They've Done It Again!

Celiac.com 01/23/2020 - Researchers at the University of Maryland, under Alessio Fasano, have, once more, expanded the boundaries of human knowledge.  The implications of their most recent discovery may soon unlock the mysteries of several autoimmune conditions including celiac disease, inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and some types of cancers.  Their discovery and subsequent report of zonulin, in 2000, was an enormous step forward.  It provided insight into one, perhaps the only, common mechanism that causes leaky gut.  Until then, many theories about leaky gut were proffered but none could be substantiated.  We only knew that some autoimmune diseases, bowel diseases, and food allergies (or delayed sensitivities as some call them) seemed to trigger a leaky gut.  Many of those with food allergies seemed to get some relief from eliminating foods to which their immune systems reacted, but we really did not understand the process by which these allergenic substances and various diseases induced a leaky gut.  

However, with the discovery and subsequent characterization of zonulin, it quickly became clear that a leaky gut was an important precursor to the development of at least some forms of autoimmunity. Although many medical practitioners continue to express skepticism about the importance of a leaky gut, emerging research findings should soon quell their concerns.  

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Subsequent pharmacological research by Alba Therapeutics suggests that we may soon be able to abolish the permeable intestine that underlies so many autoimmune and other debilitating conditions.  Currently in clinical trials, Alba Therapeutics is finding that Larazotide Acetate (formerly AT 1001) is abolishing the inflammatory sequelae when individuals with celiac disease consume gluten.  

Healthy digestion involves absorption of tiny, digested particles into the epithelial cells that line the intestine.  These particles are then passed out the other side of the cell and into the bloodstream. These cells line the gut and maintain tight junctions to provide a protective barrier, except when zonulin attaches at cellular receptors. That is when the cells move further apart, allowing larger, undigested molecules to bypass the epithelial cells.  

Larazotide is designed to capture excess zonulin, which is over-produced by genetically susceptible individuals in response to ingested gluten.  This drug is designed to capture the excess zonulin proteins and waste them in fecal matter, rather than allowing them to attach at receptors on epithelial cells.  It is by this means that Larazodide is designed to prevent the development of a leaky gut, regardless of the cause of excessive zonulin production.  

Readers familiar with my work will not be surprised to learn that I’m not planning on eating gluten anytime soon.  But I’d sure like to be able to take a pill containing an otherwise harmless substance, when dining out, whether at restaurants or at friends’ homes.  I’d also like a tool that will help me to identify any other foods against which I may be mounting an inflammatory immune response.  

I imagine getting up in the morning and eating a couple of pancakes made from bean flours that I’m currently not able to tolerate.  If I take some Larazotide first, and I get through the morning without my typical reactions–bloated stomach and heartburn–then I’ll know both what the culprit is and what I can do if I really want to have a couple of bean flour pancakes one morning. 

Similarly (and much more importantly) it will provide people with a tool for helping them to determine whether they are experiencing symptoms of food allergies or if their discomfort is caused by something else.  For instance, if someone is unsure whether their foggy thinking really is the result of eating gluten, they can try Larazotide for a couple of meals.  If their foggy brain clears up, but returns when they stop Larazotide and eat a meal containing gluten, then they will know that food (probably gluten) is likely the culprit.  They may wish to pursue further self-testing or laboratory testing to identify specific problematic foods.

This drug may also provide a tool for investigating children with attention deficit disorders (ADHD). If food sensitivities are the underlying culprit, these children should behave and pay attention fairly normally after a period of taking Larazotide before they consume any foods.  We currently have no idea just how long such an intervention might take, but I’m hoping that researchers will soon answer such questions.  

I recently attended a conference on Crohn’s and colitis.  When talking about treatments, the primary issues under discussion were the impact of various drugs on individuals present.  The patients present shared a wealth of pharmaceutical knowledge.  There was also considerable discussion of research aimed at a cure.  In fact, the hosting organization seems quite fixated on finding a cure in the very near future. What a boon it would be, for everyone concerned, if Larazotide turns out to be that cure!

