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    Jul242010

    How Microbes Defend and Define Us

    July 12, 2010

    Dr. Alexander Khoruts had run out of options.

    In 2008, Dr. Khoruts, a gastroenterologist at the University of Minnesota, took on a patient suffering from a vicious gut infection of Clostridium difficile. She was crippled by constant diarrhea, which had left her in a wheelchair wearing diapers. Dr. Khoruts treated her with an assortment of antibiotics, but nothing could stop the bacteria. His patient was wasting away, losing 60 pounds over the course of eight months. “She was just dwindling down the drain, and she probably would have died,” Dr. Khoruts said.

    Dr. Khoruts decided his patient needed a transplant. But he didn’t give her a piece of someone else’s intestines, or a stomach, or any other organ. Instead, he gave her some of her husband’s bacteria.

    Dr. Khoruts mixed a small sample of her husband’s stool with saline solution and delivered it into her colon. Writing in the Journal of Clinical Gastroenterology last month, Dr. Khoruts and his colleagues reported that her diarrhea vanished in a day. Her Clostridium difficile infection disappeared as well and has not returned since.

    The procedure — known as bacteriotherapy or fecal transplantation — had been carried out a few times over the past few decades. But Dr. Khoruts and his colleagues were able to do something previous doctors could not: they took a genetic survey of the bacteria in her intestines before and after the transplant.

    Before the transplant, they found, her gut flora was in a desperate state. “The normal bacteria just didn’t exist in her,” said Dr. Khoruts. “She was colonized by all sorts of misfits.”

    Two weeks after the transplant, the scientists analyzed the microbes again. Her husband’s microbes had taken over. “That community was able to function and cure her disease in a matter of days,” said Janet Jansson, a microbial ecologist at Lawrence Berkeley National Laboratory and a co-author of the paper. “I didn’t expect it to work. The project blew me away.”

    Scientists are regularly blown away by the complexity, power, and sheer number of microbes that live in our bodies. “We have over 10 times more microbes than human cells in our bodies,” said George Weinstock of Washington University in St. Louis. But the microbiome, as it’s known, remains mostly a mystery. “It’s as if we have these other organs, and yet these are parts of our bodies we know nothing about.”

    Dr. Weinstock is part of an international effort to shed light on those puzzling organs. He and his colleagues are cataloging thousands of new microbe species by gathering their DNA sequences. Meanwhile, other scientists are running experiments to figure out what those microbes are actually doing. They’re finding that the microbiome does a lot to keep us in good health. Ultimately, researchers hope, they will learn enough about the microbiome to enlist it in the fight against diseases.

    “In just the last year, it really went from a small cottage industry to the big time,” said David Relman of Stanford University.

    The microbiome first came to light in the mid-1600s, when the Dutch lens-grinder Antonie van Leeuwenhoek scraped the scum off his teeth, placed it under a microscope and discovered that it contained swimming creatures. Later generations of microbiologists continued to study microbes from our bodies, but they could only study the ones that could survive in a laboratory. For many species, this exile meant death.

    In recent years, scientists have started to survey the microbiome in a new way: by gathering DNA. They scrape the skin or take a cheek swab and pull out the genetic material. Getting the DNA is fairly easy. Sequencing and making sense of it is hard, however, because a single sample may yield millions of fragments of DNA from hundreds of different species.

    A number of teams are working together to tackle this problem in a systematic way. Dr. Weinstock is part of the biggest of these initiatives, known as the Human Microbiome Project. The $150 million initiative was started in 2007 by the National Institutes of Health. The project team is gathering samples from 18 different sites on the bodies of 300 volunteers.

    To make sense of the genes that they’re gathering, they are sequencing the entire genomes of some 900 species that have been cultivated in the lab. Before the project, scientists had only sequenced about 20 species in the microbiome. In May, the scientists published details on the first 178 genomes. They discovered 29,693 genes that are unlike any known genes. (The entire human genome contains only around 20,000 protein-coding genes.)

