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The Evolving Human Microbiome

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It is estimated that there are 10 times as many microbes in and on any given human as there are cells in that person's body. The microbiome is its own world, teeming with life so small and complex that it may never be possible to account for it all. Hundreds of researchers are spending hundreds of millions of dollars to study the thousands of bacteria that live in and on humans, animals, and their environments. The impact that these tiny organisms have on human health is only just beginning to be understood, as is their potential to both cause and ameliorate disease.

The questions of which diseases are affected by microbes, how, and to what extent are beginning to be asked, and the advent of cheaper sequencing methods is enabling researchers to find and analyze dozens of new species. But experts say it will be many years before there is a clear picture of the depth and breadth of the influence of microbes on human lives. The Human Microbiome Project, an initiative of the US National Institutes of Health, was launched in 2008 with a total budget of $157 million, and the mission of sequencing, characterizing, and analyzing as much of the human microbiota as possible in five years — as well as elucidating its role in matters of human health. But unlike traditional microbiology, which deals with the various microbial species individually, part of HMP's mission is to learn about microbes through metagenomics, and to study how the microbes act and interact in their communities and their environment.

The project has multiple components, says Jane Peterson, an associate director at the NHGRI Division of Extramural Research and an HMP program director. One group was tasked with collecting bacterial samples from five sites — the mouth, nasal cavity, skin, gut, and, in women, vagina — of healthy donors, and then comparing the various microbial communities found at each site.

The HMP also funded 15 demonstration projects for one year to look at the microbiome in correlation to human health. Several of those efforts dealt with the effects of microbes on obesity, diabetes, Crohn's disease, ulcerative colitis, and several skin and sexually transmitted diseases. In September, the HMP awarded a total of $42 million to eight of the projects so the researchers could continue their studies.

In addition, HMP's Data Analysis and Coordination Center serves as the central repository for all the data and sequenced genomes collected by researchers, Peterson says. The project is also looking to fund technology that is being developed to isolate and study the organisms that cannot be cultured in a lab.
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The most important priority for the project at this point is to sequence, sequence, sequence. "In order to do these kinds of metagenomic sequencing studies, you take a whole gemish of bacteria from someplace and you don't sequence bacteria-by-bacteria — you sequence all the DNA that's there," Peterson says. "Another part of the center's mission is to get more reference genomes into the central database so that when you do this gemish sequencing, you have something to refer back to, and you can pull out the known sequences and identify the unknowns."

Last May, the HMP reported an analysis of 178 microbial genomes in Science that had not been published before. The researchers also discovered 29,693 unique microbial proteins in the HMP reference collection, and 14,064 novel proteins from microbial genomes in public databases — new genes and proteins serving functions in human health. When the analysis was announced, NIH Director Francis Collins called the work "critical" to understanding the roles microbes play in humans. Though the initiative is still in a relatively early stage, project leaders hope that the reference collection will continue to grow from the initial 178 genomes analyzed. The ultimate goal is to expand the collection to about 900 bacterial, viral, and fungal genomes.

As sequencing becomes cheaper, researchers will be able to sequence deeper and deeper until they hit a plateau, Peterson says. That will not mean that they have found every kind of bacteria there is to find — something Peterson says would be almost impossible to determine — but it would bring them closer to the ultimate goal of understanding the microbiome's diverse populations.

"We're discovering all kinds of microbes everywhere we look, and just trying to understand what they do and give names to all of them is really a key challenge for the field at the moment," says Rob Knight at the University of Colorado.

Controlling microbes

Learning the shape and function of the human microbiome will eventually lead researchers to the question of how to control it. If certain microbes cause or exacerbate diseases such as obesity, Crohn's disease, and ulcerative colitis, it would seem that one way to help treat or cure these diseases would be through influencing those microbial populations.

Boston University biomedical engineer James Collins and his colleagues are experimenting with synthetic biology to create an on/off switch for microbes, enabling scientists to control the amount of certain proteins that they produce. The group's paper in PNAS describes the switch, which is created with DNA sequences that can be added to genes such that when the mRNA is transcribed, it creates a cis sequence that binds to the ribosome binding site, preventing the ribosome from attaching and producing a protein. But, Collins says, the switch can be turned back to the "on" position, allowing the ribosome to once again produce the protein in question. The "on" component of the switch produces a short, non-coding RNA that binds to the cis-repressed sequence and pulls it off the ribosome binding site.

The switch can even be tuned "like a rheostat or light dimmer, so you can go from effective off — it has incredibly low leakage — to very high levels of expression," Collins says. The switch could even be used as a biotech tool, where it could help researchers tightly regulate certain genes in order to explore their actions or tune the protein expression of certain genes to serve a number of different applications.

