Zonulin, Leaky Gut and Coeliac Disease – The Mystery Unravels

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In 2000, researchers from the University of Maryland School of Medicine identified that a protein called zonulin was a critical molecule in the development of coeliac disease and other autoimmune disorders including multiple sclerosis and diabetes. This relationship further links the risk and progression of systemic disease to the health of the gastrointestinal tract.

Zonulin has, as is typical in the  history of immunology been further clarified and renamed as  haptoglobin 2 precursor.

So what is hatoglobin?

Haptoglobin is a molecule known to scientists for many years. Originally identified as a marker of inflammation in the body the primary molecule Haptoglobin 1 is the original form of the haptoglobin molecule, it is estimated to have evolved 800 million years ago. Haptoglobin 2 is a permutation unique to humans. Scientists believe the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.

It seems zonulin is the precursor molecule for haptoglobin 2 — that is, it is an immature molecule that matures into haptoglobin 2. Precursor haptoglobin 2 is the first precursor molecule that serves another function entirely — opening a gateway in the gut, or intestines, to let gluten in. People with coeliac disease suffer from a sensitivity to gluten.

While apes, monkeys and chimpanzees do not have haptoglobin 2, 80 percent of human beings have it,” says lead author Dr. Fasano. “Apes, monkeys and chimpanzees rarely develop autoimmune disorders. Human beings suffer from more than 70 different kinds of such conditions. We believe the presence of this pre-haptoglobin 2 is responsible for this difference between species.

“This molecule could be a critical missing piece of the puzzle to lead to a treatment for coeliac disease, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 and to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier.”

People who suffer from coeliac disease have a sensitivity to gluten, a protein found in wheat, and suffer gastrointestinal distress and other serious symptoms when they eat it. In coeliac patients, gluten generates an exaggerated release of zonulin that makes the gut more permeable to large molecules, including gluten. The permeable gut allows these molecules, such as gluten, access to the rest of the body. This triggers an autoimmune response in which a coeliac patient’s immune system identifies gluten as an intruder and responds with an attack targeting the intestine instead of the intruder.

An inappropriately high level of production of zonulin also seems responsible for the passage through the intestine of intruders other than zonulin, including those related to conditions such as diabetes, multiple sclerosis and even allergies. Recently, other groups have reported elevated production of zonulin affecting the permeability of the blood brain barrier of patients suffering from brain cancer.

Managing the integrity of the gastrointestinal barrier is presenting itself as a therapeutic opportunity for a wide range of seemingly unrelated conditions. The connectivity of the mucosal immune system to all other areas of human function is gathering increasing support from the scientific community and is reflecting some of the long held but non quantified beliefs concerning the relationship between the gut and human health and disease.

In one study probiotics not only reduced the skin disease but also decreased elevated small intestinal permeability.

Key Points

  • epithelial permeability of the gastrointestinal tract can beevaluated in a site specific manner;
  • increased intestinalpermeability is observed in associationwith several autoimmunediseases. It is observed prior to diseaseand appears to beinvolved in disease pathogenesis;
  • there are new and novel therapies directed at altering abnormally increased intestinal permeability and these may play a role in treating or preventing these diseases.
  • Epithelial tight junctions open and close all the time in response to a variety of stimuli. These include dietary state, humoral or neuronal signals, inflammatory mediators, mast cell products, and a variety of cellular pathways that can be usurped by microbial or viral pathogens


  1. Sapone, L. de Magistris, M. Pietzak, M.G. Clemente, A. Tripathi, F. Cucca, R. Lampis, D. Kryszak, M. Carteni, M. Generoso, D. Iafusco, F. Prisco, F. Laghi, G. Riegler, R. Carratu, D. Counts and A. Fasano. Zonulin up-regulation is associated to increase in gut permeability in subjects with Type 1 diabetes and their relatives. Diabetes 2006; 55:1443-9.  View Abstract
  2. D. Branski, A. Fasano, R. Troncone. Latest developments in the pathogenesis and treatment of celiac disease. J Pediatr. 2006;149:295-300.View Abstract
  3. Fasano A. Systemic autoimmune disorders in celiac disease. Curr Opin Gastroenterol. 2006;22:674-9.View Abstract
  4. Rosenfeldt V , Benfeldt E , Valerius NH, et al. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr 2004;145:612–16 View Abstract
  5. Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006 Oct;55(10):1512-20. View Abstract
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