zonulin, leaky gut, gluten, autoimmune disease & thyroid: this pioneering researcher tells all

The day this national leading expert agreed to be interviewed by phone, I had goose bumps on my arms.

I love how Dr. Fasano made it so easy to understand what can be very complex topics. I was so inspired by our interview that I created images too.

Transcript of my interview with Alessio Fasano, MD

HM: I am thrilled to have you at Hypothyroid Mom. How did you become interested in celiac disease, gluten intolerance, intestinal permeability and their relationships to autoimmune disease?

AF:  So for celiac disease, this goes back to my place, Naples, where I trained. A medical school where I worked, University of Naples, it was really a place in which celiac disease was one of the main, if not the main, scientific interests in the department where I end up to work with, the department of pediatrics. So this was by default, and not just by immediate interests. Then when I moved in the United States, this interest was fueled by the fact that celiac disease was pretty much non-existent in the United States and it really solicited my curiosity.

How come that was so frequent in Europe, and so rare in United States? And the rest is history. Because we start to really to get into the detail of how eventually this difference could be explained. And the answer was, well, celiac disease was overlooked in United States.

While I was doing that because my main interest was diarrheal diseases, both chronic like celiac disease, but also acute. Diarrheal disease is 200 years and can be affected when you have an infection on your intestines. I was studying several conditions of acute diarrhea, particularly those affecting kids in the developing countries, including cholera. And doing that, I adopted this cholera toxin that makes intestines leak.

So the two worlds really, again, connected in full circle when I start to really study how this was working. And I tried to answer the mechanism of how the structure was making intestines leak. We ended up discovering almost 15 years ago, a molecule, this zonulin, that this toxin was mimicking, that that’s what was making intestines leak. And in trying to figure out the conditions in which zonulin doesn’t work the way they’re supposed to, celiac disease came on the top. So the two worlds, the infection diseases and celiac disease, met at that point. And again, that’s how my interest in celiac disease now is a model of immunity. And got the mobility, and so on and so forth, it really materialized.

HM:  Wow, that’s so fascinating. I read that in 2000 you discovered the protein zonulin and I’ve read a great deal about how it’s linked to leaky gut. One thing is a lot of people will wonder, well, what exactly is leaky gut? They hear it, but they can’t really visualize it. Could you describe what a leaky gut looks like?

AF:  Yeah, I mean, the intestine is a long tube that’s covered by single layer cells from top to bottom and you can conceptualize this single layer cells as a sort of a wall. Like the Great Wall of China, if you wish, that divided the extended wall, the one that’s outside us to our internal body so that noxious and potentially harmful substances will not gain easy access.

But of course, this wall has to have ways to make this communication, these two walls to occur. So in between cells, rather than to have cement, as we believed before, we have gates like the levee gates of castles so that you can bring in the merchandise and friends. And when you get done, you close these gates so you’re protected against the enemies. So a leaky gut is a condition in which these gates get stuck open.

So rather than do their job to open when you need and then close immediately, for reasons we only partially understand, in some individuals, these gates, they don’t close anymore. And therefore, rather than function as, again, a way to protect for this uncontrolled passage of enemies in our body, now they don’t serve anymore that function. And so enemies can come through. It depends who you are. You may have different clinical outcomes.

HM: Interesting, and so what is the connection then between zonulin and leaky gut?

AF:  Well, zonulin is the remote control, if you wish, that will open these gates. So if it works the way it’s supposed to, when you push the button, the gates they come down. And then there’s a timer that brings the gates up again. In people with serious health conditions, particularly autoimmunity, zonulin the remote control doesn’t work anymore. It’s like somebody keeps their finger pushing on the button to keep that open. So there’s so much zonulin produced, and therefore, these gates rather than to close soon after they’ve been opened, they get stuck open.

HM:  How does that leaky gut then translate to autoimmune disease?

AF:  This is another interesting question. So again, if you go back to the power of the walls that are around the castle, or around the medieval city, in the inside you have soldiers that protect this castle. They’re on the watch out to make sure that if the enemies will eventually sneak in, they will take care of it. These are the immune cells. There are many immune cells and they do different functions. But mainly in the gut, these immune cells, they are just on the other side of this single layer of cells of this wall. They are ready to fight in case an enemy will come through.