Collins says a few biotech companies have expressed interest in the kill switch. It does not currently have applications for humanhealth, simply because the researchers are still trying to find a way to introduce the switch to an already-existing microbial population. However, he adds, once the idea moves into the application phase, it's more than likely that researchers will fine-tune the application of this switch to human health issues.
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Until more complicated systems of control are perfected, other researchers are taking a more direct route. Colorado's Knight recently collaborated with researchers in Spain on a study analyzing the possibilities of reshaping the gut microbiome of rats to treat bowel diseases like Crohn's. Efforts to reshape the gut microbiome of a given organism with antibiotics and probiotics have shown little positive effect over the long term. The researchers, who published their work in Genome Research in July, thought a more effective way to readjust the gut bacteria would be to transplant gut bacteria from a healthy donor to an ill recipient.

But when they experimented with using antibiotics to kill off the existing microbiome in an ill rat before a transplant from a healthy donor rat, they found something unexpected. "What was specifically important about [the experiment] was that one important question: If you clear out the microbiome that already exists before doing a transplant, would the new microbes find it easier to colonize?" Knight asks. "And the answer, surprisingly, turned out to be no." When all the data was analyzed, it became clear that the antibiotics were counterproductive, because they killed off the donor microbes instead of giving them a clean slate on which to flourish. The researchers' current thinking is that the new microbes are vulnerable to antibiotics for a period of time after implantation, and that perhaps leaving a longer period of time between the administration of antibiotics and the transplant of healthy microbes would reduce the likelihood of their being wiped out. Knight's Spanish collaborators are continuing their work on this idea, experimenting with different time periods between administration of antibiotics and microbial transplants to find an ideal interval.

The antibiotic conundrum

But some researchers say that our dependence on antibiotics, whether in the clinic or the lab, is precisely the problem. Antibiotic-resistant super-bugs like MRSA and VRSA are causing problems for doctors because they cannot be eradicated by conventional means. It has been argued that the bugs have evolved because people are prescribed antibiotics too frequently and for too many reasons.

At the Swedish Institute for Infectious Disease Control, Cecilia Jernberg and her collaborators are arguing against the indiscriminate use of antibiotics. Antimicrobial compounds are everywhere, Jernberg says, from the pharmaceuticals used by both humans and animals to animal feed and to clothing. Bacteria also naturally produce these compounds as a defense mechanism against other microbes that compete with them for space and nutrients. Bacteria evolve to resist these compounds, so the higher the concentrations — as in an antibiotic administered by a doctor — the more resistant the evolved bacteria become. "For a bacterium to survive, it can be necessary to develop these more specific resistance mechanisms either by incorporating resistance genes into the genome, or carrying them on plasmids, or by mutations," Jernberg says. "Mobile genetic elements like plasmids can be easily shared among bacteria, even between different species, increasing the risk of spread of these resistance mechanisms."

In her research, Jernberg found that healthy subjects that had not taken any antibiotics for at least one year still carried resistant genes in their gut flora. And when they administered a seven-day antibiotic course to test subjects, the researchers found high levels of resistance genes up to two years post-treatment. "These bacterial strains can survive for years and the next time they are exposed to the drug, they will be able to multiply quickly due to the selection pressure ... thereby increasing the level of resistance genes in the gut and increasing the risk of spread of these genes to pathogenic bacteria," she says. If this trend continues, over the long term there will be an increase in antibiotic--resistant bacteria, and there may come a time when bacterial infections can no longer be treated conventionally. Even if resistance develops in non-pathogenic strains of bacteria, they can then pass those genes on to the pathogenic strains, creating more so-called superbugs, Jernberg adds.
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Just the beginning

For all researchers have already learned about the human microbiome, there is still endless work to do, and there are endless questions to ask. "You can ask about geographical areas, you can ask about children versus adults, you can ask about vaginally -delivered babies versus Caesarian sections, you can ask about diet changes," says HMP's Peterson. "In a way, it's just a never-ending area where someone can always come in and say, 'Well, I want to look at the microbiome in this condition.' And I think it's going to be years before we know all the differences that can be observed."

Colorado's Knight is involved in dozens of microbial studies, from tracking individuals to figure out the stability of microbial communities over time; to studying families to discover the extent to which the people one lives with influences one's microbial makeup; to studying identical twins (who, for all their identical DNA, never have identical microbes); as well as studies on Crohn's disease, obesity, and ulcerative colitis. "Microbes dominate the planet, both numerically and in biomass, so it shouldn't be that surprising that they're involved in just about every aspect of life," Knight says.

Even the criminal investigation field could reap benefits from microbial studies, as researchers are finding ways to identify who has touched a particular object by the composition of the skin microbes left behind.

Whatever the outcome of continuing studies, Knight says the impact of such experiments on human health will be far-reaching. "It's becoming increasingly appreciated that a lot of different diseases — from obesity to diabetes — have a microbial dimension to them, and being able to control those microbial communities could allow us to diagnose diseases much earlier, and potentially allow us to cure a lot of polyfactorial diseases that are difficult to get a handle on at the moment," Knight says.

Peterson likens microbial studies to "looking at a new planet for the first time." And, she adds, "finding all these new genes and hopefully being able to look at how they're expressed really is groundbreaking."

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