For years, bacteria have had a bad name. They are the cause of infections, of diseases. They are something to be scrubbed away, things to be avoided.
But now researchers have taken a detailed look at another set of bacteria that may play even bigger roles in health and disease: the 100 trillion good bacteria that live in or on the human body.
No one really knew much about them. They are essential for human life, needed to digest food, to synthesize certain vitamins, to form a barricade against disease-causing bacteria. But what do they look like in healthy people, and how much do they vary from person to person?
In a new five-year federal endeavor, the Human Microbiome Project, which has been compared to the Human Genome Project, 200 scientists at 80 institutions sequenced the genetic material of bacteria taken from nearly 250 healthy people.
They discovered more strains than they had ever imagined — as many as a thousand bacterial strains on each person. And each person’s collection of microbes, the microbiome, was different from the next person’s. To the scientists’ surprise, they also found genetic signatures of disease-causing bacteria lurking in everyone’s microbiome. But instead of making people ill, or even infectious, these disease-causing microbes simply live peacefully among their neighbors.
The results, published on Wednesday in Nature and three PLoS journals, are expected to change the research landscape.
The work is “fantastic,” said Bonnie Bassler, a Princeton University microbiologist who was not involved with the project. “These papers represent significant steps in our understanding of bacteria in human health.”
Until recently, Dr. Bassler added, the bacteria in the microbiome were thought to be just “passive riders.” They were barely studied, microbiologists explained, because it was hard to know much about them. They are so adapted to living on body surfaces and in bodycavities, surrounded by other bacteria, that many could not be cultured and grown in the lab. Even if they did survive in the lab, they often behaved differently in this alien environment. It was only with the advent of relatively cheap and fast gene sequencing methods that investigators were able to ask what bacteria were present.
Examinations of DNA sequences served as the equivalent of an old-time microscope, said Curtis Huttenhower of the Harvard School of Public Health, an investigator for the microbiome project. They allowed investigators to see — through their unique DNA sequences — footprints of otherwise elusive bacteria.
The work also helps establish criteria for a healthy microbiome, which can help in studies of how antibiotics perturb a person’s microbiome and how long it takes the microbiome to recover.
In recent years, as investigators began to probe the microbiome in small studies, they began to appreciate its importance. Not only do the bacteria help keep people healthy, but they also are thought to help explain why individuals react differently to various drugs and why some are susceptible to certain infectious diseases while others are impervious. When they go awry they are thought to contribute to chronic diseases and conditions likeirritable bowel syndrome, asthma, even, possibly, obesity.
Humans, said Dr. David Relman, a Stanford microbiologist, are like coral, “an assemblage of life-forms living together.”
Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute, who was not involved with the research project, had another image. Humans, he said, in some sense are made mostly of microbes. From the standpoint of our microbiome, he added, “we may just serve as packaging.”
The microbiome starts to grow at birth, said Lita Proctor, program director for the Human Microbiome Project. As babies pass through the birth canal, they pick up bacteria from the mother’s vaginal microbiome.
“Babies are microbe magnets,” Dr. Proctor said. Over the next two to three years, the babies’ microbiomes mature and grow while their immune systems develop in concert, learning not to attack the bacteria, recognizing them as friendly.
Babies born by Caesarean section, Dr. Proctor added, start out with different microbiomes, but it is not yet known whether their microbiomes remain different after they mature. In adults, the body carries two to five pounds of bacteria, even though these cells are minuscule — one-tenth to one-hundredth the size of a human cell. The gut, in particular, is stuffed with them.
“The gut is not jam-packed with food; it is jam-packed with microbes,” Dr. Proctor said. “Half of your stool is not leftover food. It is microbial biomass.” But bacteria multiply so quickly that they replenish their numbers as fast as they are excreted.
The bacteria also help the immune system, Dr. Huttenhower said. The best example is in the vagina, where they secrete chemicals that can kill other bacteria and make the environment slightly acidic, which is unappealing to other microbes.
Including the microbiome as part of an individual is, some researchers said, a new way to look at human beings.
It was a daunting task, though, to investigate the normal human microbiome. Previous studies of human microbiomes had been small and had looked mostly at fecal bacteria or bacteria in saliva in healthy people, or had examined things like fecal bacteria in individuals with certain diseases, like inflammatory bowel disease, in which bacteria are thought to play a role.
But, said Barbara B. Methé, an investigator for the microbiome study and a microbiologist at the J. Craig Venter Institute, it was hard to know what to make of those studies.
“We were stepping back and saying, ‘We don’t really have a population study. What does a normal microbiome look like?’ ” she said.
The first problem was finding completely healthy people for the study. The investigators recruited 600 subjects, ages 18 to 40, poking and prodding them. They brought in dentists to probe their gums, looking for gum disease, and pick at their teeth, looking for cavities. They brought in gynecologists to examine the women to see if they had yeast infections. They examined skin and tonsils and nasal cavities. They made sure the subjects were not too fat and not too thin. Even though those who volunteered thought they filled the bill, half were rejected because they were not completely healthy. And 80 percent of those who were eventually accepted first had to have gum disease or cavities treated by a dentist.
When they had their subjects — 242 men and women deemed free of disease in the nose, skin, mouth, gastrointestinal tract and, for the women, vagina — the investigators collected stool samples and saliva, and scraped the subjects’ gums and teeth and nostrils and their palates and tonsils and throats. They took samples from the crook of the elbow and the folds of the ear. In all, women were sampled in 18 places, including three sites in the vagina, and men in 15. The investigators resampled subjects three times during the course of the study to see if the bacterial composition of their bodies was stable, generating 11,174 samples.
To catalog the body’s bacteria, researchers searched for DNA with a specific gene, 16S rRNA, that is a marker for bacteria and whose slight sequence variations can reveal different bacterial species. They sequenced the bacterial DNA to find the unique genes in the microbiome. They ended up with a deluge of data, much too much to study with any one computer, Dr. Huttenhower said, creating “a huge computational challenge.”
The next step, he said, is to better understand how the microbiome affects health and disease and to try to improve health by deliberately altering the microbiome.
But, Dr. Relman said, “we are scratching at the surface now.”
It is, he said, “humbling.”