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Human Microbiome Project will improve knowledge about microbes’ effects on human health
Comprehensive study of microbial communities may lead to sweeping discoveries.
BOSTON — It is estimated that there are 10 times as many microbial cells as human cells within the human body, according to researchers who spoke at a press conference at the 108th General Meeting of the American Society for Microbiology.
The influence of these microbes on human health, immunity, nutrition, physiology and development, however, is largely unknown. To further understand the roles that microbes play and how they affect human health, the Human Microbiome Project has been launched.
Researchers involved in the Human Microbiome Project, which is part of the NIH Roadmap for Medical Research, will comprehensively study these microbial communities. The project largely came as a result of advances in DNA sequencing technologies that have allowed researchers to analyze genetic material derived from microbial communities harvested from natural environments like the human body. Specifically, the project will involve the study of microbes from the gastrointestinal and female urogenital tracts, the oral cavity, nasal and pharyngeal tracts and the skin. Similar projects are planned or are underway in other nations and regions of the world.
Due to the vastness of the project, there are many unanswered questions surrounding the implications of and potential discoveries that may come from this undertaking. These unanswered questions have led to a great deal of speculation about microbiology and its relationship to human health.
Variability
Claire Fraser-Liggett, PhD, professor of medicine, microbiology and immunology and director of the Institute for Genome Sciences at the University of Maryland in Baltimore, said: “Some are calling this the second Human Genome Project. If you make some assumptions about the 10-1 ratio of microbial cells to human cells in the human body, that translates into at least 1,000 times as many microbial genes as human genes.”
Although researchers initially thought it was possible to categorize the kinds of microbial communities that can be found in certain areas of the body, the amount of variability that has been observed recently has presented some substantial challenges to discovery.
This opinion was expressed by the other two researchers at the press conference, Martin Blaser, MD, Frederick H. King Professor of Internal Medicine, chairman of the department of medicine and professor of microbiology at New York University; and David Relman, MD, professor of medicine, infectious diseases, microbiology and immunology at Stanford University.
Blaser’s research has focused on the skin. “We swabbed the forearm skin of six people. There were 12 arms. We found 182 species of microbes representing seven different phyla,” he said. “Recently, another group studied skin from the crook of the elbow, just a few centimeters away from the site of our study, and found an entirely different microbial population. In our studies, we found 91 different genera, but only five of them were present in all six individuals. Sixty-one were present in just one individual, indicating a very high level of intrahost variability. Further, we looked at the same individuals eight to 10 months later and found that their microbial populations were no more similar to their own arms than to somebody else’s arm.”
Relman has made similar observations in his research, although the emergence of an individual-specific pattern is more apparent at internal mucosal sites. “We would love to know how and why the microbial communities vary from person to person, within a person from one point in space to another, or over time. Depending upon where you are in the human body, whether you are in the skin or the gut, or any of a variety of places within the gut or the mouth, whether you are on one tooth or the next tooth, the patterns of diversity differ,” he said. “A major goal will be to define the rules and factors that govern microbial biogeography within the human body.”
Microbacterial fingerprinting
Despite this variability, the researchers discussed the finding that the microbial communities are beginning to exhibit patterns that define both individuals and various species as a whole. Margaret McFall-Ngai, PhD, professor of medical microbiology and immunology at the University of Wisconsin at Madison, spoke to Infectious Disease News on the subject. “There is every indication that we have evolved with our microbial partners,” she said. “They are likely to have been integrated into our normal physiology.”
McFall-Ngai cited laboratory work led by Jeremy Nicholson. Nicholson is attempting to identify metabolic signatures on people to make designer drugs. He looked at the biochemical signature of blood, sweat and urine samples from humans. He found that the biochemical signature is largely microbial. It comes from the high metabolic rate and high activity of all the microbes in and on the human body.
“We are now starting to figure out whether an individual has a microbial signature, whether we as a species have a microbial signature,” McFall-Ngai said.
Up to this point, many researchers have focused primarily on identifying the microbes genetically. But researchers are beginning to think that a more comprehensive approach to the study of the communities could lead to a more thorough understanding of both the microbes themselves and how the communities relate to the individual.
