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If you have ever fought the battle of the bulge, then you are all too familiar with its key players: diet, exercise and your genes. The less you move (calories out) and the more you eat (calories in), the more fat you gain — an equation that may be heavily influenced by your particular genes. But scientists have long known that these three factors do not adequately explain every case of obesity, and now researchers are discovering increasingly convincing evidence of another important contributor to body weight, one that until recently has been almost completely ignored: the bacteria that live in your gut.

Technically, they're known as the gut microbiota, a universe of tens of trillions of microbes, which live and thrive in the human intestinal tract and colon and most of which survive without oxygen. These microbes perform an enormous range of vital functions, including helping regulate the calories the body obtains from food and stores as fat. In other words, they may help regulate weight. And a new study published on Nov. 12 in Science Translational Medicine suggests that the particular type and balance of bugs you harbor in your gut may help push your body toward either obesity or leanness and that these microbe populations might even be manipulated to potentially change your weight.

The new study builds on previous research in mice that suggests that heavy bodies may have a different makeup of gut bugs than thin ones. The gut microbiota of obese mice has been shown to have significantly more of one main type of bacteria called Firmicutes and fewer of another kind called Bacteroidetes (both types populate human guts as well); in normal mice, the distribution is the opposite. Jeffrey Gordon at Washington University in St. Louis, Mo., who conducted the previous research, experimented again with mice for the new paper. This time, however, he and his team used human microbiota to colonize mouse guts and then fed the rodents the equivalents of typical human diets to see how their microbes — and their weight — changed.

Researchers started with mice that were specially bred to be germ-free — with no gut microbiota of their own — and to be able to nurture human gut microbiota. Researchers injected the mice with samples of fresh and frozen human feces, the bacteria from which took hold and colonized in the gut of the mice. If that surprises you, it absolutely stunned the researchers. "We were surprised that so much of the diversity present in human microbial communities could be recaptured in mice," says Gordon, who has been studying gut microbiota for more than five years.

The fact that the human gut flora flourished in the rodents was indeed an experimental coup. Since the mice were genetically engineered to be germ-free, lacking a functioning immune system, the scientists could be certain that any bug colonies that took hold in the mouse guts originated entirely from the human sample, not the mice. Being able to recreate the living human gut environment so faithfully in an animal was a welcome prize.

The main advantage was that Gordon and his team now had the cutting-edge DNA-sequencing capability to scan and analyze all the genes contained in those bacteria. That meant researchers could determine not only which species of bacteria were present and in what proportions, but also which genes these bugs were actively using in different conditions. Before such genomic-analysis technology became available, researchers could study only the gut microbes (animal or human) that could be cultured outside their intestinal home — something that not all of the oxygen-shunning bugs were amenable to — but never the complete microbiota of the gut. "We cannot recapitulate the entire microbial diversity that exists in these complex communities. We simply don't know how to culture them, so we could miss a lot of diversity," says Gordon.

That diversity and its impact came into plain view when the researchers started experimenting with the rodents' diet. When one group of mice was fed a typical Western diet, high in fat and sugars, they tended to gain weight and grow more Firmicutes gut bacteria and fewer Bacteroidetes. In mice given a low-fat plant-based chow, the distribution of the two groups of bugs flipped and the animals remained lean. It's not clear whether the balance of gut bugs causes weight gain or is a result of it, but the findings suggest that a "gut profile" could potentially serve as a diagnostic tool for identifying who might have a propensity for obesity. If, for instance, your gut environment contains a preponderance of Firmicutes, then your body may be predisposed to digest calories in a way that leads to greater fat storage. In fact, in Gordon's earlier work with identical twins of different weights, he found that the obese twin tended to have more Firmicutes colonies than the leaner one.

Gordon also found in his mouse populations that changing the animals' diet caused a dramatic and rapid shift in the population of bacteria in their gut. Switching a mouse from low-fat plant chow to a high-fat Western diet resulted in an explosion of Firmicutes in less than a day.

That suggests that factors like gut microbes, which scientists traditionally would not think exerted influence on genes, may have a surprisingly powerful effect, changing how a body's genes would normally control the way the body digests food and breaks it down into energy. It makes sense, when you consider that the great majority of the cells and genes in the typical human body belong to the microbiota. "There is a vast reservoir of attributes associated with our human physiology that is derived from our gut microbial communities," he says. "Our genetic landscape is actually an amalgam, so it's slightly different from the genetic determinism of human genes flowing from parent to offspring. It's also the microbial genes that are acquired from early environmental exposures and transmitted within families as well."

Ultimately, says Gordon, with additional research, this work could lead to the identification of microbial markers that would make up a kind of obesity or leanness profile — a vital-stats sheet of the gut world that would help people understand how their bodies are likely to respond to calories. Beyond that, the possibilities are even more exciting. With more research, Gordon sees potential even for applying to agriculture the knowledge gained from these mice — we could grow more foods that are specifically designed to provide the optimal balance of nutrients and energy for various life stages. "This vast universe of microbes that live on and in us is terra incognita, but it is becoming more cognita every day," he says. "We are beginning to develop the toolbox necessary to describe not only which microbes live within us but to observe the consequences of our symbiosis with them on our health, our biology and our genetic landscape. There is a great deal of excitement but also a great deal of work that still needs to be done in this area."

• Alice Park
• Diet, exercise and genes aren't the only factors responsible for body weight, say researchers, who are discovering evidence of another component: the bacteria in your gut