Human gut microbes alter mouse metabolism, depending on diet

Germ-free mice that received gut bacteria from obese humans put on more weight and accumulated more fat than mice that were given bacteria from the guts of lean humans, according to a new study. This finding, which demonstrates the transmission of physical and metabolic traits via communities of microbes in the gut, depends on the rodents' diet. And the researchers responsible suggest that it may represent an important step toward developing new personalized probiotic and food-based therapies for the treatment or prevention of obesity. This new research follows on the heels of related studies showing that the variety of microbial genes in one's gut can influence obesity -- and that high-fiber food, such as fruits and vegetables, tends to boost such bacterial diversity. But, this new study shows directly that microbial communities from the gut can transmit lean or obese traits; it also begins to name specific players involved, along with their designated roles and how these roles are tied to the foods we consume. (Bacteroides, for example, which has been observed at increased levels in the microbiota of lean individuals, was found to play a protective role against increased fat accumulation in mice on certain diets.)

Vanessa Ridaura, a graduate student at Washington University's School of Medicine, and colleagues took samples of the microbes that were living in the guts of human fraternal and identical twins. For each pair of twins in the study, one sibling was lean while the other was obese. The researchers then transplanted the discordant twins' gut microbiota into the guts of germ-free mice that had been raised under sterile conditions, without any microbes of their own.

The results of their study are published in the 6 September issue of the journal Science.

"The first thing that Vanessa identified in these mice, which were consuming a standard mouse diet, was that the recipients of the obese twins' microbiota gained more fat than the recipients of the lean twins' microbiota," explained Jeffrey Gordon, director for the Center of Genome Sciences and Systems Biology at Washington University School of Medicine and a co-author of the Science report. "This wasn't attributable to differences in the amount of food they consumed, so there was something in the microbiota that was able to transmit this trait. Our question became: What were the components responsible?"

This transplantation of gut microbes from humans to mice led to metabolic changes in the rodents that are associated with obesity in humans. So, the researchers performed what Gordon called "The Battle of the Microbiota," which involved housing mice that had received microbes from a lean twin (Ln mice) with mice that were given microbes from an obese twin (Ob mice).

"Mice -- delicately put -- exchange their microbes readily," said Gordon, referring to coprophagia, or the consumption of feces.

After the mice had been cagemates for 10 days, the researchers discovered that the Ob mice that had been housed with Ln mice had adopted the "leaner" features -- including the metabolic features -- of their Ln cagemates. Ln mice that had been housed with Ob mice, on the other hand, appeared unaffected by their cagemates' microbes and metabolism.

According to the researchers' results, something about the microbes in the guts of Ln mice prevented the Ob mice from accumulating much fat. So, Ridaura used a combination of algorithms -- some that were tried-and-true and others that she cooked up herself -- to figure out which bacterial species in particular were able to invade the Ob mice. They found that specific members of the Bacteroidetes phylum were able to enter the guts of Ob mice, settling into otherwise unoccupied niches. These bacteria then triggered changes in metabolism, among other metabolic effects, but none of the bacteria from Ob mice could invade the Ln mice to make them accumulate fat.

"So, why isn't there an epidemic of leanness in America?" Gordon asked rhetorically, considering the stability of the lean microbiota.

To learn more, the researchers formulated diets for the mice that were representative of modern American diets: One was high in fiber and low and saturated fats and the other was low in fiber and high in saturated fats. "Members of our team cooked the ingredients, dried them down, pelleted them, sterilized them and then we fed them to the mice," explained Gordon.

Once again, the researchers performed "The Battle of the Microbiota," housing Ob mice with Ln mice. When the mice consumed the "healthier," high-fiber/low-fat human diet the results were the same as before. However, things were very different when the animals were given the unhealthy diet: Ln mice were not able to confer protection against increased body mass in their Ob cagemates, and there was no invasion of Bacteroidetes from Ln to Ob mouse guts.

These findings suggest that more complex interactions between diet, body mass and gut microbiota underlie human metabolic disturbances than researchers have appreciated. And the methods and "humanized" mouse models employed by Ridaura et al. might be used to safely discover other aspects of how the human gut microbiota and our diets influence our health in the future.

"We now have a way of identifying such interactions, dependent on diet, and thinking about what features of our unhealthy diets we could transform in ways that would encourage bacteria to establish themselves in our guts, and do the jobs needed to improve our well-being," said Gordon. "In the future, the nutritional value and the effects of food will involve significant consideration of our microbiota -- and developing healthy, nutritious foods will be done from the inside-out, not just the outside-in."

The report by Ridaura et al. was supported by the U.S. National Institutes of Health, the Crohn's and Colitis Foundation of America, Kraft Foods and Mondelez International.

Source: American Association for the Advancement of Science