It's an honor to welcome Dr. Alessio Fasano as a guest on the show. Dr. Fasano is globally recognized for his pioneering research in the fields of Celiac disease and gluten intolerance. In 2003, he published the groundbreaking study in the Annals of Medicine that established the prevalence rate of celiac disease at one in 133 people in the U.S - a rate nearly 100 times greater than the previous estimate. He also headed up a team that discovered (in 2000) the ancient molecule zonulin, which regulates the permeability of the intestine and is know known to be a major player in the condition known colloquially as "leaky gut".
Dr. Fasano has been featured in hundreds of interviews in media outlets such as The Wall Street Journal; NPR; New York Times Magazine; National Geographic, Bloomberg News; USA Today; Los Angeles Times; “Good Morning America”; The Globe and Mail; Vogue; and numerous health-related websites and magazines.
On a personal note, Dr. Fasano is one of my research heroes and his work has had a huge impact on my understanding of the gut and autoimmune disease. We’re extremely fortunate to have him as a guest on the show. I hope you’re as excited about this as I am!
In this episode, we cover:
3:26 How Dr. Fasano became interested in Celiac Disease, gluten intolerance, intestinal permeability, and autoimmune disease
4:34 The trinity of factors leading to autoimmune disease
9:12 What zonulin is and how it contributes to intestinal permeability and autoimmune disease
13:35 How vaccine research unexpectedly led to the discovery of zonulin
18:08 Why some still consider leaky gut a “quack diagnosis”
22:27 How long does it take to get leaky gut? How long does it last?
27:05 The differences between Celiac Disease and gluten intolerance
31:45 What’s the best commercially available way to test for leaky gut?
38:25 Everything we’ve learned about restoring gut barrier integrity
40:00 Why Celiac Disease patients have increased zonulin levels, even on a gluten-free diet
41:22 An update on Larazotide, the intestinal permeability drug
46:23 Upcoming research developments to get excited about
Links We Discuss:
Steve Wright: Hi, and welcome to another episode of the Revolution Health Radio Show. I’m Steve Wright from SCDlifestyle.com, and with me is Chris Kresser, health detective and creator of ChrisKresser.com. Chris, how are you feeling today?
Chris Kresser: You know how I’m feeling, Steve. I’m super excited. Today we’re gonna be interviewing Dr. Alessio Fasano, who is an absolute rock star in the world of gluten intolerance, intestinal permeability, and autoimmune disease, so I’m really excited.
Steve Wright: Yes, he is a superstar of research, and I’m ready with a pen and paper. This is gonna be an awesome, awesome show.
Chris Kresser: Dr. Alessio Fasano is a world-renowned pediatric gastroenterologist, research scientist, and entrepreneur. He founded the University of Maryland Center for Celiac Research in 1996 and has published more than 200 peer-reviewed papers and has filed more than 160 patent applications. Dr. Fasano leads a team of about 30 researchers in nine countries and has research partnerships with institutions around the world, and their work has led to the discovery in 2000 of the ancient molecule zonulin, which we’ll be discussing in the show, that regulates the impermeability of the intestine in a condition known as leaky gut, which of course, we have discussed a lot on this program. In 2003, Dr. Fasano published the groundbreaking study in the Annals of Medicine that established the prevalence rate of celiac disease at 1 in 133 people in the US, which is a rate nearly a hundred times greater than the previous estimate. Dr. Fasano has been featured in hundreds of interviews and media outlets such as The Wall Street Journal, NPR, The New York Times Magazine, National Geographic, USA Today, the LA Times, Good Morning America, and he has also been named as one of America’s Top Doctors by Castle Connolly for six consecutive years and was a finalist in 2005 for the NIH Director’s Pioneer Award. On a personal note, Dr. Fasano is one of my research heroes, and his work has had a huge impact on my understanding of the gut and its relationship to autoimmune disease. We’re extremely fortunate to have him as a guest on the show, so Dr. Fasano, thanks again for joining us.
Dr. Alessio Fasano: Thank you so much. It’s my pleasure.
How Dr. Fasano became interested in Celiac Disease, gluten intolerance, intestinal permeability, and autoimmune disease
Chris Kresser: So, can you tell us a little bit about how you got interested in celiac disease, gluten intolerance, intestinal permeability, and their relationship to autoimmune disease?
Dr. Alessio Fasano: Well, actually by default. I was not interested at all at the beginning, but I trained and graduated from the University of Naples in Italy, which was one of the sanctuaries of celiac disease, so I was immersed about celiac disease and related problems. So the by the time that I graduated, I got great exposure to this condition. I was fortunate enough to be in a very viable and vital environment and also to be fortunate that was the time in which our understanding of celiac disease moved from merely a food allergy to a real autoimmune disease. By the time that I moved to the United States in ‘93, I decided that that was one of the most intriguing conditions really to study to get to the bottom line or the mechanism that leads to autoimmunity.
The trinity of factors leading to autoimmune disease
Chris Kresser: Um-hum. So what’s unique about celiac disease as an autoimmune disease? You mentioned that in your article in Scientific American. I thought it was pretty interesting.
