Our bodies are teeming with life – trillions of microbes occupy virtually every surface – inside and out. They even outnumber our own cells ten to one. And much like our planet has its ecosystem of plants and animals interacting with their environments, we have our own microscopic one filled with living organisms that inhabit our bodies’ diverse environments.
“Our bodies are part of a microbial world,” says Dr. George Weinstock, associate director of The Genome Institute. “You can think of our ecosystems like you do rain forests and oceans, very different environments with communities of organisms that possess incredible, rich diversity.”
Most of the time this microbial ecosystem coexists peacefully with us. Many of our microbes help us digest food, strengthen our immune systems and even protect us from dangerous pathogens. But it has proven very difficult to study many of these microbes, which differ depending on body site and individual. The microbes are also difficult to isolate and grow in the lab. As a result, researchers have understood little about which microbes reside in specific sites of the body. Now, a consortium of some 200 U.S. scientists at Washington University School of Medicine in St. Louis and elsewhere report findings from the most comprehensive census of the microbial makeup of healthy humans.
Published June 14 in Nature and in several Public Library of Science (PLoS) journals, the research offers new details and even some surprises.
For example, the researchers found that even healthy people typically carry low levels of harmful bacteria in and on their bodies. But when a person is healthy, these pathogens don’t cause disease; they simply coexist in an abundance of beneficial microbes. Now, scientists can investigate why some pathogens can suddenly turn deadly, an endeavor that will refine current thinking on how microorganisms cause disease.
“It’s not possible to understand human health and disease without exploring the massive community of microorganisms we carry around with us,” says Dr. Weinstock, one of the project’s principal investigators. “Knowing which microbes live in various ecological niches in healthy people allows us to better investigate what goes awry in diseases that are thought to have a microbial link, like Crohn’s, acne, periodontitis, vaginosis, or urethritis, and why dangerous pathogens sometimes, but not always, cause life-threatening illnesses.”
The Genome Institute played a major role in the new research, known as the Human Microbiome Project. The five-year initiative was funded with $153 million from the National Institutes of Health (NIH), with some $32 million coming to the university. TGI scientists decoded about half of the 5,000 specimens from nearly 250 healthy volunteers.
To get a handle on the healthy human microbiome, the researchers sampled 15 body sites in men and 18 in women, including areas of the mouth (nine sites, including the teeth), skin (two behind the ear and each inner elbow), nose, vagina (three sites) and lower intestine (stool). In St. Louis, most samples were collected from study participants enrolled at the School of Medicine. Teeth and gum samples were collected at Saint Louis University’s dental school. Other samples came from Baylor College of Medicine in Houston, the other site that enrolled study participants.
In all, the scientists identified more than 10,000 species of microbes that occupy the human ecosystem, documenting the impressive diversity of microbial life in the human body with more accuracy than earlier studies.
Using new genomic techniques, TGI assistant directors Dr. Erica Sodergren and Dr. Makedonka Mitreva, took an inventory of the microbes in the samples. One approach involved sequencing a gene found in all bacteria. "This gene, 16S rDNA, serves as a barcode of life to indicate which species are there and their prevalence in the microbial community," says Dr. Sodergren. Another approach included sequencing the DNA of entire microbial communities in a subset of samples. "With this information, we could identify viruses, fungi and other non-bacterial organisms and put together a catalog of all the genes present in the samples," Dr. Mitreva says.
The researchers noted unique communities of microbes in every site in the body. Interestingly, the microbial communities that live on the teeth are different from those in saliva. And the most diverse collection of microbes was found to live on the skin, which might be expected because it is the body’s barrier to the outside world.
The scientists also reported that the body’s collection of microbes contributes more gene activity to human health than humans themselves. While the human genome includes some 22,000 genes, it’s a mere fraction of the 8 million genes that are part of the human microbiome.
These microbial genes are critical to good health. Those in the gastrointestinal tract, for example, allow humans to digest foods and absorb nutrients that our bodies otherwise could not handle. Microbial genes also produce vitamins and compounds that naturally suppress inflammation in the intestine.