    “This was quite surprising to us, because these are organisms that have been studied for a long time,” said Karen E. Nelson of the J. Craig Venter Institute in Rockville, Md.

    The new surveys are helping scientists understand the many ecosystems our bodies offer microbes. In the mouth alone, Dr. Relman estimates, there are between 500 and 1,000 species. “It hasn’t reached a plateau yet: the more people you look at, the more species you get,” he said. The mouth in turn is divided up into smaller ecosystems, like the tongue, the gums, the teeth. Each tooth—and even each side of each tooth—has a different combination of species.

    Scientists are even discovering ecosystems in our bodies where they weren’t supposed to exist. Lungs have traditionally been considered to be sterile because microbiologists have never been able to rear microbes from them. A team of scientists at Imperial College London recently went hunting for DNA instead. Analyzing lung samples from healthy volunteers, they discovered 128 species of bacteria. Every square centimeter of our lungs is home to 2,000 microbes.

    Some microbes can only survive in one part of the body, while others are more cosmopolitan. And the species found in one person’s body may be missing from another’s. Out of the 500 to 1,000 species of microbes identified in people’s mouths, for example, only about 100 to 200 live in any one person’s mouth at any given moment. Only 13 percent of the species on two people’s hands are the same. Only 17 percent of the species living on one person’s left hand also live on the right one.

    This variation means that the total number of genes in the human microbiome must be colossal. European and Chinese researchers recently catalogued all the microbial genes in stool samples they collected from 124 individuals. In March, they published a list of 3.3 million genes.

    The variation in our microbiomes emerges the moment we are born.

    “You have a sterile baby coming from a germ-free environment into the world,” said Maria Dominguez-Bello, a microbiologist at the University of Puerto Rico. Recently, she and her colleagues studied how sterile babies get colonized in a hospital in the Venezuelan city of Puerto Ayacucho. They took samples from the bodies of newborns within minutes of birth. They found that babies born vaginally were coated with microbes from their mothers’ birth canals. But babies born by Caesarean section were covered in microbes typically found on the skin of adults.

    “Our bet was that the Caesarean section babies were sterile, but it’s like they’re magnets,” said Dr. Dominguez-Bello.

    We continue to be colonized every day of our lives. “Surrounding us and infusing us is this cloud of microbes,” said Jeffrey Gordon of Washington University. We end up with different species, but those species generally carry out the same essential chemistry that we need to survive. One of those tasks is breaking down complex plant molecules. “We have a pathetic number of enzymes encoded in the human genome, whereas microbes have a large arsenal,” said Dr. Gordon.

    In addition to helping us digest, the microbiome helps us in many other ways. The microbes in our nose, for example, make antibiotics that can kill the dangerous pathogens we sniff. Our bodies wait for signals from microbes in order to fully develop. When scientists rear mice without any germ in their bodies, the mice end up with stunted intestines.

    In order to co-exist with our microbiome, our immune system has to be able to tolerate thousands of harmless species, while attacking pathogens. Scientists are finding that the microbiome itself guides the immune system to the proper balance.

    One way the immune system fights pathogens is with inflammation. Too much inflammation can be harmful, so we have immune cells that produce inflammation-reducing signals. Last month, Sarkis Mazmanian and June L. Round at Caltech reported that mice reared without a microbiome can’t produce an inflammation-reducing molecule called IL-10.

    The scientists then inoculated the mice with a single species of gut bacteria, known as Bacteroides fragilis. Once the bacteria began to breed in the guts of the mice, they produced a signal that was taken up by certain immune cells. In response to the signal, the cells developed the ability to produce IL-10.

    Scientists are not just finding new links between the microbiome and our health. They’re also finding that many diseases are accompanied by dramatic changes in the makeup of our inner ecosystems. The Imperial College team that discovered microbes in the lungs, for example, also discovered that people with asthma have a different collection of microbes than healthy people. Obese people also have a different set of species in their guts than people of normal weight.