Dr. Alessio Fasano: Sure. I mean, you know, there are a few things that make celiac disease quite unique. A matter of fact, it opened a new paradigm of the science of autoimmunity. Like all autoimmune diseases, it has a recipe with two ingredients, so that’s not unique. You have to have genes plural so that you are genetically predisposed, and then you have to be exposed to an environmental trigger that is mismanaged by the immune system because of this genetic makeup. You know, the immune system is there to defend us against attackers. And in people, they are skewed to develop autoimmunity when exposed to these enemies rather than get rid of them, they start to attack their own body. The target is the brain, and you develop MS; the joints, rheumatoid arthritis; the pancreas, diabetes; and in the intestine, you develop celiac disease. What really sets celiac disease aside is, one, as concerns the genetic component, we know some of the genes involved. We know there are many, probably hundreds, but it’s unique in celiac disease that some of these genes that belong to a specific class called HLA genes, they are present in almost 100% of the people with celiac disease. There are these two forms of HLA called DQ2 and DQ8, and all celiacs — with very, very rare exception — they have either one or both. This does not happen with any other autoimmune diseases. For example, in diabetes, there are actually no genes present in 70%-75% of the population. Same story with multiple sclerosis. Here we talk about almost totality. We know in celiac disease the antigen, i.e. the part of our body that is the object of this attack, there is this enzyme called tissue transglutaminase (TTG), and therefore antibodies against this TTG are one of the best tools that we have in clinical biology to identify people with a problem with autoimmunity, in this case, celiac disease. But really, what sets celiac disease totally apart from any other autoimmune disease is the fact that it’s the only condition for which we know the environmental trigger. We don’t know what makes people sick with diabetes or MS, but it’s indisputable gluten, this strange protein contained in many grains, including wheat, rye, and barley, to be the culprit that leads to autoimmunity on that specific genetic background. That implies that celiac disease is the only autoimmune disease for which we have a treatment.
Chris Kresser: Right. And when was that discovered, that gluten was the trigger for autoimmune disease? How long have we known that?
Dr. Alessio Fasano: Well, you know, celiac disease was described for centuries, but the guy that put two and two together was a pediatric gastroenterologist from the Netherlands, Dicke, that made a very interesting epidemiological observation during World War II. He observed that mortality — because you could die of celiac disease at that time — for celiac disease dropped from 35%-40% to zero during the war. And then when the war was over, the mortality rate for celiac disease went back to pre-war era. And when he tried to understand what was the connection between the war environment and this swing in mortality, he realized that possibly it was the availability of grains containing gluten that really was changing in parallel. So during war, there was no wheat available, and flour was made with potato starch, and that was the time in which the mortality went pretty much to zero. And when after the war, gluten was again available, the disease came back. And that’s why in the late ‘40s and early ‘50s he switched the treatment in these babies, these infants, that was mainly focused on an elimination diet that contained only bananas — that is why these were called the “banana babies” — to a diet in which the only thing that was eliminated were grains containing gluten, and sure enough, that did the trick. And that’s how he figured out that gluten was involved.
Chris Kresser: That’s fascinating. So essentially the war forced people on to a gluten-free diet without knowing that that’s what they were doing, and that’s how they figured it out.
Dr. Alessio Fasano: That’s right.
What zonulin is and how it contributes to intestinal permeability and autoimmune disease
Chris Kresser: So when you mentioned the unique features of celiac disease, you mentioned genetic predisposition and then the existence of an environmental trigger, of course, in this case, gluten. So those are two of the trinity of factors that you talked about in your Scientific American article that lead to autoimmune disease. What’s the third factor?
Dr. Alessio Fasano: Yeah, that’s another lesson that we merely learn from celiac disease, because before, you know, the entire scientific community interested in autoimmunity was puzzled by how this interaction between the environment, i.e. these molecules like gluten, for example, and the immune system can really occur. Because in order for the immune system to react and produce an autoimmune response, it needs to physically see the enemy and eventually be in touch with these molecules to build this immune response. And under normal circumstances, that has not happened ever, because of all the interfaces with the environment, the largest and by far the more important is the GI tract, the gastrointestinal tract. And the way that we conceptualize the intestine, it is a long tube that is roughly 15-20 feet long in an adult that is covered by a single layer of cells, and that this is a formidable barrier to keep the bad guys, the enemies, bacteria, the toxins, but also elements that can trigger autoimmune response at bay, out of there. So the only way to come in our body is to be dismantled — so digested — and only the single-block elements of complex molecules like proteins, you know, complex sugars and so on and so forth, can come through so that the single blocks like amino acids or single sugars can eventually be used to fuel our energy needs. So the immunologists, experts in autoimmunity, they still didn’t how triggers — in general, proteins — may come through and create the problem on a specific genetic background, because under normal circumstances, the intestine is totally impermeable to these molecules. This was also based by a concept that was in the early/mid-‘80s still valid that this layer of cells were cemented to each other by a grout or something that would prevent anything to pass in between cells, so everything that comes from the environment through our body has to go through the cells.
