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My guest today is Dr. Alessio Fasano. He’s a world-renowned expert on celiac disease, gluten intolerance, and probably the first researcher to provide the scientific evidence of the molecule zonulin that increases intestinal permeability and gave rise to the term leaky gut, which I know, I think he has mixed feelings about. Dr. Fasano is a professor of pediatrics at MassGeneral Hospital, which is a well known Harvard affiliate and in charge of the celiac program there.

Dr. Fasano’s book, Gluten Freedom, which we’ll be talking about with Susie Flaherty, by the way, is truly a classic in this area in helping a layperson and even myself as a doctor, understand how gluten can be quite harmful. And not just in patients who are predisposed to celiac disease, which obviously we know is a lot more common than we ever realized. I can’t wait for his next book too, which is due out in the spring. I already pre-ordered it, Gut Feelings: The Microbiome and Our Health, on which he’s going to be talking a lot and we will even touch on how the microbiome and the gut interact.


Main points of discussion from the podcast.

Dr. Mitchell:

It’s my great honor to welcome Dr. Alessio Fasano to the podcast.

Dr. Fasano:

Thank you Dean, for having me on your show.

Dr. Mitchell:

Yeah. I feel like we were really lucky in America. We got this Italian import, many years ago, that’s provided a lot of really great stuff. So anyway, actually the first thing I have to do a little bit with some fun and then we’ll get to the serious stuff, is that I loved reading Gluten Freedom. I really did. It was so fluid. I guess we have to also thank Susie Flaherty because it just really flowed. It was really a page turner for me. And you made complex material quite clear.

But I do have to ask you, do you think Gluten Freedom was the right title for this because I can imagine a lot of your friends back in Italy, and I know here in United States, when they can’t have pasta or bread, they don’t feel exactly like it’s freedom. I mean, even in our jails, they get bread and water. So how did you come up with that title?

Dr. Fasano:

Actually, Susie and I had this discussion with the editor and I believe that they came up with two or three suggestions that this book. It was a play on the concept gluten free and gut freedom from disease and stuff.

Dr. Mitchell:

I like that. That’s good. All right. So let’s get into it. We’re going to first just touch on celiac disease, which is obviously what you’re really known for. And I know we’re going to get to some of the other really fascinating things that you’re working on now. But I tell patients and I’ve learned this myself, in the mid 1980s, when I was in medical school, there was about a chapter, a page or two, on celiac disease in my pediatric textbook. And typically it showed young children with distended bellies and had chronic diarrhea and what we call the failure to thrive. They just weren’t developing well. When did you start to recognize in your career, that this problem was a lot bigger and more common than people realized?

The Problem of Celiac Disease

Dr. Fasano:

I would say definitely when I moved from Italy here in the United States, the early 90s. This was the time in which there had been so much was going on in the world of the science and the clinic of celiac disease from Europe. There were some new information coming up. The fact that this was genetically determined was pretty obvious. The biochemistry of the grain that used gluten came more and more in the radar screen of experts, agronomists and so on and so forth.

So the two key elements, so the genetic predisposition and environmental factor tribute to celiac disease became a more and more object of in depth analysis. And of course this was also the time that proceeds the completion of the human genome project. And the paradigm at that time was, if you have the genes you’re exposed to the environmental trigger, these are the two conditions that are necessary sufficient, to develop a problem. And when I move over here, with that mindset, I wonder why celiac disease is so frequent in Europe. At that time, the frequency was roughly one in 300 and so rare in United States. It was at that time, it was estimated to be one in 10,000.

Dr. Mitchell:

Right. We weren’t looking for it. That’s one of the things I wanted to ask you. So in Italy, I know you did lot of your residency, I guess, training. So you were seeing the cases in Italy where obviously people eat a lot of gluten products.

Dr. Fasano:

Yeah. And then again, of course, the point that may be important. The genes are the same. All of the testers come from Europe. The grains are the grains. And yet the disease was not here.

So this is the classical project in which you want to be involved as a scientist because it’s a win, win, no matter what is the outcome of your research because if indeed was that this was true, that the disease was rare here, you have to assume there was some other facts in providing these two to interplay. But unfortunately that was not the case and end up to be the second scenario that was overlooked.

The problem is again, it’s always the same story, what you find is something, and are you knowledge about this because if you don’t know what an elephant is, you may sit just beside the elephant and people who will ask you, have you ever seen an elephant? Your answer’s, “No.” And that time, the definition, celiac disease was indeed every year, disorder, only kids with a big belly. And by the way, that chapter in general was not even a chapter. It was really one paragraph.

