteers. The first strategy told them "who" was there. Called 16s rRNA tag sequencing, the MBL first adapted this method for "next-generation" sequencing in the mid-2000s, in order to identify which microbes were present in ocean samples and their relative abundances. (Next-generation sequencing produces large volumes of sequencing data much more inexpensively than traditional methods.) The second strategy the HMP adopted, called shotgun sequencing, was employed to find out what functions the microbes might be performing.
"Now we have a list of ‘who’ is in the human microbiome, and another list of what they are doing. Part of the task ahead is to tie together which organisms are doing what functions," Huse says.
Understanding how people are the same, despite the variations in their microbiomes, is another significant challenge for future investigation. "At some level there have to be similarities, because we are all eating and digesting and so forth," Huse says. "Perhaps the different aspects of digestion and immune system interaction can be performed by a variety of different assemblages of bacteria."