Researchers Discover Ways The Ulcer/Cancer Bug Can Trigger Disease

March 31, 1998

St. Louis, March 24 -- A mouse with a human gene has revealed why some people who harbor the peptic ulcer bacterium get sick while others don't. If the stomach lining provides toeholds for the bacterium, it may draw the immune system's friendly fire.

"If the right combination of circumstances occurs -- first, you're unfortunate enough to be infected with a bacterial strain that can bind to the cells lining your stomach and, second, the bacterium contains molecules on its surface that resemble some of those on your stomach cells -- the destiny of the infection may be skewed toward autoantibody production, loss of acid-producing cells and possibly neoplasia," says lead researcher Jeffrey I. Gordon, M.D., the Alumni Professor and head of the Department of Molecular Biology and Pharmacology at Washington University School of Medicine in St. Louis.

Researchers in Gordon's lab describe their findings in the March 31 issue of Proceedings of the National Academy of Sciences. First authors are postdoctoral fellow Janaki L. Guruge, Ph.D., and Per Falk, M.D., Ph.D., adjunct assistant professor of molecular biology and pharmacology at the School of Medicine and now associate director of molecular biology at the Swedish pharmaceutical company ASTRA Hässle.

Half of the world's people are colonized with Helicobacter pylori. Most have few symptoms -- some gastric inflammation, perhaps, before an apparently harmonious relationship sets in that can last for decades. But 10 to 20 percent of infected individuals are not so lucky. Some get ulcers, and others develop progressive inflammation of the stomach and lose acid-producing cells. This increases their risk for stomach cancer, which is common in countries where H. pylori infection is rife.

"This is a rather extraordinary example of a bacterium that can be relatively harmless in some people and cause cancer in others," Gordon says. "The challenge is to identify patients who are at risk for developing more serious disease."

Look into the stomach of an infected person who has severe gastritis or ulcers, and you'll see H. pylori associated with cells that line the stomach. The bacterium is able to produce molecules that allow it to attach to these stomach cells. In laboratory experiments, scientists have identified several molecular receptors that can serve as potential sites for bacterial attachment. "We wanted to find out whether -- and how -- attachment could alter the outcome of infection," Gordon says.

Australian scientists fingered H. pylori as the culprit of peptic ulcers in the 1980s, but the lack of genetically well-defined animal models has hampered attempts to understand how the organism causes disease. "Cultured stomach cells can't reveal how you would respond if H. pylori stuck to your stomach lining," Falk says.

In 1993, Falk and another Swedish scientist at Washington University, Thomas Borén, D.D.S., Ph.D., discovered that H. pylori can attach to a molecule called Lewis b (Leb) on stomach lining cells. This molecule also decorates the red blood cells of people with the Leb blood group.

In Gordon's lab, Falk introduced the human Leb gene into a mouse. He manipulated the gene so it was produced in cells that line the animal's stomach. Mice without the human Leb gene served as normal controls.

Both groups of mice were exposed to H. pylori strains retrieved from Peruvian patients with gastritis. The Leb blood group antigen is commonly found in Peruvians, and most H. pylori strains from Peru are able to bind to Leb. Guruge found that both groups of mice -- those with and those without Leb -- became infected with H. pylori easily and for long periods of time. The bacteria attached to the stomach epithelium only in animals with human Leb, however. In the control mice that lacked Leb, they simply parked in the gastric mucus.

This difference in location affected the mouse's immune response. Guruge noticed that the mouse made antibodies against H. pylori carbohydrates when the bacterium attached to the stomach lining. As it turned out, these bacterial carbohydrates resembled carbohydrates that a mouse's own acid-producing parietal cells normally produce.

Faced with this molecular mimicry, the immune system attacked the mouse's own acid-producing cells as well as the bacteria. The Leb mice developed an inflammatory reaction that resembled chronic active gastritis found in humans with symptomatic H. pylori infection. Their parietal cells disappeared, as they do in humans with atrophic gastritis, a precancerous condition. In a different study, Gordon's group has shown that undifferentiated cells in the stomach lining proliferate abnormally when parietal cells are lost. Such unrestrained cell division eventually may increase the risk of cancer, Gordon suggests. "So though attachment isn't necessary for H. pylori infection, it markedly affects the outcome of infection," he says.

This genetically well-defined model should enable researchers to identify bacterial and host genes that respond to attachment. Such information should further treatment and prevention efforts. Gordon suggests that his group's approach also could be used with other types of bacteria to understand the role of bacterial attachment in a variety of diseases. "This melding of transgenic mice and molecular microbiology offers great opportunities for the future," he says.

Guruge JL, Falk PG, Lorenz RG, Dans M, Wirth H-P, Blaser MJ, Berg DE, Gordon JI. Epithelial attachment alters the outcome of Helicobacter pylori infection. Proceedings of the National Academy of Sciences, 95, 3925-3930, 1998

This research was supported by grants from the National Institutes of Health and the Swedish Cancer Society.

Washington University School of Medicine

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