    In some cases, new microbes may simply move into our bodies when disease alters the landscape. In other cases, however, the microbes may help give rise to the disease. Some surveys suggest that babies delivered by Caesarian section are more likely to get skin infections from methicillin-resistant Staphylococcus aureus. It’s possible that they lack the defensive shield of microbes from their mother’s birth canal.

    Caesarean sections have also been linked to an increase in asthma and allergies in children. So have the increased use of antibiotics in the United States and other developed countries. Children who live on farms — where they can get a healthy dose of microbes from the soil — are less prone to getting autoimmune disorders than children who grow up in cities.

    Some scientists argue that these studies all point to the same conclusion: when children are deprived of their normal supply of microbes, their immune systems get a poor education. In some people, untutored immune cells become too eager to unleash a storm of inflammation. Instead of killing off invaders, they only damage the host’s own body.

    A better understanding of the microbiome might give doctors a new way to fight some of these diseases. For more than a century, scientists have been investigating how to treat patients with beneficial bacteria. But probiotics, as they’re sometimes called, have only had limited success. The problem may lie in our ignorance of precisely how most microbes in our bodies affect our health.

    Dr. Khoruts and his colleagues have carried out 15 more fecal transplants, 13 of which cured their patients. They’re now analyzing the microbiome of their patients to figure out precisely which species are wiping out the Clostridium difficile infections. Instead of a crude transplant, Dr. Khoruts hopes that eventually he can give his patients what he jokingly calls “God’s probiotic” — a pill containing microbes whose ability to fight infections has been scientifically validated.

    Dr. Weinstock, however, warns that a deep understanding of the microbiome is a long way off.

    “In terms of hard-boiled science, we’re falling short of the mark,” he said. A better picture of the microbiome will only emerge once scientists can use the genetic information Dr. Weinstock and his colleagues are gathering to run many more experiments.

    “It’s just old-time science. There are no short-cuts around that,” he said.

    This article has been revised to reflect the following correction:

    Correction: July 21, 2010

     An article on July 13 about new research on the role of microbes in the human body misstated part of the name of a bacterium linked to skin infections in babies delivered by Caesarean section. It is methicillin-resistant Staphylococcus aureus, not “multiply resistant.”

     

    Follow-up article:


    Our Microbes, Ourselves

    We are home to whole worlds of bacteria. New research suggests that they can tell our history and, perhaps, our future

    Television shows remind us of the traces we can leave behind, clues that could link a criminal to the scene of a crime: a careless fingerprint, a spatter of blood, a stray hair. A recent study offers a new way to identify people that might sound far-fetched even to a scriptwriter: the bacteria on our skin.

    Researchers from the University of Colorado found that when someone touches an object, they transfer bacteria that persist for days or even weeks. The team said it was able to recover the bacteria from computer keyboards and identify their owners from a database of more than 250 bacterial samples from human hands.

    The technique may eventually have applications in forensics, but it also suggests a new way of looking at our identities. We usually think of ourselves as individual human bodies. But our bodies are in fact homes to complex communities of microbes that are integrally linked to us and have evolved alongside us. Your own unique communities begin forming at birth and are partially inherited from family members and partially shaped by your experiences and actions.

    “The thing that’s intriguing to me is the possibility of a very different identifier of who you are as a person,” says David Relman, a microbiologist at Stanford University who was not involved in the research. Unlike DNA or fingerprints, which are fixed from birth, your particular mix of bacteria develops over time and “can potentially tell us about your behavior and life history, not just who you were born to be,” Relman says.

