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Microbes in the gut may be a key to helping people lose weight, according to two tantalizing new studies.

One study in mice found that gastric bypass surgery may aid weight loss not just by reducing the size of the stomach but also by changing the composition of the microbial population. The second study found that people with more methane-producing microbes were more likely to be heavy and have a high percentage of body fat.

The findings might ultimately lead to new, microbe-centered approaches to weight loss, an area in which drug development has been notoriously difficult.

The studies aren’t the first to tie gut microbes to obesity. Several years ago, when the study of the microbiome was first unfolding, researchers found that both people and mice that are overweight tend to have a population of gut microbes different in composition from that of lean individuals (see “Our Microbial Menagerie”). When they lost weight, the microbes changed accordingly. And when microbes from overweight people were transplanted into microbe-free mice, the animals gained more weight than when they were treated with microbes from lean people.

Lee Kaplan and collaborators at Harvard now have more proof that microbes can help control weight, and that they may play a role in the one of the most successful weight loss treatments available. Scientists already had hints that the benefits of gastric bypass surgery don’t derive simply from a reduction in calories consumed. (The surgery dramatically reduces the size of the stomach, and hence the amount of food people can eat.) Patients show changes in blood sugar, as well as changes in hunger-regulating hormones, even before they lose weight.

“There are several lines of evidence that it doesn’t work just by mechanically restricting how much you eat, but that it works by changing the core mechanisms of energy balance and metabolic function,” says Kaplan, director of the Massachusetts General Hospital Weight Center. Previous research in both rodents and humans suggested that the procedure alters the microbes in the gut but hadn’t shown whether this influences weight.

In the new study, published Thursday in Science Translational Medicine, researchers studied three groups of obese mice fed a high-fat diet. One group underwent a procedure similar to gastric bypass and lost 30 percent of their body mass. The two other groups had a sham procedure in which incisions were made but the anatomy wasn’t altered. Mice in one of these groups were fed a normal diet and regained weight after the surgery; the others were put on a restricted diet and lost as much weight as the gastric bypass group. The bypass animals ate the same amount as the well-fed control animals, but they seemed to expend more energy.

By analyzing DNA in fecal samples before and after the procedure, the researchers found that gastric bypass had a significant and lasting effect on gut microbes. Specifically, they saw an increase in Verrucomicrobia and Gammaproteobacteria bacteria, similar to changes seen in people post-bypass. Transplanting gut microbes from the surgically altered mice into microbe-free animals made them lose weight, suggesting that the microbes themselves are responsible for at least some of the weight loss in gastric bypass. Animals inoculated with microbes from the two control groups didn’t change weight.

“It’s not simply a consequence of surgery, or of weight loss,” says David Cummings, an endocrinologist at the University of Washington in Seattle, who was not involved in the study.

The findings raise the question of how to reap the benefits of gastric bypass without surgery. To answer that, scientists first need to figure out which microbes trigger weight loss, and how they do it.

One hypothesis is that they influence the body’s energy expenditure—the calories we burn when just sitting around. This energy expenditure is known to take place in muscle and brown fat. But how microbes might influence it is a mystery.  

The researchers are now testing the effects of altering levels of individual microbes, as well as some of the chemicals they produce. For example, gastric bypass changed the ratio of molecules called short-chain fatty acids, which often serve as chemical signals.

Depending on the results, scientists might be able to create a cocktail of weight-loss microbes. A less appetizing option is to offer microbial transplants from people who have undergone gastric bypass. These types of transplants are already under study for severe intestinal disorders.

The second study, published in the Journal of Clinical Endocrinology & Metabolism, found that people who exhale high levels of methane and hydrogen—indirect measures of certain gut microbes—are more likely to be heavy. The researchers have set their sights on one particular methane-producing microbe, Methanobrevibacter smithii, which helps extract calories from food. They are now running a clinical trial in which they give people targeted antibiotics to knock out this microbe and then measure whether their calorie extraction is reduced.

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Tagged: Biomedicine, microbes, weight loss, Massachusetts General Hospital

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