Are Gut Microbes a Key to Weight Control?

Whenever you eat, even if it's just a bowl of cereal while standing at the kitchen counter, you're feasting with trillions of your closest compadres. Bacteria, fungi and other microbes share the bounty as food churns through the vital inner tube that makes up your gut. It isn't a one-way relationship. These microscopic critters are essential contributors to our good health. They break down toxins, manufacture some vitamins and essential amino acids, educate the immune system and form a barrier against infective invaders. A provocative new avenue of research suggests that the makeup of microbes in the gut may influence our weight, too. If true, this could provide new strategies for weight control.

Which species of microbes live in the gut and what they do in there are just two of the many key questions that scientists are asking about this largely unexplored realm. "The landscape of the human gut is truly terra incognita," says Jeffrey Gordon, a genome scientist at Washington University in St. Louis whose research team is spearheading this effort. "The menagerie of microscopic organisms living there acts like an organ that carries out functions that we humans have not had to evolve."

The early work on our gut microbiota (loosely translated from Latin as "community of tiny living things") is challenging our notion of what it means to be human. From an early age, the human body is home to a huge but ever-changing community of microbes: for each one of our cells, there are 10 microbial cells in or on the body. Most of them live in the intestines; the bulk of the rest inhabit the mouth, esophagus, stomach, upper airway, skin and vagina. No one knows how many different species coexist inside the human gut. In the first comprehensive census of the gut, David Relman and his colleagues at Stanford University quit counting after they hit 395 different species in three healthy subjects. The real cast of characters will almost certainly number in the thousands.

Curiously, we don't start life with such a microbial partnership. A developing baby floats in sterile amniotic fluid, protected from bumps—and bugs. That isolation ends during the baby's trip through the birth canal, which is a haven for bacteria. The baby picks up microbes on his or her skin; some get into the mouth. From then on, helpful microbes somehow convince the immune system that they mean no harm. They settle down in hospitable regions, and crowd out those that can't compete.

At first, the microbes in a baby's body resemble those in the mother. Over time, the community takes on its own identity, nudged this way and that by the child's genes, the environment and the unceasing flow of new microbes from food, beverages and unwashed hands. Eventually, an individual's gut microbiota becomes as unique as a fingerprint.

The gut is composed of the small and large intestine. Stretched out, it's as long as a schoolbus. Flatten out the millions of fingerlike projections that line its sides and it would easily cover a tennis court. The small intestine is where much of the food you eat is broken down into simple sugars, fats and amino acids. These are all small enough to be shuttled across the lining of the intestine and into nearby blood vessels. Fiber from fruits, vegetables and grains, along with other indigestible material, passes largely unchanged into the large intestine, also known as the colon.

What's indigestible to you is a seven-course meal to your gut microbiota. The conditions in the colon—dark, moist and free of oxygen—are just what your gut microbiota needs to ferment indigestible material passed on from the small intestine and produce simple sugars and short, chain-free fatty acids. They do this for their own good, but they also share some of these energy-rich substances with their host—us. Some people get up to 10 percent of their daily calories from substances produced by their gut bugs.

Gordon and his colleagues think that the gut microbes in some people are more efficient at extracting energy than those in other people. This could partly explain why some individuals gain more weight on the same diet that allows others to stay lean. Gordon's hypothesis is supported by a series of elegant experiments.

First, Gordon's team raised generations of mice in sterile conditions. These microbe-free mice downed almost one third more food each day than their ordinary counterparts—yet had 40 percent less body fat. When the researchers took samples of gut microbes from ordinary mice and transplanted them into germ-free mice, the newly inoculated rodents began to gain weight even though they weren't eating any extra food. The team took the work a step further with help from a strain of genetically obese mice. Transplanting gut microbes from these fat mice into lean, germ-free mice led to greater gains in body fat than transplanting gut microbes from normal mice.

