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Dr. Fasano, of Massachusetts General Hospital, discovered the protein zonulin, "the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance."  He is the foremost expert on gluten and Celiac Disease.

 

You may be thinking, I don't have Celiac Disease, so what does this have to do with me? Gluten is the culprit. Why? Gluten, genetically modified (GM) in wheat has an unusual composition that cannot be completely digested.  Gluten has too many proline and glutamine amino acids and our enzymes do not recognize this sequence. The same can be said for GM barley and rye, said Dr. Fasano during his talk at the Gluten Summit. Gluten is comprised of two main proteins, gliadins and glutenins, and both are toxic for Celiac Disease patients. Gliadins triggers the release of zonulin, which opens up the TJ, or doors, and allows gliadins and sometimes other molecules, to pass through. When gliadins are seen, it triggers an immune response, which leads to inflammation.  

   

Since gluten can not be completely digested, zonulin is released loosing the tight junctions (TJs) of the intestinal wall.  When gluten passes through the intestinal wall into the blood stream, it triggers the immune system resulting in inflammation. Source: Scientific America, Inc..

  

When food molecules pass through, it triggers the immune system and one can form food sensitivities in response to these molecules.  When immune cells pass through, they can travel anywhere in the body, said Dr. Fasano.  If the immune cells reach the joints, they can cause joint pain.  If they reach the nerves, they can cause peripheral neuropathy. If they reach the skin, they can cause dermatitis herpetiformis and so forth.  One theory is that the TJ-- or doors-- may remain open longer than usual, thus allowing food molecules and immune cells to pass through, possibly due to an overproduction of zonulin.  Scientists don't know why this happens, but in Celiac patients there is an up-regulation of zonulin in the acute phase "and that zonulin is released from intestinal mucosa following exposure to either gluten or microorganisms."

 

For many people, our immune system takes care of the gliadins and everything is fine. For others, depending on their genetic make-up or predisposition, the immune system goes awry. In Celiac patients, there is a miscommunication between the innate and the adaptive immune system and the adaptive immune system starts attacking its own cells, leading to gut damage.  Since Celiac Disease is a genetic disorder, it is believed that these people have at least one of two genes needed to develop Celiac; HLA-DQ2 and HLA-DQ8.  Dr. Fasano believes that these two genes act like "docking stations" for gluten when it has been changed by transgutaminase, which is the only way the immune system recognizes gluten as the enemy.  Antigen-presenting cells (APC) present deliver or transport this complex to T cells and T cells start producing cytokines that will be used against its own cells. In classic Celiac Disease the damage occurs in the intestine.

 

In gluten sensitivity, it exclusively involves the innate immune system and leads to inflammation and symptoms, but will never lead to enteropapthy, stated Fasano.  Symptoms of non-Celiac gluten sensitivity include the following: abdominal pain, headaches, foggy mind, chronic fatigue and depression.  These symptoms long-term can lead to poor quality of life and possibly shorter life expectancy.

 

According to Dr. Fasano's paper "Zonulin has been observed to be involved in intestinal innate immunity and to be up-regulated in several autoimmune diseases, including Celiac Disease (CD) and type 1 diabetes (T1D), in which TJ dysfunction seems to be the primary defect."

 

Dr. Fasano believes the gut is the most sophisticated immunological component in our body that is controlled by a neuroendocrine network.  He believes our intestine is our interface with the environment.  Information is exchanged in a highly controlled and coordinated manner.  Our state of health or disease is the coordination of our genes and the environment and our "gut is the point of entry in which these two elements, they will meet."

 

Fasano believes that there has been an epidemic of autoimmune disease that has developed over the last 40-50 years. He said we can't blame genetic changes because genetic mutations take centuries to develop. We are unable to adapt to our fast changing environment. Our intestinal barriers function as a integral part of the equation, where specific genes control our gut permeability and the proteins or fragments that cross this barrier are the instigators that lead to autoimmunity.

 

"A fast-growing number of diseases are recognized to involve alterations in intestinal permeability related to changes in TJ competency. These comprise autoimmune diseases, including T1D, CD, multiple sclerosis, and rheumatoid arthritis, in which intestinal TJs allow the passage of antigens from the intestinal milieu, challenging the immune system to produce an immune response that can target any organ or tissue in genetically predisposed individuals. TJs are also involved in cancer development, infections, and allergies."

 

"Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, the autoantibody titers are normalized, the autoimmune process shuts off and, consequently, the intestinal damage (that represents the biological outcome of the autoimmune process) heals completely."

 

The composition of the bacteria in our gut is the key factor impacting intestinal physiology, where microbiome helps the intestinal immune function to maturity, stated Fasano. He said that 99% of the bacteria in the gut can't be cultured and that our microbiome is 100 times more complex genetically. Our microbiome affects how our genes are expressed. As humans, we have a rudimentary genetic make-up of 25,000 genes, compared to an earthworm, that has 90,000 genes. Our micrbiome is highly affected by our nutrition and environment and is impacted by pollution, chemicals and radiation. We are constantly exposed to antibiotics, not only from antibiotic usage, but also from the vegetable and animal products that we eat, the vast majority grown with the use of antibiotics.

 

Dr. Fasano's paper states " Enteric infections have been implicated in the pathogenesis of several pathological conditions, including allergic, autoimmune, and inflammatory diseases, by causing impairment of the intestinal barrier. We have generated evidence that small intestines exposed to enteric bacteria secreted zonulin...... This zonulin-driven opening of the paracellular pathway may represent a defensive mechanism which flushes out microorganisms so contributing to the innate immune response of the host against bacterial colonization of the small intestine."

 

Since the first paper detailing the human microflora, there has been an uptick in the interest of microbiome research in the past 10 years. There are currently five start-ups and there may be more that are focusing on this field:

 

1) Seres Health, founded by Flagship VentureLabs, is "developing Ecobiotic™ therapeutic products, the first therapeutics that catalyze a shift to health by augmenting the biology of the microbiome, " according to Flagship's website.

2) Second Genome, founded in 2010, secured a Series A deal with Janssen to advance new microbiome-based therapies for ulcerative colitis.

3) Vedanta Biosciences, founded by PureTech Ventures and a team of immunology and microbiology experts, is focused on developing microbiome modulators for autoimmune and inflammatory diseases.

4) Microbiome Therapeutics, previously known as NuMe, is running two clinical trials of a microbiome modulator designed to enhance insulin sensitivity in patients with prediabetes, and lessen adverse GI effects in those who are taking the antidiabetic drug metformin.

5) ViThera Pharmaceuticals, founded in 2009, is engineering bacteria to deliver therapies to the gut. Their lead program is in preclinical development for inflammatory bowel disease.