Researchers at UT Southwestern Medical Center have discovered that a protein that binds to bile in the small intestine may hold the key to preventing infection and intestinal breakdown in people with conditions such as obstructive jaundice or irritable bowel syndrome.

" What we've identified is one of the mechanisms for how the body keeps the number of bacteria low in the small intestine, and how it prevents them from getting into other organs," said Steven Kliewer.

The study is published in the Proceedings of the National Academy of Sciences ( PNAS ).

Bile, which is generated by the liver and flows into the small intestine via a duct, contains harsh acids that help the body absorb nutrients, kill certain bacteria and help keep intact the lining of the intestine, a major barrier against the infiltration of infectious microorganisms. That's no small task; if the innermost lining of the small intestine alone were unfolded, it would be the size of a tennis court.

When there's no bile in the intestine, as happens in people with obstructive jaundice or in those who rely on feeding tubes for nourishment, the lining breaks down and bacteria pass through it into the body, sometimes causing the massive blood infection known as sepsis. Simply giving bile acids orally as a substitute isn't a good solution because they can cause liver damage, Kliewer said.

The researchers focused on a molecule – FXR – in the wall of the lining, which binds to bile acids. When FXR was activated by a synthetic binding chemical called GW4064, it was found to activate several genes that are known to protect the intestinal lining or attack bacteria.

The research team also found that FXR molecules heavily lined the inside folds of the intestine in adult mice.

" It's perfectly positioned," Kliewer said. " It's expressed in just the right place to protect us from the environment."

When the bile ducts of mice were tied off, preventing bile from reaching the intestine, adding GW4064 prevented damage to the intestines, showing that it can replace bile in protecting the small intestine.

Genetically engineered mice that lacked FXR showed overall damage to the intestines, "strong evidence that this protein is crucial," Kliewer said. Drugs that bind to FXR, he said, could eventually become useful in treating various conditions of the small intestine.

Source: UT Southwestern Medical Center, 2006


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