And then in the mid-‘80s, a group of Japanese scientists said, well, actually the spacing between cells is not cemented. They are doors, almost always closed, but they are doors. And that was quite an interesting discovery. And then over the years, more and more information came about, you know, how these doors are made, but what was the missing link was what kind of molecule, substance, or signal or whatever would modulate these doors so they can be opened and closed. And that’s where we stumbled by mistake studying celiac disease that we make a molecule that we call zonulin that regulates the permeability of this space. And again, through celiac disease we learned that this molecule is produced in excess, in an exaggerated fashion, by people with celiac disease, now finally explaining the inexplicable, how this protein can come through, because now if you have this door stuck open, everybody from the environment can sneak into our body, including gluten, and with that, trigger the autoimmune response. So that led us to put forward this new paradigm in which the recipe for autoimmunity is made not by two, but three ingredients: You have to be genetically predisposed, you have to have an environmental factor that is the instigator of the immune response, but at the same time you have to have a breach of this barrier so these two elements can interplay.
How vaccine research unexpectedly led to the discovery of zonulin
Chris Kresser: Uh-huh. So you mentioned the protein that mediates the permeability of the tight junctions, which is zonulin. Can you tell us a little bit about how you discovered zonulin? I found that to be also really fascinating.
Dr. Alessio Fasano: Ha-ha, you know, all discoveries, including the breakthrough discoveries to date, rarely come by a planned design.
Chris Kresser: Right.
Dr. Alessio Fasano: Typically they are by serendipity. You know, a good scientist is the one that is trained to design the experiment, to perform the experiment in a correct fashion, and then eventually interpret the data. And you do this by formulating a hypothesis. And nine out of ten times, the outcome of the experiment is different from the hypothesis that you formulated.
Chris Kresser: Ha-ha, right.
Dr. Alessio Fasano: That’s the same way that the discovery of zonulin came about. I was studying something else. I was asked to generate and engineer a vaccine against cholera, this bacterium that is causing, travesty still nowadays during epidemics. A disease with a high mortality rate, particularly in kids. And this is all due to a weapon that cholerae produces, a very powerful weapon called cholera toxin. This toxin in miniscule amounts can cause liters and liters of diarrhea. So anyhow, bottom line, in the late ‘80s I was asked to engineer this vaccine by eliminating this weapon in cholera and generate a live attenuated vaccine. Now, I did that, and when all the studies proved that the vaccine was correctly designed and was working beautifully in animal models and so on and so forth, it was the time to try this in humans. And you now, we had volunteers, in general, they were students at that time, that for a ridiculous amount of money volunteered to go through the study. And we explained that the study was designed in a way that probably two out of three will be fine, because blindly they will either receive placebo, nothing, so they will just get the money to do nothing; the vaccine that I was absolutely convinced that was going to be nonreactive and therefore they also will be fine; or the real-deal cholera, and they will be getting sick, but we would take care of them.
Chris Kresser: Yeah, brave people!
Dr. Alessio Fasano: That’s right. Very, very brave. And sure enough, the placebo did nothing. The real-deal caused a tremendous amount of diarrhea, but thank God, nobody really got tremendously sick. But unfortunately, the vaccine that was engineered had residual diarrhea. So not 20 liters like the ones that got the real-deal, but 3 or 4 liters that made the vaccine unacceptable. So I was very upset. You know, years of work literally flushed in the toilet. And you know, I gave up. For a couple days, I decided not even to walk in the lab. And then when I regrouped I said, OK, there must be an explanation why there is residual diarrhea. And sure enough, we ended up discovering a toxin that had a very peculiar mechanism. It was indeed opening this gate in between cells, what they call the tight junctions, making the intestine leak. And when we discovered that, then we started to ask ourselves how this toxin works, and we got more insight on the mechanism. We realized that there was very complicated signalling and machinery in place needed to make this opening to occur. And my reasoning was I can’t believe that Mother Nature put this machinery just to be a target of a molecule that actually is making us sick. It’s more likely that Vibrio, as a smart bug, studied our physiology and produced something similar to a substance and a molecule that we use to regulate this gate, and that’s how we ended up over the years to discover zonulin. And from there, we realized that this leaky gut is not the premises of celiac disease but many other autoimmune diseases, so it explained the inexplicable.
Why some still consider leaky gut a “quack diagnosis”
Chris Kresser: Right, so leaky gut, as you just mentioned, it’s a precondition to developing autoimmunity because without that, the immune system won’t even see the antigen and can’t mount an immune response. So up until pretty recently and actually in a lot of cases, my patients, when they go to their doctor and they ask the doctor about leaky gut, the doctor looks at them like they’re crazy and might say: Oh, you’ve been reading on the Internet too much. And yet there are hundreds, if not thousands, of papers in the literature published on intestinal permeability and its relationship with autoimmune disease and several other diseases. So why do you think there’s just skepticism in the mainstream medical community about leaky gut, and what changes have you seen in the acceptance of that condition over time?
