In the Sept. 27 issue of Science, researchers identify a fragment of gluten called gliadin as the celiac culprit. They showed that this fragment is resistant to digestion and is responsible for the intestine-damaging inflammatory response experienced by celiac patients. They also report the use of a dietary enzyme made by a bacterium that can break down the fragment into harmless bits, suggesting future treatment through dietary supplements.
"These findings are the first step to giving people with celiac disease real hope for a normal life," said Chaitan Khosla, PhD, professor of chemistry, chemical engineering and, by courtesy, of biochemistry. Lu Shan, a graduate student in Khosla's lab, was lead author on the paper. The team included other Stanford researchers as well as a group from the University of Oslo in Norway.
The lining of the small intestine is normally carpetlike, covered with small protrusions called villi. Celiac disease, however, results in a smooth, pipelike intestine. The reduced surface area keeps the body from absorbing nutrients. Often diagnosed in childhood, the disease can lead to the distended stomach and stunted growth typical of starvation.
"The only effective therapy for most people is a lifelong gluten-free diet, and that's fairly restrictive," explained co-author Gary M. Gray, professor of medicine, emeritus. The diet is essential over the long term both to restore normal intestinal function and to reduce the risk of developing osteoporosis, lymphoma or cancer of the small intestine, he added.
In the laboratory, Shan simulated the digestive process, exposing gliadin to digestive enzymes in test tubes. She identified a protein fragment made up of 33 amino acids that was resistant to further digestion and whose structure was known to be toxic. Most proteins are broken down into small peptides of between two and six amino acids or into single amino acids. She then repeated her study in rats and again in test tubes using tissue taken by biopsy from patients undergoing unrelated medical procedures. "Even with prolonged treatment (exposure to intestinal enzymes), the peptide doesn't lose the ability to induce the inflammatory response," Shan said.
When they looked more closely at the fragment, Shan and her colleagues found that it was made up of even smaller fragments already known to induce human T-cells to attack the intestine. The team in Norway then measured the ability of the gliadin fragment to induce autoimmune activity. "The response by T-cells was about 10 to 20 times higher than the smaller peptides themselves," Shan said.
Because the fragment is rich in the amino acid proline, investigators reasoned that a peptidase (an enzyme that breaks down proteins) with the ability to digest proline-rich chains might be able to break down the gliadin fragment, rendering it harmless to celiac patients. They have now shown that this is the case in test tubes and in rats. Because there are no animal models of celiac disease, testing this approach in humans is a long way off and will require further preclinical work, Khosla said. "We think that this mode of therapy - peptidase supplementation - may offer hope in treating celiac sprue eventually, and we're going to test this hypothesis."
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.