The microbes that inhabit our bodies are intimately involved in human health and disease yet we still know relatively little about them. A new major census of these tiny symbionts has revealed that they are an even more diverse bunch than was once presumed.
We have long focused on single bacteria as sources of disease (E. coli or streptococcus, for example). But we have now been learning that, for the most part, these trillions of microbes that make their homes in and on us do an excellent job keeping us healthy (crowding out harmful microbes) and sated (breaking down a lot of the food we ingest).
Now that disturbances in this rich microbiome community have been linked to weight gain, inflammatory bowel disease, vaginal infections and risk for infection with harmful microbes (such as methicillin-resistant Staphylococcus aureus, or MRSA), the importance of understanding what makes up a "healthy" microbiome has become even more apparent.
We have been adding names to the attendee list for years, but scientists still do not have a full rundown of all of the bacteria, where they live in our bodies and their role in health and disease. "We need a reference to say what is normal before we can say what is abnormal," Eric Green, director of the National Human Genome Research Institute, said in a press briefing Wednesday.
Green and his colleagues at the Human Microbiome Project have taken a big step forward in charting this complex territory, publishing an extensive new survey of the microbial profiles of hundreds of individuals. The findings are described in two papers and an essay online June 13 in Nature and in more than a dozen papers in PLoS ONE. (Scientific American is part of Nature Publishing Group.) The findings only reinforce the suspicion that this invisible landscape is even more nuanced—and important—than we thought. For example, each person might carry around hundreds of thousands of species. These bugs bring with them some eight million different genes, which far outshines our own paltry 22,000.
"This is really a new vista on biology," Phillip Tarr, director of pediatric gastroenterology and nutrition at Washington University School of Medicine in Saint Louis and a collaborator on the research, said in the press briefing. "It opens up many opportunities to improve the health of our population."
To get their results, the team collected samples from 242 healthy adults aged 18 to 40 living in Houston or Saint Louis. From each person, researchers sampled 15 to 18 specific "habitats" (nine from the mouth, four from the skin, one from the nose and three from the female genitals) as well as from stool samples.
"Healthy humans carry a remarkable diversity of organisms," says Bruce Birren, director of the Genomic Sequencing Center for Infectious Diseases at the Broad Institute and study collaborator, said at the briefing. The oral and fecal samples had the highest microbe diversity, whereas the vaginal samples had the lowest.
Each person had a relatively different microbiome, reinforcing the notion that there is no single "healthy" microbiome profile. "Apparently there are many different ways to be healthy when it comes to our microbes," Birren said. The group found that even with so many different microbial communities at each location, the same metabolic functions seem to be getting done. Birren likens it to a potluck dinner, where everyone brings something different to the table so everyone gets to eat.
More than half of the study subjects had samples collected a month to a year following the initial collection and some had three samples taken. In general, microbial populations present in the first sample were there in the last one as well and did not show any big blooms in the study subjects.
Getting a sense of which microbes are living in our intestines turns out to be a much more complicated task than simply looking at slides under a microscope. Many of the microbes that live inside our bodies don't do well in an oxygen-filled lab environment, so they have proved difficult to culture. This project sidestepped that problem by using genetic sequencing to catalogue species by their genetic profiles instead.
The question, however, of how to measure, track and count these organisms that we know so little about also presents some research dilemmas. One method researchers used to identify different species involves tracking the bacterial 16s gene, which humans lack. This gene appears to be different enough in each bacterial species to allow for rapid scanning and sorting of the organisms. The effectiveness of this detection method remains unclear. "In some ways, we're simply counting different features that are easiest for us to measure, but we don't know that those are the most important things," says David Relman, of the Stanford School of Medicine, who was not involved in the new studies but wrote an essay about them in the same issue of Nature.
Nevertheless, Relman notes, the findings are important early first steps, which will help inform and streamline later research. "I think it would be hubris to say this project answers something or provides the end of the story," he says. Coming work will need to zero in on individual variables, such as diet, environment and health status, to look more closely for trends in microbiome communities.
Tarr suggested that better understanding what a healthy microbiome looks like, for example, could help us prevent virulent infections, such as Clostridium difficile. C. diff is often acquired in a hospital. Our best preventative weapon so far has been better hygiene, and our treatments are only mediocre. But, he noted, if we could find out the characteristics of a microbiome that puts people more at risk for acquiring a difficult C. diff infection, we could theoretically screen incoming patients for their microbiome's genetic profile at admission, heading off potentially fatal infections.
These "who's who" lists of our microbiome "are potentially useful and biologically important as a frame of reference, but they do not tell you what the microbes are actually doing at any one time," notes Jeremy Nicholson, head of the Department of Surgery and Cancer at Imperial College London, who was not involved in the most recent studies. He and his colleagues published a study in Science last week examining some of the metabolic interactions of the microbes in the human gut and their host. "To understand them functionally as part of the big human health picture," he notes, we will need a more detailed picture of how human diet and lifestyles—including stress and medications—are impacting the microbial communities, along with how their changes are then changing us. "Understanding these interactions is where the new therapies are to be found."
Another study, published online today in Nature, reveals how a diet high in saturated fat can, in fact, change the microbial communities in the gut. This shifting population can spur an immune response that can lead to inflammatory bowel disease in those who are genetically prone.
A better picture of these kinds of interactions should help us better understand how microbes help us metabolize food as well as drugs, Nicholson notes. "So the sky is the limit in terms of potential therapeutic interventions if we can understand all this complexity," he says. "This is going to be a major part of personalized health care in the future."
For another Human Microbiome Project collaborator, Baylor College of Medicine's Amy McGuire, the findings of the vast accumulation of varied microbes that live in all of us presents an additional existential facet: "It changes how we think about what it means to be human."