Also, confirming earlier, smaller studies, the new research shows that components of the human microbiome clearly change during an illness. When a patient is sick or takes antibiotics, the species of the microbiome may shift substantially as one bacterial species or another is affected. Eventually, however, the microbiome settles into a steady state, even if the previous composition is not completely restored.
As part of the Human Microbiome Project, the NIH funded a number of studies to look for links between particular communities of microbes in the body and illness. Results of some of this research, reported in PLoS, underscore the clinical applications of microbiome research to improve human health.
At Washington University, researchers led by Dr. Gregory Storch, Professor of Pediatrics, examined the microbes in the noses and blood of children who developed sudden, high fevers that couldn’t be traced to a specific cause. Unexplained fever is a common problem in children under age 3, and they are often treated with antibiotics as a precaution, which contributes to antibiotic resistance.
Dr. Storch and his colleagues, including Dr. Kristine Wylie, a postdoctoral research associate at The Genome Institute, found that specimens from the sick kids contained more total viral DNA and more species of viruses, some of them potentially novel, than children without fever, who also were included in the study as a comparison.
“We found things we did not expect to see,” says Dr. Wylie, including the discovery of astrovirus in the children with fever, a viral type that causes childhood diarrhea and one that had not been previously found in blood. The researchers also showed that children without fever carried viruses, though in lower numbers. They plan to follow up this work with the most extensive characterization of viruses to date of healthy people. Understanding the difference between viral infections with and without fever will be important in applying microbiome techniques in the clinic, the scientists say.
In another project, Dr. Weinstock, Dr. Wylie and their colleagues, along with Dr. Katherine Pollard and her team at the University of California, San Francisco, identified previously unknown types of microbes in stool samples from 11 healthy individuals. Stool samples are among the most well-characterized of any from the Human Microbiome Project, yet the group was still able to discover new bacteria. While these new, not-yet-named microbes were found in relatively low levels, the research indicates they may be quite common because they were found in multiple volunteers.
And in research at St. Louis Children’s Hospital, Dr. Phillip Tarr, Professor in Pediatrics, and neonatologist Dr. Barbara Warner, and others are investigating whether a life-threatening gastrointestinal illness in premature babies is linked to microbes in the intestinal tract. Necrotizing enterocolitis affects about 10 percent of premature babies, usually in the first month of life, and is fatal in 15 percent to 30 percent of cases. The researchers are collecting stool samples from premature babies to identify and quantify differences between the microbial communities of the infants who develop the illness and those who don’t. This information may provide a foundation for developing ways to prevent or cure the illness.
NIH has funded a number of other medical studies using HMP data and techniques that TGI is involved in, including: the role of the gut microbiome in Crohn’s disease; the skin microbiome in acne; and the urogenital microbiome in sexually transmitted infections.
“The future of microbiome research is very exciting,” Weinstock says. “This large-scale effort will open doors in many areas of medicine to improve our understanding of good health and the treatment and prevention of disease.”
All the data collected on the human microbiome is uploaded to a central repository called the Data Analysis and Coordination center (http://hmpdacc.org) and is available for free to the scientific community.
Other TGI scientists who contributed to the work include: Sahar Abubucker, Elizabeth Appelbaum, Veena Bhonagiri, Darina Cejková, Lei Chen, Kimberley D. Delehaunty, David J. Dooling, Candace N. Farmer, Catrina C. Fronick, Lucinda L. Fulton, Robert S. Fulton, Hongyu Gao, Kymberlie Hallsworth-Pepin, Brandi Herter, Vincent Magrini, Elaine R. Mardis, John C. Martin, Kathie A. Mihindukulasuriya, Patrick J. Minx, Makedonka Mitreva, Maze Ndonwi, Michelle O’Laughlin, Craig Pohl, Erica J. Sodergren, Michal Strouhal, Chad M. Tomlinson, Jason Walker, Wesley Warren, George M. Weinstock, Richard K. Wilson, Aye M. Wollam, Kristine M. Wylie, Todd Wylie, Guohui Yao & Yanjiao Zhou.