But looking in that direction, we were looking the wrong thing. We are looking probably a tip on the iceberg and it was much bigger than that.

Why is Celiac Disease Presenting More in Adults Now

Dr. Mitchell:

Why do you think that it shifted, that we’re seeing there’s more now older people, like they’re not presenting as children as much any more?

Dr. Fasano:

As a matter of fact, all the major experts historically were pediatricians because we thought they was a pediatric conditions.

There were already adult cases described. But our interpretation of the matter was, “Okay, these are people that probably have celiac disease forever.” And had symptoms there are so known specific or there were asymptomatic.

This came under the radar screen. And then they full blown with the symptoms later on in life. And again, partially to try to answer why celiac disease was so rare in United States, started to follow perspectively, these families, in which there were a family history of celiac disease. And so the kids had celiac disease, mom and dad not, but they were part of the screening and we followed for them for years. And we are start to realize that these people that test negative for years, then all of a sudden they shifted, they became positive.

And again, this is the other reason why we overlooked. But your patients is the quintessential example, why we were under the impression that celiac disease was one in 10,000. Because in adults with anemia, it doesn’t respond to our supplement. It will never be considered as a possibility, as you did not.

It could be related to a malabsorption of iron, the secondary to skin disease because a part of that was celiac disease developed early.

And can be at this age. Or if you’re obese, you would not screen anybody that’s obese.

And now we know that again, now that we have the tools, that we never at that time for general screening, that we have, again, the understanding with celiac disease, really all about, and so on and so forth. Now we know that celiac disease can occur at any age.

I have patients develop celiac disease in their late 80s.

Dr. Mitchell:

Yeah. That’s crazy! Wow!

Dr. Fasano:

And that’s the most frequent way that the disease present itself. Not with diarrhea. To have diarrhea, weight loss, you have to have a substantial amount of your intestine inflamed. Well, we absorb iron all in a few inches of our GI tract.

With that fatigue and so on and so forth. So the reality of the story, that’s this big events on the screening tools, the background, understanding what these is, all nine yards, they now make us pretty in tune with what is the epidemiologists and the disease, you can develop is at any age. Remember that when we start this, I personally was used to trying to sell the refrigerator in the North pole because said, “You’re wasting your time.”

And there was a lot of pushback at that time because they said, we checked for it and it’s not here. Now this is memories, it’s not there anymore. But now nobody would even question the celiac disease.

The Biblical Diet & Gluten Intolerance

Dr. Mitchell:

Just to talk about in the past also, which I find interesting, and you mentioned that we think that some of our ancestors, whether it was the last 50, 100 years, and obviously going back, maybe 1000’s of years, ate a different diet that we ate. And I sometimes like to tell my patients, obviously we’re going to get into this later, there’s so much confusion about what’s the best diet to eat. And, and obviously I think it’s very particular to where you live, but I sometimes say to patients, I believe in the biblical diet, if it was around the biblical times, you could eat it, because it was fresh food and they ate the olives and they ate the fruits and the vegetables that they grew. And, of course, they killed the animals and they fished for the fish. But I was thinking about it the other day, you can count on a little bit of my biblical training, that they also eat grains. It was Joseph, the Prince of Egypt, who saved Egypt by eating grains. And why wasn’t that a problem back then?

Dr. Fasano:

That’s right. So, indeed, you mentioned the three pillars, that now became five. And then we can go a little bit more in detail. But the reality of the story is, nutrition is absolutely instrumental. But not because different grains and the amount of gluten and so on and so forth. Because the nutrition influences so many other functions of our body, particularly how belligerent or friendly is your immune system with yourself. And again, we can discuss a little bit more in details why that’s the case. But the reality of the story, we have been having a shift of the way that we eat that has been dramatically fast in a very last short period of time. So for 99% of our evolution, we’ve been eating in the same way. And then three major events occurred, that’s really changed the entire ordeal of these 2,000,000 years of history.

The first major change was 10,000 years ago, with the events of agriculture. And therefore, you are not the hunter-gatherer anymore, but you can predict. So you will develop the capability to have a predictable amount of food. You domesticated crops and animals and so on and so forth. The second major change was urbanizations, so that people they start to move to cities, because that’s where the job opportunity was. And therefore, less and less people were in the countryside doing agriculture. I mean, 10,000 years ago, everybody was cultivating whatever they were consuming. Now there are consumers and producers. And, of course, the number of people that produces are less and less, and the number of consumers were more and more. So the demands increased and the offer was pretty much limited by the capability of farmers to produce that amount.

