3/5/10 Obesity: How Intestinal Bacteria May Cause Wt Gain

by **embm** » Mar 5th, '10, 16:14

By ALICE PARK Alice Park – Fri Mar 5, 7:10 am ET
If you're fighting the battle of the bulge, most of your attention - and frustration - is probably aimed at your midsection. It makes sense, since that's where the extra pounds tend to gravitate, especially with the creep of middle age, piling on to form that dreaded spare tire.

But a growing body of research suggests there's another, less visible reason to focus on your gut if you want to lose weight. Scientists led by Andrew Gewirtz at Emory University reveal that your intestines harbor a universe of bacteria - the so-called gut microbiota - that may play an important role in whether your body will store the food you eat as extra pounds.(See the top 10 medical breakthroughs of 2009.)

Gewirtz's team, including researchers at Emory, Cornell University and the University of Colorado at Boulder, became intrigued by the relationship between gut bugs and weight when they noticed that lab mice lacking a certain protein had more of the bugs than other animals and were about 15% heavier. These mice also had a higher level of inflammation, which the authors explain in their paper published online Thursday in Science Express is what may account for the extra weight. Inflammatory signaling can promote a condition called metabolic syndrome, which causes weight gain, high blood pressure and high cholesterol levels and a higher risk for developing diabetes and heart disease.

The fatter mice in Gewirtz's study had been bred to lack a protein known as toll-like receptor 5 (TLR5), which most intestinal cells sprout on their surface. Its job is to recognize and bind to the whiplike flagella that bacteria use to move around. TLR5 acts as a traffic cop for controlling the mass of pathogens living in the intestine; without it, the normally harmless gut bacteria tend to overflourish and expand in number.

When that happens, the study found, it triggers an inflammatory state, as the body attempts to respond to the increasing population of bugs, and at the same time makes cells less sensitive to insulin. In a way, inflammatory factors and insulin compete for the attention of the same intestinal cells; if the cells are busy responding to inflammatory factors, then they are less likely to take up glucose and process it effectively. Such a desensitization to insulin and glucose then leads to the symptoms of metabolic syndrome, such as weight gain, high cholesterol and triglyceride levels and elevated blood pressure - which were all present in the TLR5-deficient mice. (See how to prevent illness at any age.)

"We don't think the bacteria are directly making the mice eat more, but the bacteria are causing low-grade inflammation, which causes insulin resistance and then makes the mice eat more," says Gewirtz.

To test that theory, the researchers conducted a series of experiments, the most illuminating of which revealed that when the TLR5-deficient mice were given unrestricted diets, they ate 10% more than normal mice, and that even when their food was limited, they were still less sensitive to insulin than their normal counterparts.

The finding was confirmed when the team transferred the bacterial gut population from TLR5-deficient mice into animals that were specially bred to have no immune system, making them incapable of rejecting foreign cells and bacteria. When these animals received the teeming gut world of the TLR5-deficient mice, they too began eating more and developed the same metabolic-syndrome symptoms that their donors had. In other words, the obesity profile of the heavier mice had been transferred to normal mice. "So, applying the logic to humans," says Gewirtz, "we know that to gain weight and become obese, [it] requires you to eat more. The question is, Why do people eat more? Our results suggest that one reason people might be eating more is because of changes in their intestinal bacteria."

A more fundamental question, then, is, What causes changes in gut microbiota? Many things, says Gewirtz, including the use of antibiotics, cleaner water and improved sanitation and hygiene in general, which influences the type and amount of microbes that reside in the intestines. In the current study, scientists found that in TLR5-deficient animals, the total percentage of 150 species of bacteria in the gut was three to four times higher than in normal mice, while 125 other types of bacteria were less common. "We don't have a sense of which is more important yet - that some of those species are missing, or that some are in greater abundance," he says. The net effect, however, is that in the absence of TLR5, the community of microbes changes and, as Gewirtz says, "when the intestinal bacteria is changed, the host response changes with them, and that may predispose you to a variety of diseases of which obesity and metabolic syndrome are perhaps the most mild."

Studying those changes is the next step for scientists like Gewirtz who want to understand the precise link between intestinal microbiota and obesity. An important part of that investigation will involve having an accurate map of the genetic makeup of those gut bugs. And in a separate paper published Wednesday in Nature, an international group of scientists generated the most comprehensive genetic map to date of human gut microbes, using 124 human fecal samples, which gives scientists just the critical window they need to figure out which species of bugs tend to reside in our intestines and which may contribute to weight gain.

While Gewirtz's latest findings are limited to mice, experts believe they may be just as applicable to humans; previous work on gut microbiota has found that obese individuals tend to have a makeup of pathogens in their intestines different from that of people who are of normal weight. "Our results suggest that the tendency to eat more may not only be driven by the fact that food is cheaper and more available, but by a change in the bacteria in the intestines," he says. "People may be eating too much because their appetite is stronger due to a low-grade inflammation they have, which could be due to changes in their gut bacteria relative to what their grandparents or someone else might have had 50 years ago."

If that's true, then studies like this one could open new doors into understanding the myriad ways that pathogens like bacteria can cause disease - including methods that have nothing to do with infection.