But we knew all of this before.  In fact, I’ve detailed most of this information in previous issues.  What is new, and intensely exciting, is that the research group at U.  Maryland has now determined that zonulin not only functions to increase intestinal permeability and inflammation, it is also a precursor to haptoglobin 2, a marker of inflammation  that is exclusive to human beings.  No other primates produce this protein, and only 80% of humans produce it.  Considerable research has connected sub-groups of this marker to a variety of cardiovascular diseases, a range of autoimmune conditions, and many cancers.  

Thus, the production of zonulin, which will ultimately mature into haptoglobin 2, is a feature of many more ailments than was previously imagined.  Since Larazotide is designed to capture and waste zonulin in fecal matter, we will soon be able to see what impact this drug can have on a variety of autoimmune diseases–and it promises to offer a tremendous benefit by halting the leakage of undigested proteins into the bloodstream that may be triggering autoimmune reactions by a process known as molecular mimicry.  

But that isn’t all Larazotide might offer.  It could also offer insight into what has been characterized as the plague of the Twentieth Century, cancer.  These inflammatory markers, haptaglobin 2, are elevated in association with many cancers.  If the inflammation proves to be a significant factor in the survival of tumors, we will be able to block its production and deny this substance to the cancerous tissues.  If, on the other hand, these inflammatory markers help the immune system to destroy tumors, we know how to trigger its production (in 80% of humans) and autoimmunity can be deterred by intravenous feeding during treatment.  Either way, there is genuine cause for hope.  

My money is on the former possibility.  I suspect removal of excess zonulin will reduce malignancies, but that is because diet can play an enormous role in cancer.  There is already considerable anecdotal evidence suggesting a ketogenic diet is a viable therapy for insulin sensitive cancers.  Time magazine ran a feature article titled “Can a High Fat Diet Beat Cancer?” in their September 17, 2007 issue.  (The greatest difficulty these researchers are encountering with these trials is dietary compliance. Another serious problem is that their ethical approval required that all conventional treatments be exhausted before beginning the dietary trial.  Thus, many of their research subjects are very sick before they begin the diet.  For these reasons, one of the universities has stopped running these trials despite some promising preliminary results.) Whichever way it goes, Larazotide may well lead to some dramatic advances in cancer research in the very near future.  

Larazotide may also help some type 1 diabetics turn back the clock.  Those who undergo islet cell transplants can usually only expect a year or two of reduced insulin requirements before they return to their former status.  Larazotide may be able to halt the autoimmune destruction of the islet cells which produce insulin, allowing individuals who undergo transplants to experience relatively normal lives, without worrying about balancing the size of their insulin injections with their carbohydrate intake.  They may well be able to forego injections entirely for the rest of their lives.  

Individuals with various autoimmune diseases may be able to halt the progression of their illness and return to more normal lives.  Those with multiple sclerosis, Crohn’s disease, some forms of arthritis, lupus, and a host of other ailments may be stopped in their tracks.  There may even be hope that people like me, with chronic lung disease, will be able to begin rebuilding healthy lung tissues.  Reduced haptoglobin 2 may result in reductions in inflammatory reactions to airborne allergens.  This, in turn, may permit us to breathe well enough that we can exercise and build healthy lung tissues without scar tissues.  I’m not suggesting that we will be able to return to our 25 year-old activities, but I believe we may be able to live more normal, more productive lives for whatever time we have left.  

Finally, Larazotide may even bring about reductions in the excess mortality found in the celiac disease and gluten sensitive community.  We have a lot to be grateful for. The research group directed by Alessio Fasano is making enormous contributions to broadening medical understanding of celiac disease, expanding medical knowledge of autoimmunity and cancer, and increasing celiac awareness (see:  Scientific American, August 2008, “Surprises from Celiac Disease” by Alessio Fasano). As I said at the beginning, “They’ve done it again!”