Fasano, Zonulin and autoimmunity: The leaky gut hypothesis

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The intestinal epithelium is the largest mucosal surface in the body, providing an interface between the external environment and the host. Macromolecule trafficking between the environment and the host is dictated mainly by intestinal paracellular permeability, whose regulation depends on the modulation of intercellular tight junctions (TJ). A fast growing number of diseases, including autoimmune diseases, are recognized to involve alterations in intestinal permeability related to changes in TJ competency.

The connection between infection and autoimmune disease is often explained by a mechanism known as “molecular mimicry,” whereby microbial antigens are postulated to resemble self-antigens. The induction of an immune response to the microbial antigens results in a cross-reaction with the self-antigens and the induction of autoimmunity, according to Perl.

There are always several pre-existing conditions that lead to an autoimmune process:

  • Genetic susceptibility
  • Exposition to an antigen
  • Antigen crosses the tight junctions

Contrary to general belief, Fasano says that the autoimmune response can theoretically be stopped and perhaps even reversed if the interplay between genes predisposing individuals to the development of autoimmunity and environmental triggers is prevented or eliminated, as happens in Celiac disease after stopping the consumption of gluten. Moreover, the vast majority of AI diseases present with non competent tight junctions.

Zonulin is, as of now, the only known regulator of the tight junctions (although it is surely not the only one). It should be known that, in celiac disease, the initial breach of the intestinal barrier function caused by zonulin can be perpetuated by the inflammatory process after the access of gliadin to the submucosa. 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. Furthermore, the administration of a Zonulin inhibitor decreased the apparition of diabetes type 1 in susceptible rats. According to some studies, ~50% of T1D patients has elevated serum zonulin levels that correlate with increased intestinal permeability.  In clinically asymptomatic Crohn’s disease patients, increased intestinal epithelial permeability precedes clinical relapse by as much as 1 year. We can see an increase in intestinal permeability in IBD patients during flare ups, though the remission periods are followed by marked decrease. Larazotide acetate, which decreases intestinal permeability has been proved useful for refractary Celiac patients, and represents an interesting approach for other AI diseases.

Proposed role of abnormal intestinal permeability in the pathogenesis of celiac disease. Source: Nature

Even if this is interesting, it should be noted that siblings of T1D, Ankylosing Spondylitis and other AI patients also have increased intestinal permeability and serum Zonulin levels without suffering an AI disease. This means that the loss of intestinal barrier is necessary but not sufficient for the onset of the autoimmune proccess.

The leaky gut theory is pointing us in the right direction but we’re still far away from explaining the pathogenesis of AI diseases. Zonulin isn’t the only regulator of tight junctions and, if the immune dysregulation doesn’t stop, the manipulation of the intestinal permeability will provide only partial results.

Since one can read plenty of erroneous assumptions on some famous websites, we would like to clarify that with the current knowledge, one can’t cure “leaky gut”. No L-Glutamine or bone broth will cure your AI condition. That’s not even necessary as even healthy individuals have “leaky gut”. Management of symptoms is the best you can achieve, especially through a low lectin diet. Do you have a leaky gut? Of course! We all do. Our gut is naturally leaky. What may be problematic is having an abnormally increased intestinal permeability. In Fasano’s words: “the term leaky gut has for decades been used and abused by some alternative medicine practitioners who—without scientific evidence—cited it as the cause of everything from autism to cancer”.

Intestinal permeability is also increased in obese patients. Source: The Lancet

There is a test available that shows whether an individual has increased intestinal permeability. It works by measuring levels of two indigestible sugars, mannitol and lactose, in the urine. Most physicians do not use this test and research shows that it is not very reliable. Using it would be nonsense, as an increased intestinal permeability is a symptom and not a disease itself. Why would you like to measure a marker that is also present in healthy individuals? If you have an AI disease you certainly have an increased intestinal permeability, together with genetic predisposition. As you can see The Leaky Gut theory is not so obvious nor definitive.

We recommend reading Ballantyne’s book, where this theory is perfectly explained:






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