    And these vast, invisible communities are more than just passengers, scientists suggest: They are a critical part of who we are. Microbes influence our health in far-reaching ways. Imbalances in bacterial communities are involved in conditions like eczema, psoriasis, gum disease, inflammatory bowel disease, celiac disease, and possibly even autism. And a growing body of evidence shows that bacteria play a role in obesity. It increasingly appears that microbes can communicate directly with our bodies by releasing chemicals that affect our own biology and even behavior. Some scientists argue that we shouldn’t see the human body as an individual entity but as part of a “superorganism” that includes all of its inhabitants living together.

    “We have a symbiotic relationship with our microbes,” says Jacques Ravel, a microbiologist at the University of Maryland’s Institute for Genome Sciences.

    This shift in thinking emerged from new technologies that made it possible to study microbes living in complex communities, rather than as isolated cells in a lab. These techniques were first used to study bacterial communities in soils, oceans, and other environments, but eventually scientists began exploring the habitat of the human body. So far, initial studies in this new frontier have revealed incredibly complex and active populations of microbes that seem to have an important role in many aspects of our health.

    Scientists are now working to detect, categorize, and understand the entire complement of microbes living in and on the human body — what they call the human microbiome. A federally funded effort, called the Human Microbiome Project, is working to better understand the body’s microbes and our relationship to them. This, of course, involves delving into a hidden world that many of us might prefer not to think about. Microbes cover every surface of our bodies — they cling to our skin, form sticky films in our mouths, and build megalopolises in our digestive tracts. You may think you’re wiping them out when you wash your hands or shower, but in fact the communities quickly bounce back intact. The forensics study, published this month in Proceedings of the National Academy of Sciences, suggests that the items we handle frequently — our furniture, dishes, iPods, and clothing — could be coated in a living imprint of ourselves.

    “In forensic science, you start realizing you’re shedding yourself all the time — it really changes the way you look at hotel rooms,” jokes Robin Cotton, director of the biomedical forensic sciences program at Boston University School of Medicine. “And now this is going to make it worse.”

    Cotton says that the method is far from ready for use in forensics, but that it might eventually be useful for confirming an identification made by other means. For instance, forensic scientists sometimes rely on “touch DNA,” the DNA found in small samples of human cells left behind on an object. In some cases, the amount of DNA that can be recovered is so small or damaged that the identification it produces is less reliable than investigators would like. In these cases, they could turn to bacteria to confirm the human DNA findings, or vice versa.

    Just as bacterial communities could be used as a marker of identity in forensics, they could also serve as signs of disease. We depend on certain microbes for functions such as digesting nutrients, but we also depend on the overall balance of microbial communities to prevent infections and keep us healthy. For instance, obesity is associated with different types of bacteria in the digestive tract, and their levels change with weight loss. These bacteria not only help to digest food but produce chemical signals that can influence whether our bodies burn the energy from food or store it as fat. A recent study in mice found that bacteria in the gut may even help drive appetite. Ravel says it could some day be possible to test patients for microbial imbalances and give them treatments or recommend lifestyle changes to restore equilibrium.

    That bacteria can have far-reaching influence on our biology requires us to view microbes in a new light. Most people consider bacteria to be agents of disease, and we don’t stop to consider the consequences of taking antibiotics or slathering on antibacterial lotions. Rob Knight, a microbiologist at the University of Colorado and coauthor of the new study, says that a better approach is to think about “how to tend your unique microbial garden.” So far, we’ve been treating it with the equivalent of bulldozers and pesticides; there might be a better way to cultivate communities of bacteria that aid our health.

    Knight says that studying the microbiome requires a more ecological view of the human body. The body is essentially a living island, with its own topography housing billions of inhabitants, which interact with one another and their host. Bacteria outnumber our own cells 10 to 1. Our understanding of our microbial selves is just beginning. But for now, we can take comfort in the fact that we’re not alone. Perhaps man is an island, but a very crowded one.

    Courtney Humphries is a freelance science writer and author of ”Superdove: How the Pigeon Took Manhattan...And the World.”  

    © Copyright 2010 The New York Times Company
     

     

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