For the 35 percent of American adults who do daily battle with obesity, the main causes of their condition are all too familiar: an unhealthy diet, a sedentary lifestyle and perhaps some unlucky genes. In recent years, however, researchers have become increasingly convinced that important hidden players literally lurk in human bowels: billions on billions of gut microbes.

Throughout our evolutionary history, the microscopic denizens of our intestines have helped us break down tough plant fibers in exchange for the privilege of living in such a nutritious broth. Yet their roles appear to extend beyond digestion. New evidence indicates that gut bacteria alter the way we store fat, how we balance levels of glucose in the blood, and how we respond to hormones that make us feel hungry or full. The wrong mix of microbes, it seems, can help set the stage for obesity and diabetes from the moment of birth.

Fortunately, researchers are beginning to understand the differences between the wrong mix and a healthy one, as well as the specific factors that shape those differences. They hope to learn how to cultivate this inner ecosystem in ways that could prevent—and possibly treat—obesity, which doctors define as having a particular ratio of height and weight, known as the body mass index, that is greater than 30. Imagine, for example, foods, baby formulas or supplements devised to promote virtuous microbes while suppressing the harmful types. “We need to think about designing foods from the inside out,” suggests Jeffrey Gordon of Washington University in St. Louis. Keeping our gut microbes happy could be the elusive secret to weight control.

An Inner Rain Forest

Researchers have long known that the human body is home to all manner of microorganisms, but only in the past decade or so have they come to realize that these microbes outnumber our own cells 10 to one. Rapid gene-sequencing techniques have revealed that the biggest and most diverse metropolises of “microbiota” reside in the large intestine and mouth, although impressive communities also flourish in the genital tract and on our skin.

Each of us begins to assemble a unique congregation of microbes the moment we pass through the birth canal, acquiring our mother's bacteria first and continuing to gather new members from the environment throughout life. By studying the genes of these various microbes—collectively referred to as the microbiome—investigators have identified many of the most common residents, although these can vary greatly from person to person and among different human populations. In recent years researchers have begun the transition from mere census taking to determining the kind of jobs these minute inhabitants fill in the human body and the effect they have on our overall health.

An early hint that gut microbes might play a role in obesity came from studies comparing intestinal bacteria in obese and lean individuals. In studies of twins who were both lean or both obese, researchers found that the gut community in lean people was like a rain forest brimming with many species but that the community in obese people was less diverse—more like a nutrient-overloaded pond where relatively few species dominate. Lean individuals, for example, tended to have a wider variety of Bacteroidetes, a large tribe of microbes that specialize in breaking down bulky plant starches and fibers into shorter molecules that the body can use as a source of energy.

Documenting such differences does not mean the discrepancies are responsible for obesity, however. To demonstrate cause and effect, Gordon and his colleagues conducted an elegant series of experiments with so-called humanized mice, published last September in Science. First, they raised genetically identical baby rodents in a germ-free environment so that their bodies would be free of any bacteria. Then they populated their guts with intestinal microbes collected from obese women and their lean twin sisters (three pairs of fraternal female twins and one set of identical twins were used in the studies). The mice ate the same diet in equal amounts, yet the animals that received bacteria from an obese twin grew heavier and had more body fat than mice with microbes from a thin twin. As expected, the fat mice also had a less diverse community of microbes in the gut.

Gordon's team then repeated the experiment with one small twist: after giving the baby mice microbes from their respective twins, they moved the animals into a shared cage. This time both groups remained lean. Studies showed that the mice carrying microbes from the obese human had picked up some of their lean roommates' gut bacteria—especially varieties of Bacteroidetes—probably by consuming their feces, a typical, if unappealing, mouse behavior. To further prove the point, the researchers transferred 54 varieties of bacteria from some lean mice to those with the obese-type community of germs and found that the animals that had been destined to become obese developed a healthy weight instead. Transferring just 39 strains did not do the trick. “Taken together, these experiments provide pretty compelling proof that there is a cause-and-effect relationship and that it was possible to prevent the development of obesity,” Gordon says.

Gordon theorizes that the gut community in obese mice has certain “job vacancies” for microbes that perform key roles in maintaining a healthy body weight and normal metabolism. His studies, as well as those by other researchers, offer enticing clues about what those roles might be. Compared with the thin mice, for example, Gordon's fat mice had higher levels in their blood and muscles of substances known as branched-chain amino acids and acylcarnitines. Both these chemicals are typically elevated in people with obesity and type 2 diabetes.