“During the next few years, with funding and research, we will find data to help sort out the signal from the noise,” Fraser-Liggett said. “But I am not entirely convinced that taking a census based on 16S ribosomal RNA is the only way to find out all we are going to find out about these microbial communities. There may be functional redundancy built into these communities. We should begin to look at function in parallel as we begin to ask the question about which microbes are there. Maybe some of the answers we are looking for are at the functional level rather than at the 16S level. But this is only speculation.”
If understanding the function of the microbes can help define an individual’s signature, familiarity with the signature can influence treatment.
McFall-Ngai again cited Nicholson’s research. She offered some opinions about what may be happening at the microbiological level and how this can impact treatment methods. “The microbes act on the chemicals that go into your body. They take in compounds, alter them, and then you take them up as something altered or something the same depending on the individual’s microbial signature.”
Fraser-Liggett also commented on the potential influence this signature may have on treatment methods. “The Human Microbiome Project could eventually become the ultimate definition of personalized medicine,” she said.
Many researchers involved in the project have a hard time foreseeing just how dramatically this research could influence medical practice.
In an interview with Infectious Disease News, Lora Hooper, PhD, assistant professor at the Center for Immunology and Microbiology at the University of Texas Southwestern, had as many questions as answers regarding the overwhelming nature of the project and its potential implications. “We have 100 trillion bacteria in our guts and they are supposed to be there,” she said. “How do these bacteria talk to the host, and how does the host talk back to them in terms of the immune system? How does the immune system corral these bacteria and keep them from causing disease?”
The project may lead to an entire re-evaluation of how to deal with pathogens.
“We need to think of communities as the pathogen,” Relman said. “There are many chronic diseases where there is no one organism or handful of organisms that suffice to explain the disease, so maybe a particular disturbance in the microbial community structure should be viewed as the pathogenic factor.”
This way of thinking can lead to changes in treatment. “Think about resistance and resiliency of community structure,” Relman said. “How do we reinforce the microbial community? I think there will be some important clinical applications that come of all this in the areas of diagnostics and prognostics, for example. Community profiles will help predict disease and flare ups. Treatment may involve restoring the numbers of a microbial community or treating members of the community to restore them to their original state,” he said.
McFall-Ngai said: “This is the only place in human health where the physician’s starting place is pathogenesis. In our interactions with microorganisms, we do not look at the normal state as the starting point and then attempt to figure out what has happened to cause a disease. We are looking at the microbiota as pathogens,” she said.
Further complicating matters are the indirect and more distant effects of the microbial communities. Although there are often direct correlations between microbes in certain places and the diseases they cause, researchers are beginning to find that the influence of these communities spreads far beyond their immediate area. “Of course microbes in the gastrointestinal tract may play a role in colon cancer, inflammatory bowel disease and obesity, but we are seeing signs that they may reach beyond their microbial environment into neurodevelopmental diseases such as autism,” Fraser-Liggett said.
Researchers expect similar discoveries to come about as findings from the project are published.
Future concerns
The researchers addressed the issue of antibiotic resistance problem as it relates to the Human Microbiome Project. Maintaining the health of the microbes may become more important in the future.
“Future strategies may have a large degree of differentiation. Depending on who you are and what your microbial communities are like, you may have different strategies for how to maintain the health of your microbial community,” Relman said.
“We should limit our exposure to antibiotics to the times when they are absolutely necessary,” Blaser said.
McFall-Ngai said that antibiotics should be a “last resort.”
The complex relationship of the microbial communities to the host may also affect the way clinicians view pathogens. Because of that, the way clinicians treat diseases may shift completely.
“If we are looking at shifts in commensal microbial communities as contributors to various disease states, whether they are causal or whether they provide a readout of the disease state, I do not think we know yet,” Fraser-Liggett said. “We may not be able to see an absolute distinction between health and disease in every situation.” – by Rob Volansky
For more information:
- For more information about the Human Microbiome Project, visit the NIH website at http://nihroadmap.nih.gov/hmp.