An international team led by The Burnham Institute's Minoru Fukuda, Ph.D., has discovered that a human glycoprotein inhibits Helicobacter pylori ("H. pylori"), the bacterium that causes stomach ulcers and is linked with 90% of stomach cancers.
Published on August 13th in Science magazine, these results present a new way of looking at treating chronic inflammation associated with stomach ulcers, and introduces the possibility of preventing stomach cancer associated with H. pylori.
Over fifty percent of the world's population is infected with H. pylori, yet only 2% are afflicted with stomach ulcers and only 1% with stomach cancer. A collaboration between The Burnham Institute and Japan's Shinsu University has discovered the defense mechanism that protects the stomach against H. pylori infection.
H. pylori is found in mostly in the stomach, where it thrives in the superficial mucin layer lining the stomach. The bacterium is rarely found in the deeper portion of the mucin layer, where the mucous cells produce a particular class of glycoproteins, called O-glycans, linked with the carbohydrate alpha 1,4-N-acetylglusosamine, cloned previously in Dr. Fukuda’s laboratory. Because the alpha 1,4-linked N-acetylgucosamine is confined to the stomach's deeper mucosa lining, which also lacks H. pylori, the scientists investigated the possibility that it might play a role against infection by H. pylori.
They isolated mucin from the upper and lower layers and found a key difference: surface-derived mucin actively supported H. pylori growth, while mucins from the second layer inhibited growth. H. pylori in the presence of alpha 1,4-linked N-acetylgucosamine lost its shape, became immobile, and eventually died. This cell-growth immobilizing effect is very similar to the effect of antibiotics, which dissolve or "lyse" the bacterium's cell wall.
The researchers lysed H. pylori cells and set up a biochemical assay using mass spectrometry to analyze the bacterium's cell wall components. They discovered a cholesterol unique to H. pylori, cholesteryl-alpha-D-glucopyranoside, which is a major component of the bacterium's cell wall essential for its growth. Additional experiments confirmed that the O-glycans capped with alpha 1,4-linked N-acetylglucosamine blocked H. pylori's ability to synthesize the cholesterol.
"This is the first time that a glycoprotein has been shown to behave like an antibiotic," says Dr. Minoru Fukuda, who has devoted 20 years of his research career to the study of glycobiology and cancer. "This naturally-occurring cholesterol offers a very specific target for the design of safer drugs that could treat stomach ulcers and, long-term, prevent stomach cancer linked with H. pylori."
Dr. Fukuda believes that it will be possible to breed cows and genetically engineer soy beans that produce milk bearing the inhibitory O-glycans capped with alpha 1,4-linked N-acetylglucosamine.
"This offers an inexpensive way to help people suffering in less developed countries," says Dr. Fukuda. "If we could use transgenic cows and plants to produce this milk, we could possibly eradicate H. pylori infection and eliminate stomach cancer."
The Burnham Institute has applied for patents based on this work.
Dr. Minoru Fukuda is a Professor in the Glycobiology Program of The Burnham Institute's Cancer Center. Other co-authors from The Burnham Institute include Dr. Michiko Fukuda, Professor, and Dr. Motohiro Kobayashi, postdoctoral fellow.
This work was done in collaboration with Dr. Jun Nakayama, corresponding author, and Drs. Masatomo Kawakubo, Yuki Ito, Yukie Okimura, Kyoko Sakura, Susumu Kasama, and Tsutomu Katsuyama of Shinsu University, Japan.