Altering mix of gut microbes prevents obesity, but diet remains key factor

Vanessa Ridaura handles bacteria cultures from twins that will be transplanted into mice as she discusses the research with Jeffrey I. Gordon, MD, director of the Center for Genome Sciences and Systems Biology at Washington University. Click here to view an animated video of the study. (Credit: E. Holland Durando)

Working in mice transplanted with intestinal microbes from lean and obese twins, a new study shows that altering the microbial mix prevents mice destined for obesity from gaining weight and fat or developing related metabolic problems linked to insulin resistance.

But there’s a caveat: Microbes associated with leanness can’t take up residence in mice with “obese” gut microbes unless the animals eat a healthy diet. The research, at Washington University School of Medicine in St. Louis, is reported Sept. 6 in the journal Science.

The findings point to the intimate connection between gut microbes and diet as a key factor in the path to obesity, setting the stage for development of next-generation probiotics that can be added to foods to treat or prevent the disease.

The research involved identical and fraternal female human twin pairs, ranging in age from 21 to 32, in which one twin is obese and the other lean. This stark weight disparity occurs in about 6 percent of twins and is more common among fraternal twins than those who are identical.

As part of the study, the twins’ gut microbes (captured from fecal samples) were transferred into mice that had been raised in a previously microbe-free environment. Because mice naturally eat each other’s feces, the researchers had a chance to observe what happens when a mouse carrying a collection of gut microbes from an obese twin is housed with another mouse carrying gut microbes from the lean twin.

Do the mice transfer microbes to one another through their feces, the researchers asked. And if so, which microbes ultimately take over?

The answer depends on diet.

If the animals ate a healthy diet low in saturated fat and high in fruits and vegetables, microbes from the lean twin invaded the gut of the mouse with the obese twin’s microbes, preventing weight gain and the development of metabolic problems associated with insulin resistance. In people, insulin resistance is associated with significant weight gain and typically is the first sign of metabolic problems that eventually can lead to diabetes.

“Eating a healthy diet encourages microbes associated with leanness to quickly become incorporated into the gut,” said senior author Jeffrey I. Gordon, MD, director of the Center for Genome Sciences & Systems Biology at Washington University. “But a diet high in saturated fat and low in fruits and vegetables thwarts the invasion of microbes associated with leanness. This is important as we look to develop next-generation probiotics as a treatment for obesity.”

In 2009, a study by Gordon and his colleagues indicated that the collections of microbes in the guts of obese people lack the diversity and richness of people who are lean. This observation was confirmed by the new research.

“We think the lack of diversity leaves open niches – or jobs, if you will – that can be filled by microbes associated with leanness,” he said. “Our results underscore the strong interactions between gut microbes and diet and help illustrate how unhealthy diets select against gut microbes associated with leanness.”

The intestine is home to tens of trillions of microbes that help break down food and synthesize nutrients and vitamins from our diets. Gordon’s earlier research also established that collections of gut microbes vary substantially from person to person, even among identical twins. This inherent variation makes it difficult to know whether diseases like obesity are rooted in “sick” gut microbial communities, a person’s own genetic makeup, or both.

As part of the study, first author and graduate student Vanessa Ridaura showed that by transplanting entire collections of human microbes into different groups of mice, the researchers could mimic the body composition of each twin. Mice fed low-fat mouse chow and given gut microbes from an obese twin gained weight and fat and took on the metabolic dysfunction of the donor, while mice given gut microbes from a lean twin stayed lean.

In another set of experiments, the twins’ microbes again were transplanted into germ-free mice. This time, mice with microbes from a lean twin were put in cages with mice carrying microbes from an obese twin. The animals were fed healthy or unhealthy human diets.

The researchers showed that weight gain, accumulation of fat and development of metabolic problems were prevented only in mice that had “obese” microbes and ate healthy diets. This observation was associated with an invasion of a group of bacteria called Bacteroidetes from mice with “lean” microbes into the guts of mice with “obese” microbes. Bacteroidetes are efficient at harvesting calories and nutrients from food and have been associated with leanness.

When the animals were fed an all-too-typical diet common in the United States – high in saturated fat and low in fruits and vegetables – there was no colonization of “lean” microbes into the guts of mice carrying microbes from an “obese” twin. These mice gained weight and fat and developed metabolic problems.

Throughout their experiments, the researchers found they could transmit an individual’s body composition and associated metabolic dysfunction to the mice regardless of whether a donor’s gut microbes were first grown in the laboratory or transferred from a fecal sample.

“That’s good news from a therapeutic standpoint because there’s intense interest in identifying microbes that could be used to treat diseases,” Gordon said. “Ideally, you want to be able to grow these naturally occurring unmodified human gut microbes in a lab and test whether various combinations of these organisms, with or without specified diet ingredients, can treat and/or prevent disease,” Gordon explained.

Ridaura VK, Faith JJ, Rey FE, Chen J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Health AC and Jordon JI. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. Sept. 6, 2013.

The research is funded by the National Institutes of Health (NIH), grants DK078669, DK70977, P30-AG028716 and DK58398, the Crohn’s and Colitis Foundation of America, Kraft Foods and Mondelez International.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.