The kiss of death of what’s going on now, I believe, is the third reiteration of the change in the globalization. So the farmers that would produce and sell locally are getting more and more rare because it’s not viable economical paradigm. While big corporation, they took over and they produce large amount of food. That means that this would probably produce one place that needs to be moved thousands of miles. And in doing that, you have to preserve this food because if you lose part of this it’s a major economic loss. And even when you grow this stuff, let’s say, crops like wheat, you can’t afford to lose that products. And then you have to use pesticides and so on and so forth. All this needs to be shipped, so they have to use preservatives, that they have to be protected and therefore pesticides, led to the change, the dramatic change of what we did.

Because you can make the argument, as you were saying, in the biblical time, that we are eating gluten with grains. But these are very different grains. So bottom line is that, at the biblical times, you were eating the same grains maybe that we’re eating now. From the organoleptic point of view though, that’s not the case. Because they need to be produced in one place, shipped in another place, preserved the crops and so on and so forth.

Screening for Gluten Intolerance

Dr. Mitchell:

I want to bring up even before biblical times, because you’re such a good speaker. I was watching one of your presentations. I’m not sure if you’re a part-time comedian, if you go to the clubs in Boston, but because you were saying was, pre-urbanization times, man, 99% of the time was searching for food and 1% was thinking about reproduction. And you thought that balance was a little bit off.

You had me laughing very hard. Whenever you listen to a medical lecture, having some very good humor interspersed definitely drives home the points. But let me ask you something, do you think, again with what’s going on, that celiac disease or gluten, we’re going to get to sensitivity and tolerance, should be screened for pretty regularly? And if so, which tests would you do? Because, again, and we’ll try to make this helpful for the listeners. Because all they know is they want to be checked for… They’ll come in and say, “I want to be checked for celiac”.

Dr. Fasano:

Well, the premise, in terms of if screening, how frequently and why, is the fact that celiac disease is a one of a kind autoimmune disease. So, this is not like diabetes. You pee a lot. You drink a lot. It can be anything else but diabetes.  Here I can really challenge you to tell me any kind of sign or symptoms that I will make an argument that can be associated with celiac disease.

Well, the reality of the story is, when I started all this there were no labs available. We have to set up our own lab. Now everybody can screen for celiac diseaseIf you really think that this could be celiac disease, the blood test that looks for specific autoantibodies, called anti-tissue transglutaminase, tTG for short. That will give you a great level of confidence that you’re in the right direction. And if you are, then it’s the time to refer your patient to a gastroenterologist, a celiac expert, and then eventually they take it from there.

There are a big difference between the anti-tTG and the anti-gliadin antibodies. The anti-tTG antibodies and antibodies, again, one protein that we produce. So it’s what we call technically autoantibody. So you attack your own body. So it’s a good biomarker of our immunity. The anti-gliadin antibodies and antibodies again, something that doesn’t belong to our body.

In this case gliadin. It tells me only three things. One that I know already, that you’re eating gluten. The second one, that the fragment in gluten will sneak through your gut barrier in your body. And the third, that the immune system sees an enemy, something that doesn’t belong to your body, that’s it’s own job. Fight against it by producing specific weapons, in this case, the antibodies. And then these are the anti-gliadin antibodies. In the seventies, when we didn’t discover TTG yet, that was the only test that we had. And we use that. And again, was just to tell us that we have probably gliadin, but we’re not telling us what that means. A lot of people, they’re healthy, they may have anti-gliadin antibodies just because their gut leaks. That’s all.

When it’s IgG, that’s systemic, goes everywhere. And so that’s the reason why the IgA are more specific with what we’re looking for, because we’re looking for inflammation at the mucosal level i.e. the battlefield. And the IG antibodies gives us more confidence that’s what is going on there. The IgG are more systemic and can be non-specific, because you can have an inflammation somewhere else, that with the death of cells it leaks out this.

Dr. Mitchell:

If somebody was positive to them, and obviously they’re having some various symptoms, you would probably would say, “No, let’s cut out the gluten for a month and just see how you feel”. Or would you also say, “Let’s see if those antibodies go down if you”…

Dr. Fasano:

So we went through three different stages when it comes to gluten-related disorders and therefore the interpretation of these antibodies. The first one that I was telling you, until the seventies, that was the only thing that we have. So we use the anti-gliadin antibodies as a guide of what’s going on. The second stage, when we were finally having more specific tests like the tTG, in which we abandoned the anti-gliadin antibodies. So you should not use these two modes for celiac disease. And this was the time in which we were convinced, including myself, and the only reaction to gluten was celiac disease. And if celiac disease was ruled out, you have no business to go on a gluten-free diet.