Dr. Alessio Fasano: Well, you know, you have to appreciate that unfortunately besides the fact that people, they have preconceptions and so on and so forth, there is the objective fact that this term that actually I really don’t like of “leaky gut” has been used and abused — And I don’t want to classify people and be stereotyped here, but mainly, I should say, mainly by the alternative and complementary medicine network that had, in a visionary fashion, I should say, identified leaky gut as a possible mechanism leading to many problems. The problem, though, is that most of these statements were not based on factual evidence, to the point in which we went to the extreme to develop an entire field called leaky gut syndrome that had very few facts and a lot of fantasies, and that’s the reason why the traditional medicine establishment has been so skeptical for many years. Keep in mind that, again, this leaky gut, leaky gut syndrome was into the pipeline of alternative medicine even before the discovery of these doors. So no surprise that the establishment was skeptical, that this was something that had no merit whatsoever. And then, you know, as typically happens in life, in which there is no black and white, but there are grays, and we have these two camps that saw this topic as either black, it does not exist, it’s bogus, or white and it would explain all the problems of humankind.
Chris Kresser: Ha-ha.
Dr. Alessio Fasano: We end up to be more factual, and the discovery of the tight junctions, the discovery that they can be modulated, the clinical evidence that people may eventually have a breach in the intestinal barrier that is associated with autoimmunity. The Genome Project, they gave us the tool to search for specific genes associated to diseases, including autoimmune disease, that led to the discovery of some genes regulating this permeability being associated to autoimmune diseases until the discovery of zonulin, and now it’s used as a biomarker. Now you see also the establishment start thinking that there is some merit there. And therefore, the cloud of the confusion and this heated debate has been more gentle, if you wish, and now you have no extreme fields anymore. And still there is a lot of confusion.
Chris Kresser: Right.
Dr. Alessio Fasano: Still there are so many factors that we don’t know. And you still see people that may say that this is a fantasy or other people that say that if you don’t like the current government or the weather is not good, it’s because of the leaky gut syndrome.
Chris Kresser: Ha-ha.
Dr. Alessio Fasano: So that’s the reason why there is a lack of trust, if you wish, sometimes from the two camps.
Chris Kresser: Yeah. That makes sense. I wasn’t aware that leaky gut had been developed as a theory even before the discovery of the tight junctions. That’s interesting.
Dr. Alessio Fasano: Oh, yeah, but again, that’s the reason why it was visionary.
How long does it take to get leaky gut? How long does it last?
Chris Kresser: Yeah, exactly. So let’s talk a little bit more about intestinal permeability and particularly the timing of it. How long does it take to appear once someone with celiac, for example, or even someone with gluten intolerance is exposed to gluten? And then how long can it persist after something like even just a single exposure to gluten?
Dr. Alessio Fasano: Well, this is one of the most intriguing parts of the topic here because, again, we only have partial evidence of how all this works. And two questions that are important are, who eventually regulates this permeability? And what can go wrong so that this tightly, tightly regulated mechanism goes out of control and then you have this breach of the barrier long enough to create a problem? And again, we’ve just started to have some sense and understanding of this because the other key element is corollary to what I just told you — is the breach of the barrier an epiphenomenon, i.e. it just happened to be there, or is it an integral part of the pathogenesis of these conditions? So that if you fix that, you can prevent the problem.
Chris Kresser: Right, so it is cause or correlation is another way of saying that.
Dr. Alessio Fasano: Exactly. So what we understand is that at least for the zonulin pathway — and I’m sure there are going to be many others if they physiologically control the permeability — there are two major stimuli that we found to release zonulin in everybody — everybody. If you have bacteria in your small intestine, where supposedly they should not be there because we’ve been built so that bacteria will be confined in our intestinal tract all in the colon at the very end, where there are no nutrients anymore so they cannot steal. But if there are bacteria, they eventually will be able to colonize the small intestine by going through all these layers of defense that we have been evolving with as human beings, like saliva, the gastric juice defending from almost all bacteria, pancreatic juice, bile, glycocholic — in other words, if this bacteria will go through all of this and will land on the epithelial cells of the intestine and start to sit there and steal nutrients that we ingest with diet, if we have one last thing that we can do to get rid of these guys, enterocytes, i.e. these epithelial cells, when colonized by bacteria, they release a large amount of zonulin. They open this space, water comes in from underneath the intestine into the lumen, will dilute the toxins produced by these bacteria, but at the same time will flush them out so that they will be moved out and removed from the small intestine. This is one stimulus. The other stimulus — and I believe that this is more by mistake of evolution rather than planned design as for the proximal bile contamination — is gluten itself. We identified two fragments, one of the gluten components, it’s called gliadin, that when introduced to epithelial cells they induce, like for bacteria, zonulin release. And this, again, happens to everybody. What is the difference between everybody and the people that develop a problem with gluten like celiac disease is that while for me, for example, because I don’t have a problem. I eat a Big Mac. I have gluten in there. These fragments release zonulin, which increases permeability. Stuff comes through, including gluten. My immune system that is tuned to do the job right will clean up the mess, and I will not even know that all that happened. Also because this open-and-close is short. It’s a matter of minutes that it will open and a matter of minutes that will turn to be closed. People with celiac disease, on the other hand, when they do something like that, not only do they have much more zonulin produced than I do, but also the opening is much more prolonged because these doors get stuck open, and therefore you give much more time for substances from the environment, including gluten, to come through. And now on this other side, you find this immune system that is not tuned to do the job right, and when they see this enemy, they start to mount an immune response to attack your own body, and that leads to celiac disease.