The issue is that when you have too much zonulin, these levee bridges will not come back up. There is a flow of enemies coming into the city, so to speak, and these enemies will instigate the immune cells. These soldiers will fight the enemies. And when you fight, there is always collateral damage, and the collateral damage is called inflammation. Now if this fight is confined to the intestine, then the inflammation occurs in the gut and you develop conditions with inflammation of the intestine like inflammatory bowel disease and so forth. Sometimes, and for reasons that we don’t know, the soldiers won’t engage in this battle. They eventually are programmed to leave the battlefield and go somewhere else. Some of the soldiers may go to the thyroid and you develop Hashimoto’s. Some go to the pancreas, you develop diabetes. Others, the joints and you have rheumathoid arthritis, etc. That’s as much as we know.

HM:  You have truly provided the best description of these complex topics that I have ever read. I find this so helpful because we can read about these topics in scientific terms but sometimes it’s just hard to understand. So thank you so much for explaining it this way. I’d also love to know are there specific triggers that induce the release of the excess zonulin which then leads to the leaky gut?

AF:  There are two that there are undisputably involved in zonulin release. One is gluten by itself. So gluten is a complex protein that we are not able to completely digest. So the final product, rather than the single elements of proteins, of the amino acids, sometimes you have these pieces of undigestable fragments of this gluten. And some of them are able to communicate to the cells, to instigate the cells to release zonulin. So we know exactly how gluten does this, we know the machinery that’s turned on, and so on and so forth.

The second one, and probably the most fascinating one, is the microbiota. This ecosystem in the gut, it goes off balance. So either if you have, what we call dysbiosis, so that there is no peace among the different microbiota. Or the distribution of microbiota in the gut is not what it’s supposed to be i.e., in the colon but is present in the small intestine. What we call small intestinal bacterial growth or SIBO. That is probably the strongest stimulus that we know that releases zonulin. So if bacteria are not balanced or they are in the wrong places in the intestine, that will instigate the release of zonulin, therefore, leaky gut.

HM:  If you look at those two triggers, what would be your recommendations for how to either prevent this from happening in the first place or to treat it once it’s begun?

AF:  I wish I would have an easy answer here. The question is that again, when we have the evidence that one, an individual has too much zonulin in the blood. Two, that intestine is leaking. And three, that this individual has clinical consequences, let’s say an autoimmune disease. You may eventually connect the dots and make the assumption that is not proved yet, that indeed, this individual is having the problem because of the leaky gut caused by the zonulin. If that’s the case, then we would be able to answer your question what to do about it. So we can eventually modify the diet.

Now there are medications to block zonulin in the clinical trial for celiac disease. I mean, again, there is a possibility to eventually fix the problem. The caveat here is that two of the three pieces of information are missing. One the zonulin measurement is still in the making, so there are very few labs that can do it. And therefore, this is not something you can go to your doctor and ask for. Hopefully this is going to happen sooner rather than later. Two, and even more challenging is, the diagnosis of quote unquote leaky gut and it’s a term that personally I’m not really fond of but lots of barrier filters.

That is very difficult. There are some tests out there, like the double sugar test with lactose and maltose but they are very finicky and complicated to do. And I believe until then there’s gonna be something more practical that will become available to test for a loss in barrier function that’s another question mark. But once we have these tools, then I believe we can answer your question. So we can say, okay, you know what? There is too much zonulin, I see that this individual has, for example, SIBO that leads to loss in barrier function. Now I know that if I fix SIBO, zonulin comes down and this will fix the problem. Or there is no SIBO but I take the gluten out of the diet, and this gluten free diet will decrease the zonulin levels. And consequentially the gut permeability that is impaired can be fixed. When we have that news, we can make that kind of move.

HM:  Maybe Dr. Fasano, you are the person who is going to create these tools.

