A New Drug For Celiac Disease?
As you know, there is currently no known cure for celiac disease or gluten sensitivity, adopting a gluten-free diet being the only measure available to those who are sensitive to gluten. Because CD disrupts normal absorption of nutrients in the digestive system, sufferers can easily become deficient in important nutrients, potentially leading to disorders such as chronic fatigue, arthritis, schizophrenia, dementia, epilepsy and short stature.
One researcher who has come up with an insightful view of CD is Professor Alessio Fasano of Maryland University. He noticed that among the spectrum of potential autoimmune disorders, CD is the only disorder that can be remediated by removing a single substance from the diet – gluten. He pointed out that there could be a third trigger to CD: we already know that celiacs have a genetic predisposition and that there is an environmental trigger to the onset of CD. However, Professor Fasano has added a third factor: an unusually permeable gut.
It was while he was working on a vaccine for cholera some years ago, that Fasano made a fascinating discovery. Along with other scientists, he began with the assumption that the sole cause of the severe diarrhea associated with cholera was the cholera toxin. He therefore deleted the cholera toxin gene from the infectious organism Vibrio cholerae and administered the attenuated bacteria to volunteers. To his amazement, the volunteers suffered the same severe diarrhea response as if they had been administered the intact organism. This finding nullified Fasano’s hypothesis. Although tempted to give up, his curiosity led him to discover some important new findings regarding the nature of the intestine.
In the course of their research to find out what went wrong, Fasano’s team discovered a new toxin which they named zonula occludens toxin or zot for short. This discovery dovetailed nicely with concurrent findings on the nature of the tight junction cells of the intestine. Previously assumed to be biologically inert, researchers had found that a complicated network of proteins formed the tight junction cells that lined the intestines. Fasano found that zot could loosen the structure of the tight junction cells, leading to increased intestinal permeability. He therefore concluded that the cholera organism exploited pre-existing pathways that regulated intestinal permeability.
A few years later, Fasano’s team discovered a protein that they named zonulin, which was capable of increasing intestinal permeability in the same way as zot. The full capability of this molecule is yet to be elucidated, but it seems that zonulin, which is produced by epithelial cells of the intestine and other parts of the body, regulates the movement of large molecules, fluid and cells of the immune system between different areas of the body.
After searching the medical literature, Fasano found that many autoimmune disorders are known to involve increased intestinal permeability. These include type 1 diabetes, rheumatoid arthritis, CD, multiple sclerosis and various inflammatory bowel diseases. He found that the presence of high amounts of zonulin is responsible for many of these diseases, and that gluten can provoke the release of increased amounts of zonulin in the body. Fasano reasoned that it is high intestinal permeability that allows gluten to escape from the gut and potentially react with cells of the immune system. He concluded, therefore, that removing one of the 3 causative factors – genetic susceptibility, environmental trigger or the intestinal permeability – could halt the disease process.
Fasano founded a company that is currently developing a drug which addresses the intestinal permeability factor in CD. His team formulated an inhibitor of zonulin called Larazotide. This drug has already begun clinical trials and the results are promising. Larazotide reduced inflammatory response, intestinal barrier dysfunction and gastrointestinal symptoms and produced negligible side effects in CD patients. Fasano does not tout his invention as a cure, rather he proposes that it could be a useful adjunct to a gluten-free diet.
The first year of life is crucial for the development of a child’s immune system. This is when the immune system learns to distinguish between substances that are ‘friendly’ to the body and those that the body should attack and destroy. Disturbances in this system can lead to autoimmune disorders. So, in an attempt to delay age of onset of celiac disease, Fasano’s team is conducting an experiment which consists of completely banning all gluten-containing foods in babies known to have a familial genetic predisposition to CD. Employing this strategy they hope that the immune system could be trained to tolerate gluten. The results of this study are already impressive. With 700 children enrolled in the trial, it has already been found that this system reduces by fourfold the likelihood that the child will develop CD.