The differences between Celiac Disease and gluten intolerance
Chris Kresser: OK, well, that’s very clear. Dr. Fasano, we’ve been talking so far about celiac disease, but we haven’t yet touched on the phenomenon known as gluten intolerance. Can you talk a little bit about the difference between the two and particularly in terms of pathophysiology?
Dr. Alessio Fasano: Sure, sure. Until the recent past, we were convinced that the only reaction that we have to gluten would be celiac disease, so this autoimmune reaction to gluten. Over the years, with the increase of awareness about celiac, with the increase of products in the market and with the popularity of what this gluten-free diet was all about, more and more people became aware of celiac disease and the gluten-free diet. Now, contrary to diabetes, in which the symptoms are very straightforward and clear, narrow, you know, you pee a lot, you drink a lot, you’re gonna have diabetes unless proved otherwise. You have MS, the symptoms, the neurological symptoms are clear. Celiac disease is a clinical chameleon, and the symptoms can really affect any organ or tissue in your body, but also they are very unspecific. It can go from a stomachache to fatigue to anemia to the tingling of your fingertips and so on and so forth, so you can imagine how many people will have these kinds of symptoms and how many of these people have been told: You know, there is nothing wrong with you if you have chronic fatigue. We’ll look into the reason why you have anemia, but we can’t find anything wrong, and you need just to take an iron supplement. When they start to learn that celiac disease can do that, they ask themselves maybe this is what is the problem. Some of these people, indeed, turn out to have celiac disease, and therefore are diagnosed and resolve the problem and so on and so forth. Some people eventually fail to be diagnosed with celiac disease because they don’t fit the criteria, but because they were desperate because nothing else explained their symptoms, they decide, despite the negative results, to try the diet no matter what. And some of them, sure enough, had their symptoms improved or completely resolved.
So as typically happens in these situations, it was from the grassroots that the problem really became a problem, because when we saw this critical mass of people come into our clinic, at the beginning we sent them away. We said, you know, you don’t have celiac disease. You have no reason to be on a gluten-free diet. But when we saw this phenomenon to take great proportion, we asked ourselves: Is that possible that all these people are nuts? Are they all responding as a placebo effect? So we started to dig into this situation a little bit more, and sure enough, we discovered that there is another form of gluten reaction that we don’t call gluten intolerance anymore because we went through a revision of nomenclature, but we call it gluten sensitivity. And it turns out to be an immune response to gluten not on an autoimmune basis like in celiac disease, not even on an allergic basis because we know that sometimes wheat can induce an allergic reaction like any other foodstuff.
Chris Kresser: Right.
Dr. Alessio Fasano: But it’s a different form of immune reaction that will create a minimal inflammation without damage of the intestine. And that caused the symptoms intestinally and extraintestinal that these people may eventually experience when ingesting gluten.
Chris Kresser: So in people with gluten sensitivity, they get some GI inflammation, but they don’t get the blunting and destruction of the villi as people with celiac disease get. Do they experience intestinal permeability at a lower level and for a lesser amount of time than celiac disease patients? Or is there no leaky gut?
Dr. Alessio Fasano: Yeah, probably they do, but it’s much more transient. And therefore, when we look for that, we don’t see what we see in celiac disease with this breach of the barrier that can be measurable for a long time and so on and so forth. So they probably experience what everybody does, so a transient increase in permeability but long enough to allow gluten to come through and be seen by the immune system that will generate an inflammatory response that’s not as severe as the one that’s typical of celiac disease.
What’s the best commercially available way to test for leaky gut?
Chris Kresser: OK. So in your opinion, Dr. Fasano, what’s the best commercially available way to test for intestinal permeability? A lot of my listeners are interested and concerned about this. We have the lactulose/mannitol test, but I’m also wondering if you’re aware of Dr. Aristo Vojdani’s work in Cyrex Laboratories and what your opinion is on that test, which screens for antibodies to gluten and zonulin and actinomycin and lipopolysaccharide.
Dr. Alessio Fasano: That’s right. So you know, unfortunately none of these tests are validated. Who has interest in testing permeability is finding the conundrum of how to do this. The lactulose/mannitol test is the one that has been used for a longer time. It has been the only test that has been used for scientific purposes but not for clinical diagnosis, because doing that is a little bit finicky and complicated, even if there are labs and a commercially available test is provided, but you know, it’s very, very difficult to interpret that when you are not under tightly controlled conditions so to make sure that the patient takes the sugars, the urine is collected the right way, it’s sent immediately to the lab, you do the right HPLC and so on and so forth.