Then, more recently from the 2000 going forward, we realize there’s a spectrum of gluten-related disorder. So not just the auto-immune response, but it’s also the allergic response to gluten. But with celiac disease, we look into the value of testing these people with gluten-sensitivity with anti-gliadin antibodies.

We don’t use genetic testing routinely, but under specific circumstances. So if you have a clear suspicious, the tTG positive, the symptoms compatible are enough to move to the next step, i.e. screens to the endoscopy. However, sometimes, and I’m pretty sure you’ve experienced this, patients already come to you on a gluten-free diet without having secured the diagnosis and the only way to make the diagnosis is to do a gluten challenge. And a lot of them, they are really reluctant to do that. So a compromise will be, let’s do the HLA.

It’s not to confirm the diagnosis, because it’s 95, 97% of people see that these are positive, but so one third of the general population. So we do the test to rule out, rather than rule in celiac disease. So if you are on a gluten-free diet and you test for the HLA and you’re negative, with great level of confidence, you are not celiac and you may have gluten sensitivity. And that’s reason why you benefit on a gluten-free diet. And it’s important to distinguish between these conditions. But if you’re HLA compatible, then you will eventually need to consider a gluten challenge for that patient. See if you want to make sure, and they want to know, “Am I celiac or something else?”

Gluten Intolerance & Leaky Gut

Dr. Fasano:

In order to develop any chronic inflammatory conditions that affect humankind, it looks like there are another three elements that must be there. One, a bridge of these barriers that segregate the enemies from our bodies. So that this, to a world, the genes that live in our body, and these instigators in general, large molecules that are kept at bay under normal circumstance can physically interact.

So you have to have an increased permeability. The gut being the largest interface. But as you said, the lungs, the genitourinary tract and so on and so forth. The fourth element is the immune system.  And the fifth, and probably the most important of all, that explain why, for example, people end develop celiac disease, at 70 is the microbiome. So in other words, this ecosystem of micro organisms that can eventually epigenetically push on your genes. So then you switch from genetic predisposition to clinical outcome.

What is interesting that these three last elements that we were not aware of, they highly influence each other. We know now, scientifically speaking, that if you have a leaky gut, that again, a term that I don’t like too much, but if you have a barrier that is jeopardized the immune system will be affected.

And if the immune system is affected, the composition of microbiome is affected. If the composition microbiome is affected, your gut can become leakier. So they all influence each other.

Dr. Mitchell:

So leaky gut became the buzz word. Now, you discovered Zonulin, the molecule that basically, as you describe in your lectures, which I again, I’m going to encourage people to watch online if they’re really interested in this stuff too, is that essentially they’re the draw bridge that opens up the gut permeability. But, did you use that term or did that just get taken in the lay press? That this thing, leaky gut, or… Because again, obviously if you say increased intestinal permeability, people are like, “What?”. So, because you do use it in your book and it does drive home a really important point, again, maybe misused sometimes.

Dr. Fasano:

That’s right. But anyhow, the bottom line is I don’t have a problem as much with the leaky gut. My problem is with the leaky gut syndrome, that seems to be an entity that describe a variety of diseases. That I believe there’s not have too much of a science. But one comes to the fact that the permeability of the guts, or the blood brain barrier, or the lung can be modulated when Zonulin was discovered in 20 years ago already.

Now again, historical memory is gone. Nobody would dispute that this virus can be modulated. Nobody. And this is based on proteomic analysis, on genomic analysis. In other words, that over and over again, all of these conditions seem to be associated with genes that control these barriers.

But, the point that I was trying to make is the only logical explanation of chronic inflammation is that the immune system is chronically exposed, because of the leakiness of this barrier to the enemies and continue to do the job they’re supposed to do. To fight when under attack.

Healing Leaky Gut

Dr. Mitchell:

Let me ask you a question too, because this is the question I get all the time from patients that are seeing me that know that I do functional complementary medicine, along with my conventional practice. They say, “What can I do to heal my leaky gut?” They’ll ask me about L-glutamine, they’ll ask about probiotics. I know you can mention the drug that you have been working on, but do those things work? The… Or anything nutritionally that you are aware of?