To see if fat mice had different gut bugs than lean mice, the Washington University team took genetic snapshots using high-tech DNA sequencers. In ordinary normal-weight mice, bacteria belonging to the group known as Firmicutes accounted for about two thirds of the gut's bacterial community. Members of the Bacteroidetes group made up most of the rest. In contrast, genetically obese mice had even more Firmicutes and many fewer Bacteroidetes. By analyzing the sequence of genes extracted from various microbiota samples, Gordon's team discovered that the bacterial community in obese mice had more genes for breaking down complex starches and fiber. In other words, microbes from obese mice were better at releasing calories from the gut's contents than were the microbes from lean mice.

Think of it this way: the gut community in obese mice is like a fuel-efficient car, extracting more energy from food and passing more along to its host than its gas-guzzler counterpart in lean mice.

Mice are mice. Does any of this apply to humans? To find out, the Washington University team asked a dozen obese men and women to follow a low-fat or low-carbohydrate diet for a year. Before starting these diets, these obese volunteers had more Firmicutes and fewer Bacteroidetes in their guts than did several lean volunteers acting as controls—just as was seen in obese and lean mice. As the volunteers lost weight, their microbial communities underwent a remarkable shift, with an increase in the gas guzzlers (Bacteroidetes) and a decrease in the efficient energy extractors (Firmicutes). The type of diet didn't matter; only significant weight loss sparked the shift.

One implication of this work is that the energy content of food isn't a fixed quantity. Consider the 110 calories per cup listed on a box of Cheerios. Some people may get that much, others may get less, depending on their gut microbiota. A difference of just 25 calories a day—that's half a rice cake or one chocolate kiss—between what you take in and what you burn could mean a gain or loss of more than two pounds in a year and 20 pounds over a decade.

On a more practical note, this work suggests that somehow altering the microbial populations in the gut could be one way to modify weight. If Gordon's work continues to pan out, it may be possible someday to use probiotics—dietary supplements containing potentially beneficial microbes—or other microbe-manipulating strategies to aid weight loss by nudging the gut microbiota to be less efficient at extracting energy.

Probiotics are already on the market, most of them containing some form of Lactobacillus, best known for its yogurt-making abilities. They're used to fight allergies, diarrhea and a variety of other conditions, although the evidence for their use remains spotty. Major companies such as General Mills and food-ingredient supplier Danisco are exploring links between probiotics and weight control.

It's a bit early to do such microbial gardening for weight loss, cautions Randy Seeley, associate director of the Obesity Research Center at the University of Cincinnati College of Medicine. Though he's impressed with the work Gordon's team has done, he isn't sure the results make sense from an evolutionary perspective. As the obese volunteers lost weight, their gut microbes shifted toward a community that would extract less energy from its food supply. That doesn't make sense from a survival point of view: "If I saw myself getting leaner, I'd want my body to say to my microbes, 'Guys, help me out here,' and make the extra more calories, not fewer," says Seeley.

Gordon is the first to acknowledge that there's a lot of work to be done before anyone can point to gut microbes as a cause of obesity or start manipulating them as a way to lose weight. Even if this line of research doesn't pan out, the convergence of microbiology, molecular biology and a host of other disciplines will shine new light on how we process what we eat and what causes obesity.

While scientists have known for more than a century that we humans live with a huge community of permanent tiny neighbors, it is only recently that research like Gordon's has suggested that these neighbors may have unexpected effects on our health. In response, the National Institutes of Health has launched the Human Microbiome Project, in order to learn more about our gut bugs—starting with their genes. Sequencing of bacterial genes could also help researchers prospect for hitherto unknown chemicals made by our microbes that protect our health. What is making the Human Microbiome Project feasible is the recent development of superfast gene sequencing technologies.

Taking a census is important for several reasons. "We need to know who's there, especially the good bugs that make up the majority of the microbial community, so we can minimize any harm to them when we go after the bad guys," says George Weinstock, a professor of molecular and human genetics at Baylor College of Medicine who is working on the project.

While obesity gets most of the attention, Gordon has his eyes on another prize: fighting malnutrition. Making microbes in the gut more efficient could be one way to help the millions of people around the globe who don't get enough to eat each day or those who involuntarily lose weight while battling cancer or heart failure.

Skerrett is editor of the Harvard Heart Letter. Walker is the Conrad Taff Professor of Pediatrics at Harvard Medical School. For more on nutrition and health go to health.harvard.edu and health.harvard.edu/newsweek.

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