Bacteria of human intestinal tract
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Jane Hurd
Bacteria of human intestinal tract

Gut Reactions

The body of evidence tying gut bacteria to obesity is growing fatter.

A couple of weeks ago, researchers reported that overweight people show a distinct chemical profile in their breath — too much hydrogen and methane — that could be due to a particular species of bug in their gut. Then another group found that in mice, gastric bypass surgery changes the microbial make-up of the gut, and this shift might explain the animals’ subsequent weight loss.

Both of these studies, like many others published in the last few years, suggest that there’s some kind of connection between gut microbes and weight. The latest report, out today in the Proceedings of the National Academy of Sciences, digs a bit deeper, analyzing how bacteria and fatty foods interact in the mouse gut.

More provocatively: The new study uncovers a natural enzyme that might prevent — or even reverse — obesity in people.

Trillions of bacteria lurk in our digestive tract, eating our food and helping us digest it in return. In that cozy space, the bugs have a remarkably copacetic relationship with our immune system (which, after all, doesn’t typically get along with bacteria). But if the microbes travel outside of the gut, it can cause trouble.

The cell walls of gram-negative bacteria hold a molecule called lipopolysaccharide. More commonly known as endotoxin, the molecule triggers the human immune system and can be extremely dangerous in large quantities. “When people have very bad infections, they can get very high levels of endotoxin in their blood and get sepsis or die,” says Richard Hodin, a professor of surgery at Harvard.

Even low levels of endotoxin can be harmful. In 2007, a study led by Rémy Burcelin at INSERM in Toulouse, France, showed that when mice eat a high-fat diet, it (somehow) increases the amount of endotoxin in their gut. Burcelin’s experiments also suggested that endotoxin causes intestinal inflammation, which in turn makes the gut more permeable, allowing endotoxin to leak into the blood supply and further aggravate the immune system. Over time, mice carrying excess endotoxin develop chronic inflammation, insulin resistance and obesity — all features of metabolic syndrome, which affects more than 20 percent of people in the U.S. and ups the risk of heart disease, stroke and diabetes.

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More recent studies have shown that in people, too, eating fatty foods induces a dramatic spike in blood endotoxin.

So: Too much endotoxin is bad. The new study focuses on a natural gut enzyme — called intestinal alkaline phosphatase (IAP) — that helps keep endotoxin in check.

IAP has been studied for several decades for its role in helping the body absorb fat. When rats eat a fatty meal, IAP levels shoot up in their blood and lymph. When the animals don’t eat anything, they stop making IAP. And when mice lacking the IAP gene go on a long-term high-fat diet, they get very fat.

IAP is found on cells that line the small intestine. But researchers are just beginning to understand what it does there, Hodin says. “It’s only in the past five or so years that we’ve started to figure out that this enzyme primarily functions as a protective mechanism against the bacteria in the gut.”

In 2010 Hodin’s team reported that in cells cultured in the lab, IAP can detoxify bacteria, effectively blotting out endotoxin. In the new study, the researchers tested whether IAP could also curb the detrimental effects of endotoxin in living animals.

The researchers found that mice lacking IAP have leaky guts, as well as excess endotoxin and inflammatory molecules in their blood. The knockout animals are also obese and have insulin resistance, a sign of diabetes.

The team then looked at the effects feeding mice IAP as a supplement to a high-fat diet. A daily dose of IAP (it’s a powder that dissolves in the animals’ drinking water) for 11 weeks prevented all of the problems that develop in mice eating the high-fat diet alone — insulin resistance, leaky gut, blood endotoxin, inflammation, and weight gain.

In yet another set of experiments, the researchers fed mice a high-fat diet and allowed them to fully develop metabolic syndrome and obesity. Then they gave them the IAP supplement for six weeks. In these animals, IAP reduced endotoxin levels, inflammation and glucose intolerance. If the fat mice had taken the supplement for a longer period of time, their condition may have reversed even more, Hodin says.

Like all mouse studies, it’s unclear whether the same patterns would hold in people taking IAP. Hodin’s team is working on a formulation of the enzyme that can be tested in people in the next couple of years.

Unlike most obesity drugs, toxicity and side effects are not likely to be a problem for this substance. “We think it’s going to be safe because it’s an enzyme that’s naturally occurring in our intestines anyway,” Hodin says. One small clinical trial in Europe used IAP to treat ulcerative colitis and found no side effects of the enzyme, he adds.

A bigger question is how many people with metabolic syndrome or obesity might benefit from IAP treatment. “There’s roughly 400 million people with diabetes and even more with obesity, and they don’t all have the same metabolic syndrome and types of diabetes. Some might have a problem with the IAP system and others might not,” says Burcelin, whose team found the link between a fatty diet and endotoxin. “We probably need to identify biomarkers first to identify which patients should be treated with that type of strategy or not. But I think that it could work.”

Other scientists are curious about the mechanism that allows IAP to work. Hodin’s hypothesis is that it works by somehow blocking the passage of endotoxin through a leaky gut. But there are alternative explanations, notes Peter Holt, a gastroenterologist and senior research associate at the Rockefeller University who has studied the relationship between fat and endotoxin. “It could be that IAP changes the gut bacteria in such a way that less endotoxin is formed,” Holt says. If that’s the case, he adds, then there might be other ways to adjust the bacterial populations of the gut that wouldn’t require high doses of IAP.

Regardless of the mechanism, though, the new study is part of an exciting wave of research on the (still largely mysterious) interactions between our food, immune system and microbial residents. Just yesterday, a study in Nature Medicine reported that when eaten in large quantities, an ingredient in red meat causes gut bacteria to produce a chemical that accelerates heart disease. As my fellow Phenomena blogger Carl Zimmer wrote this morning, despite the fact that nobody really understands the underlying biology, these discoveries have fueled a microbiome industry of yogurts, pills and creams already worth $8.7 billion.

“We’re at the beginning of a whole age of altering microbiota at will,” Holt says. “It’s bound to happen in the next few years. And to my mind that’s the most interesting and potentially powerful experimental manipulation in humans that’s on the horizon.”


In addition to the scientists quoted above, many thanks to Pauline Lund of the University of North Carolina at Chapel Hill for sharing her thoughts on the new study.