Dr. Fasano:

I’m going to use the same terminology that I’ve been using with you when I’ve been asked to comment about COVID-19. So, we really are building the airplane we’re flying. So, that’s the reason why I don’t have an intelligible answer of what can be done to quote unqoute, fix a leaky gut. We know that this is multifactorial. We know, for example, that you drink a lot. Do you know, alcohol can shut off your mucus layer that protects you? So that’s a cause effect relationship. But, most of the time we don’t know. And of course L-glutamine is good because it allows, to give energy to the intestine, to repair. Probiotics is good because this imbalance of the gut microbiome seems to be one of them, the strongest stimuli for Zonulin releasing, therefore for increased permeability.

The reality of the story is that until we do not have more basic understanding of what are the stimuli that create the problem in that particular person, you don’t have a target intervention. So, you can do general things, as we said, and I have to say, going back to nutrition, sometimes just a healthy nutrition is the best way to go. Because, if you have a dysbiosis, because you eat a Western diet, that will give advantage to some microorganism that we know as a fact can increase gut permeability because of regulating the Zonulin pathway.

Should Everyone Be Gluten-Free?

Dr. Mitchell:

I’m going to ask you one last question. As we wind down in this amazingly informative fun interview. Do you feel pretty much everybody should be gluten free? Or at least, I’m not saying they can’t have fun once in a while, like I tell my patients are getting… Obviously you don’t have celiac disease, but do you think the general population would be better off?

Dr. Fasano:

So I want to go back to that word of wisdom that you started this interview with. The fact that the more we depart part from the way that we evolved as a species in terms of what we eat, the more we are in trouble. And that’s the reason why the Western diet is so detrimental for us. I think that it’s not a matter of gluten that needs to be eliminated from everybody. Because a lot of people, they ask me this because you, gluten is one of the risk zones. So we all we are all weak when eat gluten. But there are consequences, consequences. If you don’t have the other genes that create your risk for chronic inflammation, that link goes on and off and that’s it. It’s not staying on forever.

So personally I think that everything, everything including gluten that is consumed the moderation and balance, is good for you. Because it’s the access that is a problem. Red meats, for example. We are omnivore. I think that red meat is fine. It was fine for our gathers hunters. But you’re not an animal. You need to work much more than getting a piece of fruit or tubers that grow around anywhere.

Dr. Mitchell:

And they weren’t eating 16 ounce steaks back in the day. They were lucky if they got a little piece of meat for a couple of days.

Dr. Fasano:

Absolutely. And again, because in general they caught those really small animal. We have to share with the other people. So if we eat a lot of fruits a lot of vegetables, a lot of nuts, tubers, olive oil, and especially, meats, fish and so on and so forth, and gluten, I think that that will really feed the microbiome that is being engineered to live in a symbiotic relationship and therefore in a peaceful way with us. That’s what I think. So I don’t recommend gluten free for everybody but moderation for everybody, for sure.

Closing Statements

Basically celiac disease and gluten intolerance is a lot more prevalent than we previously imagined.

Increased intestinal permeability or leaky gut is a real phenomenon and has serious implications and probably for auto immune conditions and other extra intestinal symptoms. Gluten evaluation is now more accessible than ever. Your doctor can order a simple test to screen you for that. I’m definitely encouraging all of our listeners who have any interest in this to get the book Gluten Freedom. It’s terrific. Really great read. And just as I said, I can not wait for Gut Feelings to come out in the spring and maybe I can schedule another podcast with Dr. Fasano because I’m sure once I get to read that I’m going to have a lot more questions.

About the Author – Dr. Dean Mitchell, M.D.

Dr. Dean Mitchell, M.D.

Dr. Dean Mitchell M.D. is a Board-Certified and Immunologist based out of NYC. He graduated from the Sackler School of Medicine and completed training at the Robert Cooke Allergy Institute in New York City. He is also a Professor of Clinical Immunology at Touro College of Osteopathic Medicine, a fellow of the American Academy of Allergy, Asthma and Immunology, and the author of Allergy and Asthma Solution: The Ultimate Program for Reversing Your Symptoms One Drop at a Time. Dr. Dean Mitchell, M.D. has also been featured in The New York Times, The Huffington Post, Fitness Magazine, Dr. Oz and News NY 1. Dr. Mitchell also hosts the podcast The Smartest Doctor in the Room – a combination of a lively, personal and in-depth interview with top healthcare specialists.


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