AF:  Well, we are working extremely hard for that. [LAUGH]

HM:  The leading cause of hypothyroidism is the autoimmune disease Hashimoto’s. The majority of my readers, I would guess, don’t even know that they have Hashimoto’s. But my guess is that the majority of them do or they have had Graves’ disease and they’ve been treated and they no longer have a thyroid and they are now following me at Hypothyroid Mom. I wonder this connection that you talk about between zonulin and leaky gut, I’m assuming it plays a role in Hashimoto’s and Graves’ disease as well. I wonder is there anything specific or different that you’ve found for Hashimoto’s and Graves’ disease? Or is it really exactly the same for every autoimmune disease?

AF:  Well, again, I wish that I had an intellectual answer here. The more we study this condition, the more we get convinced that the key elements to develop an autoimmune disease, no matter which one, are pretty much the same. So you need to have of course the genetic predisposition, they tend to occur in the same family. You need to be exposed to an environmental trigger that is the one that will eventually instigate the immune system to do something inappropriate. The third element of the recipe has to be that you have to have, again, an intestinal barrier that is jeopardized, that doesn’t work. The fourth element is the immune system that, rather than get rid of these enemies that will come in they would not do the job in an appropriate way. And again, in the case of Hashimoto’s or Graves’ disease, once they’re exposed, rather to get rid of the enemy not only are armed. But then they are programmed to leave the intestine and go to the thyroid. And the fifth element now is very strong. Once again, it is this imbalance in the microbiota. So in other words, we call this dysbiosis because this may be the reason why this immune system on a specific genetic background is instructed to do something inappropriate, ie, to make the soldiers leave the battlefield and go to the thyroid.

DT:  I also wonder about the connection between Celiac disease and Hashimoto’s. You know, I have so many Hypothyroid Mom readers that have multiple autoimmune diseases. When you have one autoimmune disease, you’re more vulnerable to develop others. You published your groundbreaking study in the Annals of Medicine in 2003 that established the prevalence rate of celiac disease at 1 in 133 people in the US. To me, that’s shocking, because no one would have expected that it would be that high. Do you have any sense of the rate of Celiac disease among the Hashimoto’s community?

AF:  I do, and this is one of the most puzzling things that we are facing. So when that study was done, the rate of comorbidity between Hashimoto’s and Celiac disease was roughly 4 to 6%, six times more than in the general population.

Now that we are continually surveilling this, this number, in only 20 years, has ballooned to between 15 and 20%.

Clearly, there is something in the environment that is fueling this epidemic of Hashimoto’s disease among people with celiac disease. And again, the explanation is not all that clear. My more logical explanation is if we review these five ingredients to the recipe, the genetics could not have been changed so fast.

The way that I interpret this comorbidity, for example, between celiac disease and Hashimoto’s disease is that for some people the exposure to this trigger that we know to be gluten in a condition of a permissible gut barrier will lead to the passage of these enemies, ie, gluten into the body. The immune system sees the enemy and at this point, there is a split, if you wish. Some people, they will have all the soldiers stay in the battlefield. And these are the people, they have only celiac disease. Some people will have half of the soldiers stay on the battlefield and half go to the thyroid. And these are the ones that have both celiac disease and Hashimoto’s disease. And probably, there are others in which all the soldiers 100%, will leave the battlefield and will go to the thyroid and these ones will develop only Hashimoto’s.

HM:  That is so fascinating, I have never read that before. I write a great deal on my Hypothyroid Moms Facebook page about how important it is to have full thyroid testing. Sadly, the majority of my readers don’t know they have Hashimoto’s until they find my Facebook page and they push for the thyroid antibody testing. I also write about celiac testing because I have a feeling that many have celiac disease too and don’t know it. The other issue that I find is that many of my readers will go back with these great articles, great interviews about gluten and Hashimoto’s to their doctors but their doctors will say that’s nonsense. You don’t need to go gluten free because that’s just a fad. Then they might test them for celiac and they come back negative for celiac. The doctor will say it doesn’t make sense for them to try gluten free because they don’t have celiac disease. I can’t help but wonder how many of the ones that don’t have celiac disease may have gluten sensitivity that’s not being picked up on by the testing?

