Zonulin, Leaky Gut and Coeliac Disease – The Mystery Unravels

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 onestudy probiotics not only reduced the skin disease but alsodecreased 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 noveltherapies directed at altering abnormallyincreased intestinalpermeability and these may play a rolein treating or preventingthese diseases.
  
• Epithelial tight junctions openand close all the time in response to a variety of stimuli.These include dietary state, humoral or neuronal signals, inflammatorymediators, mast cell products, and a variety of cellular pathwaysthat can be usurped by microbial or viral pathogens
  

References

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