Researchers find trigger for devastating digestive disease, propose treatment

September 26, 2002

Researchers have found a peptide molecule that triggers celiac sprue - a severe inflammation of the intestine that results from eating wheat and related grains - and propose a treatment strategy that relies on bacterial enzymes to break down the offending molecule in the digestive tract. As many as 1 in every 200 Americans suffers from the condition.

In the September 27 issue of Science, Chaitan Khosla and his coworkers at Stanford University and the University of Norway in Oslo, report disassembling the large, complex mixture of gluten proteins and identifying a single component that triggers the autoimmune response characteristic of celiac sprue.

The study presents, "a combined chemical-physiological-immunological answer to the question 'why is gluten toxic to a person with celiac sprue?,'" said Khosla, whose work is supported by the National Science Foundation (NSF). "If proven correct, the findings will lead to new insights into the causes of celiac sprue, and perhaps certain other types of autoimmune diseases."

The researchers determined that the autoimmune response in people with celiac sprue can be traced to an unusually long molecule - a chain of 33 amino acids - that cannot be broken down by the human digestive system. They immersed the 33-amino acid chain in digestive enzymes derived from bacteria and found that a bacterial enzyme, prolyl endopeptidase, can break the chain into apparently harmless components.

"The technology used to isolate and identify the peptide trigger for celiac sprue, and the enzymology used to neutralize the disease, are marvelous examples of how research into the fundamental understanding of life processes can directly influence human health," said Fred Heineken, program director in NSF's Biochemical Engineering/Biotechnology Program.

Celiac sprue is often diagnosed only after years of painful symptoms. Presently, there is no cure. The only treatment is to completely avoid grains that contain gluten, such as wheat, rye and barley.

The disease usually surfaces in early childhood when intestinal tissue begins to show signs of devastation. Symptoms include chronic diarrhea and an inability to gain weight or grow normally. When the disease arises in adulthood, symptoms can also include fatigue, weight loss, anemia and neurological symptoms. Over time, celiac sprue can lead to overall sickness and even intestinal cancer. In the small intestine, enzymes from the pancreas initially digest gluten by breaking it into a number of fragments called peptides. In most people, the larger peptides probably work their way down to the lower intestine where they are eaten by microorganisms.

"But in people with celiac sprue, the stable 33-amino acid peptide causes big problems because the molecule is recognized as being a threat to the person's immune system," said Khosla, who also received NSF's Alan T. Waterman Award in 1999. On learning that his family was faced with the illness, Khosla used the award to pursue research on the disease.

Khosla and his coworkers believe the bacterial enzymes, which worked in human tissue cultures as well as intact rats, may result in a simple, oral supplement that can eliminate the harmful effects of gluten. The treatment approach would be similar to enzyme supplements taken orally by people who cannot digest lactose, a sugar found in milk.

Khosla adds that an approved therapy could be as many as 5 to 8 years away, although research is already underway and the treatment should be testable in people within 2 to 3 years.
-end-
Note to broadcasters: b-roll is available of an interview with Chaitan Khosla; Khosla in his laboratory; and an interview with a woman and her 6-year-old son, who discuss the challenges of living with celiac sprue. For a static illustration series of the disease process, see: http://www.nsf.gov/od/lpa/celiac_sprue/hi_res.htm

For more information on Celiac Sprue, see: http://www.nlm.nih.gov/medlineplus/celiacdisease.html
For more information on the Alan T. Waterman Award, see: http://www.nsf.gov/nsb/awards/waterman/waterman.htm

Additional media contact:
Michelle Brand, Stanford University
650-723-0272/mbrandt@stanford.edu

Program contact:
Fred Heineken
703-292-7944/fheineke@nsf.gov

Images available: http://www.nsf.gov/od/lpa/celiac_sprue/hi_res.htm
Video available: Contact Dena Headlee, dheadlee@nsf.gov, 703-292-8070

National Science Foundation

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