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    Research led by Jeffrey Gordon, MD (center), has found an intimate connection between gut microbes and diet as a key factor in the path to obesity. One day, probiotics might be added to foods to treat or prevent obesity. (Mark Katzman)

Frontrunners

Gut Microbes, Diet and Obesity Linked

Next-generation probiotics could prevent obesity — but there's a catch.

by Caroline Arbanas

A new study by researchers in the School of Medicine is helping to illuminate how diet and gut microbes interact to affect weight gain. Microbes of the gut number in the trillions, vary substantially from person to person, and help break down food and synthesize nutrients and vitamins from our diets.

The mix of microbes living inside the gut can protect against obesity, but a healthy diet is critical, according to School of Medicine scientists who transplanted intestinal microbes from obese and lean twins into mice and fed the animals different diets.

The scientists worked with mice that had been transplanted with intestinal microbes from lean and obese human twins. Their study shows that altering the microbial mix of the mice’s guts prevents the mice destined for obesity from gaining weight and fat or from developing related metabolic problems linked to insulin resistance.

But there’s a caveat: Microbes associated with leanness can take up residence in mice with “obese” gut microbes only when the animals eat a healthy diet. The research was led by Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Center for Genome Sciences & Systems Biology, and was reported 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 the development of next-generation probiotics that can be added to foods to treat or prevent the disease.

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 the 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. But a diet high in saturated fat and low in fruits and vegetables thwarts the invasion of microbes associated with leanness.”Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor

“Eating a healthy diet encourages microbes associated with leanness to quickly become incorporated into the gut,” Gordon says. “But a diet high in saturated fat and low in fruits and vegetables thwarts the invasion of microbes associated with leanness.”

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.

Caroline Arbanas is executive director of Research Communications Strategy in the Medical Public Affairs office.

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