Another job vacancy associated with obesity might be one normally filled by a stomach bacterium called Helicobacter pylori. Research by Martin Blaser of New York University suggests that it helps to regulate appetite by modulating levels of ghrelin—a hunger-stimulating hormone. H. pylori was once abundant in the American digestive tract but is now rare, thanks to more hygienic living conditions and the use of antibiotics, says Blaser, author of a new book entitled Missing Microbes.

Diet is an important factor in shaping the gut ecosystem. A diet of highly processed foods, for example, has been linked to a less diverse gut community in people. Gordon's team demonstrated the complex interaction among food, microbes and body weight by feeding their humanized mice a specially prepared unhealthy chow that was high in fat and low in fruits, vegetables and fiber (as opposed to the usual high-fiber, low-fat mouse kibble). Given this “Western diet,” the mice with obese-type microbes proceeded to grow fat even when housed with lean cagemates. The unhealthy diet somehow prevented the virtuous bacteria from moving in and flourishing.

The interaction between diet and gut bacteria can predispose us to obesity from the day we are born, as can the mode by which we enter the world. Studies have shown that both formula-fed babies and infants delivered by cesarean section have a higher risk for obesity and diabetes than those who are breast-fed or delivered vaginally. Working together, Rob Knight of the University of Colorado Boulder and Maria Gloria Dominguez-Bello of N.Y.U. have found that as newborns traverse the birth canal, they swallow bacteria that will later help them digest milk. C-section babies skip this bacterial baptism. Babies raised on formula face a different disadvantage: they do not get substances in breast milk that nurture beneficial bacteria and limit colonization by harmful ones. According to a recent Canadian study, babies drinking formula have bacteria in their gut that are not seen in breast-fed babies until solid foods are introduced. Their presence before the gut and immune system are mature, says Dominguez-Bello, may be one reason these babies are more susceptible to allergies, asthma, eczema and celiac disease, as well as obesity.

A new appreciation for the impact of gut microbes on body weight has intensified concerns about the profligate use of antibiotics in children. Blaser has shown that when young mice are given low doses of antibiotics, similar to what farmers give livestock, they develop about 15 percent more body fat than mice that are not given such drugs. Antibiotics may annihilate some of the bacteria that help us maintain a healthy body weight. “Antibiotics are like a fire in the forest,” Dominguez-Bello says. “The baby is forming a forest. If you have a fire in a forest that is new, you get extinction.” When Laurie Cox, a graduate student in Blaser's laboratory, combined a high-fat diet with the antibiotics, the mice became obese. “There's a synergy,” Blaser explains. He notes that antibiotic use varies greatly from state to state in the U.S., as does the prevalence of obesity, and intriguingly, the two maps line up—with both rates highest in parts of the South.

Beyond Probiotics

Many scientists who work on the microbiome think their research will inspire a new generation of tools to treat and prevent obesity. Still, researchers are quick to point out that this is a young field with far more questions than answers. “Data from human studies are a lot messier than the mouse data,” observes Claire Fraser of the University of Maryland, who is studying obesity and gut microbes in the Old Order Amish population. Even in a homogeneous population such as the Amish, she says, there is vast individual variation that makes it difficult to isolate the role of microbiota in a complex disease like obesity.

Even so, a number of scientists are actively developing potential treatments. Dominguez-Bello, for example, is conducting a clinical trial in Puerto Rico in which babies born by cesarean section are immediately swabbed with a gauze cloth laced with the mother's vaginal fluids and resident microbes. She will track the weight and overall health of the infants in her study, comparing them with C-section babies who did not receive the gauze treatment.

A group in Amsterdam, meanwhile, is investigating whether transferring feces from lean to overweight people will lead to weight loss. U.S. researchers tend to view such “fecal transplants” as imprecise and risky. A more promising approach, says Robert Karp, who oversees National Institutes of Health grants related to obesity and the microbiome, is to identify the precise strains of bacteria associated with leanness, determine their roles and develop treatments accordingly. Gordon has proposed enriching foods with beneficial bacteria and any nutrients needed to establish them in the gut—a science-based version of today's probiotic yogurts. No one in the field believes that probiotics alone will win the war on obesity, but it seems that, along with exercising and eating right, we need to enlist our inner microbial army.