Chris Kresser: Right.
Dr. Alessio Fasano: And then there are much more gross and not sensitive tests, like for example, you can look for proteins that are lost in the stools that should not be lost, like alpha 1-antitrypsin that tells you you have a protein-losing enteropathy that implies that the intestine is leaking, but that is positive only in the most severe cases of leaky gut. Then of course, there are all these tests at Cyrex that you were mentioning now. You know, when you talk about antibodies against the components of the tight junctions, i.e. occludin and ZO-1 and so on and so forth, now you are talking about a small subgroup of conditions in which you have a breach of the intestinal barrier. Because in those cases, you have antibodies against the components of the tight junctions, and you don’t see these in all autoimmune diseases because the autoimmune response is not against the tight junctions in celiac disease, for example, but against gluten. So you can just have a change in functionality of the tight junction without having a problem.
Chris Kresser: Without an autoimmune response.
Dr. Alessio Fasano: That’s right. So in other words, when you have an autoimmune response against this component, it’s like you crush this door. You destroy the door. But you can also use a key and open the door without crushing it, and the final result is the same. So in looking at just those conditions in which the door is destroyed, you look at the subgroup of possible leaky gut situations. LPS, on the other hand, is a test in which you can tell there has been a breach in the barrier. Why? LPS is a component of bacteria. We know that bacteria are in the gut. And if this LPS is found in the bloodstream, that means that something went wrong, that there has been a breach in the barrier, and therefore this LPS is testimonial that the intestinal barrier gave in, allowing components of bacteria, like LPS, to be absorbed. Now again, besides the complexity to measure LPS in the bloodstream is not a trivial proposition, sometimes you have a breach of the barrier that can be still biologically significant but not enough to permit enough LPS to be absorbed in a quantifiable manner.
Chris Kresser: As a clinician, then, since it sounds like none of the commercial tests that are available are necessarily validated or even easy to interpret, is there any need to test for intestinal permeability? You know, from my perspective as a clinician, one of my benchmarks for whether I run a test is whether it will change the outcome of the treatment.
Dr. Alessio Fasano: Well, again, I’m biased in answering the question because, again, I’m among the people that believe that intestinal permeability is not epiphenomenon, an integral part of the problem. This is based on some animal studies that we have done and also on clinical trials of this anti-zonulin peptide that blocks permeability, so preventing gluten to come through and therefore preventing the reaction to gluten in people, like celiac people, that may be harmed by ingesting gluten. So I really do believe that it’s an integral part. That means that, you know, it will be a tremendous merit to have a biomarker of intestinal permeability because not only will it allow you to say: OK, I do have a problem here, that if fixed may eventually help me out to manage this condition, and I can manipulate this problem, I don’t know, if this is due to bacterial contamination, to use probiotics or molecules that will come in the pipeline that will help fix permeability. I mean, as you probably know, the literature is invaded by papers showing that probiotics can improve the leakiness of a gut and so on and so forth.
Chris Kresser: Um-hum.
Dr. Alessio Fasano: But also, and I believe even more importantly, is prevention. I mean, you know, we have seen, for example, that this regulation of zonulin prevents the onset of diabetes by years. We know that, for example, in the literature you can predict flare-ups of people with inflammatory bowel disease by looking at their gut permeability. Those with increased permeability are the ones that most likely will have a flare-up in the next few months, while the ones that have a normal permeability do not. So I believe that there is going to be a tremendous need to have validated biomarkers of gut permeability. We hope to have the zonulin ELISA assay that now is being developed by a major diagnostic company commercially available soon so that can be used for that purpose.
Chris Kresser: Oh, great.
Dr. Alessio Fasano: And I’m pretty sure that there are going to be others that will be developed and become available, including eventually a validation of the lactulose/mannitol test, the alpha 1-antitrypsin, and so on and so forth, when people will really appreciate the clinical validity to have such tests in the clinician’s office available.
Everything we’ve learned about restoring gut barrier integrity
Chris Kresser: Right. We’ve been talking about pathology and etiology so far. Let’s talk a little bit about treatment, and maybe you could tell us what we’ve learned so far about how to restore gut barrier integrity.
Dr. Alessio Fasano: Yeah, well, we mentioned it a little bit already. For example, of course, if we know the cause of the breach of the barrier, then we can remove the cause. And you know, if it’s gluten for gluten sensitivity or celiac disease, you remove gluten. If bacterial overgrowth or dysbiosis, eventually you fix the problem, either treating the bacterial overgrowth or with probiotics. If it’s genetic, it’s a little bit more complicated at that point because, again, it’s an intrinsic defect of the individual, so you need to eventually go after the genetic defect and try to fix that. For example, zonulin is an example. If you have a genetic defect that makes you produce more zonulin than you should, the only way that you can do that is eventually to use some mechanism to block zonulin’s effect on tight junctions and that kind of stuff. So it’s typically like any other treatment. Either you treat the symptom, in this case the leaky gut, by going after the problem or you treat the cause. If you know the cause, you remove the cause so that it will go away that way.