AF:  Well again, our old dogma that if you don’t have celiac disease, you don’t have business to go on a gluten free diet is gone. Because now we know that there are other conditions like, again, gluten sensitivity. How many people have gluten sensitivity? We don’t know. And the reason why is simple. For celiac disease, we have tests that can tell us who does and does not. For gluten sensitivity, these tests are not available yet. So, meaning that, right now, until somebody, and we’re really working hard on that, will identify validated biomarkers, it will be just an educated guess. So, there are people that believe they are rare, some people that believe we all should be gluten free because we are all sensitive to gluten, and everything in between.

So how do we find if somebody with Hashimoto’s or with pre-clinical Hashimoto’s may have gluten sensitivity as the culprit. It’s not possible to establish right now. And again, in my very humble opinion, the reason why this field has gotten so confused is because there are these extremes. The ones that believe that we should all go gluten free and the ones that believe that nobody should other than celiacs. Probably the truth is somewhere in the middle.

These conditions like Hashimoto’s are very, very complex. How you can get there can be very different from one individual to another. For example, for some, it can be a viral infection that will lead to Hashimoto’s. For others, it can be gluten. How to treat this individual?

If we treat all the Hashimoto’s people right now or the ones that are at the pre-Hashimoto’s stage. So they have the outer antibodies, but the thyroid is not giving in quite yet. And let’s say that 20% of them, they reach the final destination through gluten. You put all of them on a gluten free diet, only 20% will respond. The other 80 will not respond. You may eventually conclude that a gluten free diet is not beneficial for people that are at risk for Hashimoto’s because you have only 20% efficacy. But if you have a way to identify those 20% who’ve got to the final destination through gluten and treat only them on a gluten free diet, you have 100% efficacy.

So see, this, what I explain is what we call precision medicine, or personalized medicine. And that’s where the field, not just Hashimoto’s, the field of medicine is moving. We started 2,000 years ago taking care of patients. That time, the doctors were not even called doctors, they were called healers. Then we shift our attention from the person to the disease. So we don’t treat us, we treat Hashimoto’s and doing that we made the assumption that everybody is equal. We’re not. Now we are going back to paying attention to the patient.

HM:  What you have said is what I have noticed from Hypothyroid Mom readers. I have found that it is individual. Whenever I include information about gluten-free for Hashimoto’s, since gluten is a very real possible trigger for Hashimoto’s it’s important to at least try, many of my readers will say it has been life changing for them, their antibodies have reduced and they feel better. Then I will have others that will say that despite going on a strict gluten-free diet for months they have not noticed any change. I find it just so individual, so what you’ve said just makes so much sense to me.

AF:  Yeah and the argument to give a try with a gluten free diet is a valid argument if you exclude any other conditions that we know that’s triggered by gluten so in other words you rule out disease you rule out allergy. If you exclude any other possible reason why people develop Hashimoto’s at that point, when you exclude any alternative that brings the final disease. Still this can be a mixed bag of people. But at that point, I believe that eventually a trial on a gluten free diet would clear disclaimer that is not for sure the solution. For example a very close colleague of mine, whose daughter out of west coast was having problems with her thyroid. She had antibodies, her TSH was very high, the T4 was still you know hanging in there but the antibodies were already present. He asked me, should I put my daughter on a gluten free diet? And I told him, you know, this is going to be a shot in the dark. But you know because he already ruled out Celiac disease and with allergies you have nothing to lose. Three months on a gluten free diet and the TSH came back to normal and the antibodies were gone.

It’s simply telling that probably a subgroup of individuals affected by or at risk for Hashimoto’s may reach that final destination through this absorption and through gluten ingestion and leaky gut as we discussed.

About Alessio Fasano, MD

Dr. Alessio Fasano is director of the Center for Celiac Research and Treatment at Massachusetts General Hospital. His visionary research, which established the rate of celiac disease at one in 133 people, led to the awareness of celiac disease as a growing public health problem in the United States. He is widely sought after for his expertise in gluten-related disorders.