Why Celiac Disease patients have increased zonulin levels, even on a gluten-free diet
Chris Kresser: Um-hum. In one of your papers, you mentioned that celiac patients sometimes have upregulated zonulin levels even after they have adopted a gluten-free diet. Is that true only for celiac patients, or is it also true for other people with different kinds of autoimmune diseases?
Dr. Alessio Fasano: Yeah, so far, we have seen this, because we had enough data, in three autoimmune diseases. We have seen this in celiac disease and type 1 diabetes and multiple sclerosis. When we discovered what zonulin is all about in terms of genes, now we know that zonulin is the precursor of a molecule, a protein called haptoglobin 2, so we know what kind of molecule it is. And using that as a biomarker, we see that there are three major categories of conditions that see zonulin upregulated or present in a mutated fashion. These are autoimmune diseases, and besides the three that I just mentioned, it has been proven in Crohn’s disease, for example, and in another category there are tumors ovarian cancer, pancreatic cancer, glioma, these kinds of cancers, and then in diseases of the nervous system, including schizophrenia and autism.
An update on Larazotide, the intestinal permeability drug
Chris Kresser: You mention possibly pharmacological agents that would help block the actions of zonulin and prevent gluten from causing intestinal permeability. Can you give us an update on larazotide and how that’s progressing?
Dr. Alessio Fasano: Larazotide was, again, another serendipitous discovery. It’s a small peptide. It’s made by eight amino acids. And we don’t know yet for sure the mechanism of action, but what is the projected mechanism of action is that it binds to the zonulin receptor, so preventing zonulin to communicate with the cell to instruct the cell to open this shortcut of the tight junction. This molecule has been through an extensive preclinical evaluation and showing all these effects and so on and so forth, and since 2006, it has been in clinical trials through Alba Therapeutics, a spin-off company of the University of Maryland. So far, the molecule has been given to roughly 500 people with celiac disease, and what I can tell you is that, one, it’s been very safe, so there are no side effects whatsoever, and this was expected because the mechanism of the molecule is to stay outside the body and block zonulin in the intestinal lumen. Therefore, all the side effects that typically you have with molecules that come in our body are not served.
Chris Kresser: Right.
Dr. Alessio Fasano: And in terms of efficacy, so far it seems to be quite efficacious in preventing the symptoms that typically celiacs experience when ingesting gluten in their diet, so all the symptoms that typically they have are prevented by the use of larazotide. Also biomarkers of inflammation, the ones that eventually will create the problem that leads to symptoms, seem to be kept under control by this molecule, while celiac people ingesting gluten with no protection will have the increase of this inflammatory biomarkers.
Chris Kresser: Um-hum. So I know it’s impossible to make accurate predictions on this kind of thing, but can you give us your best guess on, if things go well, when this might become available to the public?
Dr. Alessio Fasano: I can’t. And the reason why is because I did before and was proved so wrong!
Chris Kresser: Ha-ha!
Dr. Alessio Fasano: Because I was so naive to believe that the limiting step was science. No, it’s not science. That is not true at all. The limiting step is purely and simply economical after you go through the first step of a clinical trial. The clinical trials are done in steps.
Chris Kresser: Yeah.
Dr. Alessio Fasano: There’s a phase 1 in which you just look for safety. And then you go for phase 2 that is efficacy of different [45:48]. And then you go in phase 3, they go in these big, large studies and so on and so forth. Average time to do all this is 15 years. Average cost is 1.2 or 1.3 billion — with a B — dollars.
Chris Kresser: Wow.
Dr. Alessio Fasano: Yep. And the efficiency: miserable. You start with a thousand molecules, and only two or three will go on the shelves in a drugstore.
Chris Kresser: Right, so obviously there has to be a big enough market to justify that expense.
Dr. Alessio Fasano: Well, if you don’t have a justifiable market, they don’t even start, because otherwise they will not have the return on investment.
Chris Kresser: Yeah.
Dr. Alessio Fasano: But once you start, you’ve done this analysis and there is a market that eventually can pay you your investment back, the problem is you move from one phase to another, you know, at the pace that is really dictated by availability of the money, what’s going in, and so on and so forth. So, all this to say who could have predicted the 2008 debacle of the clinical economy worldwide? And with that, the money to be invested in any kind of enterprise, including drug development, really dried out.
Chris Kresser: Right.
Dr. Alessio Fasano: And it slowed down tremendously the situation. Thank God, the molecule now is back in a clinical trial because money became available again. The molecule now is in phase 2B, where only 20 of the thousand will reach that level. So all this to say there is still room for failure because of the 20, only two will get there.
Chris Kresser: Um-hum.
Dr. Alessio Fasano: But also, how fast it will go there, assuming that the molecule will go through the scrutiny, it all depends on money availability. So it’s truly an economical situation. So if the economy would not tank again, maybe we’re talking about two or three years. If we tank again, God knows.
Upcoming research developments to get excited about
Chris Kresser: OK, well, we’ll keep our fingers crossed. Last question, Dr. Fasano. What developments in this field are you most excited about, and is there something that you feel is important that we haven’t touched on on this topic?
Dr. Alessio Fasano: You know, I really do believe that the best achievement for anybody that is involved in clinical research and translation of the research, is not to fix the problem when it’s there. It’s to prevent it to that it’s not gonna happen at all. So I believe that in this field the most exciting development is to try to understand how people may eventually develop celiac disease, because epidemiologically speaking, we know that you can develop celiac disease at any age right now. So there are people that develop celiac disease at 2 and people that develop celiac disease at 72. And because the corollary that we had was that you have to have at least these two elements, genes and gluten, to interplay to develop celiac disease, we were convinced, absolutely convinced, that the celiac disease autoimmune process starts in everybody when gluten is introduced in the diet in the first year of life. And we also explain the difference between who develops celiac disease at 2 or 72 with, you know, the way that the immune system reacts to gluten. If you have an aggressive immune system that will create inflammation right away and will put you over the edge right away, you develop celiac disease as a child. But if you have a slow-paced immune system, the critical mass of the damage can occur in many, many years, and you develop symptoms later on. We were convinced about that. That’s one of the dogmas that I thought would never, never, ever be put in discussion, and that was not the case. Two years ago, we did a study on 3000 adults, once again, a study designed for a totally different reason. We wanted to know of these 3000 people that had been followed over the years since the ‘70s, and 1%, that’s roughly what we think is in the general population the prevalence of celiac disease, 1% of them must have celiac. Let’s see how they move from no symptoms to symptoms over time and see if we can link that to any event in their lives so that we can understand what’s going on. We were shocked — shocked — to learn that celiac disease doubled every 15 years in this court. It was 1 in 500 in the ‘70s, 1 in 250 in the mid-’80s, and 1% in 2000.
Chris Kresser: Wow.
Dr. Alessio Fasano: That implied that there was something else that was going on here. We had two ladies that for 70 years-plus eating gluten had no problem whatsoever. They were tolerating gluten. No problem with ingesting gluten. Then all of a sudden, they lost this luxury and they switched from tolerance to immune response and developed autoimmunity in their late 70s. This implies two questions that really, I believe, is the most intriguing part of this entire story for the years to come: Number one, what kind of tricks did these ladies use to tolerate what is an indisputable trigger of autoimmunity for people genetically predisposed to celiac disease? We learned that we may have the holy grail to prevent autoimmunity in general. It is material for a Nobel prize. Number two, more feasible, is to answer the question, what happened to these ladies that after so many years lost that luxury and then switched from tolerance to an immune response? And here, I believe that the most likely answer is the microbiome, the bacteria that live with us in symbiosis, have to be the ones that made them to switch from tolerance to immune response.
Chris Kresser: Um-hum.
Dr. Alessio Fasano: So they had a friendly microbiome before, and then something happened to them — I don’t know. They got an infection, they took antibiotics, they changed their diet, whatever — And now rather than having a friendly neighbor, now they have somebody that is not in peace with this neighbor and starts to touch genes of the host that when expressed or repressed will put these people at risk to switch from tolerance to immune response and develop celiac disease at a later age. I believe that those are the two fields of great interest that I’m looking very much forward to learning a little bit more.
Chris Kresser: That is fascinating. And you also mentioned some preliminary research that suggests — and correct me if I’m wrong here — that if an infant avoids gluten for the first year of life, then the risk of celiac goes down by four-fold. Is that right?
Dr. Alessio Fasano: Well, you know, this is part of the corollary of what I just told you, because the idea is if indeed the game is not over, if indeed it is not destiny that you’re born to develop celiac disease because you have the genes, but destiny can be manipulated, the question is what can be done to eventually prevent or delay the onset of the disease. And one of the most debatable and far to be settled issues is time of introduction of gluten into the diet for whom is genetically predisposed. We know that introducing it too early will be harmful. This is well known. It’s settled. Everybody agrees on that. The question is, if we delay, can we do the opposite, delay or prevent celiac disease? And nobody has done anything like this so far because these are very complex and long and expensive studies. And we embarked on one of those in which we are recruiting neonates from families at risk and then we follow them over time, and at the time of weaning, because it’s a double-blind study, we blindly leave half on a gluten-free diet and half will be introduced to gluten, as it’s supposed to be based on the current recommendation of the American Academy of Pediatrics, and then we follow a time, asking as a primary question how many of the ones that were introduced early to gluten developed celiac disease compared to the ones that we postponed. Now, the data that you mentioned are correct, but the caveat here is that this is only a three-year follow-up. There is still the possibility that later on these kids will catch up, the ones introduced to gluten late.
Chris Kresser: Right.
Dr. Alessio Fasano: So, we don’t know yet if indeed you can prevent celiac disease by delaying the introduction of gluten. But at least I can tell you, based on the data that we have so far, that you can delay it. That is, I think, a good thing so that eventually these kids have more time to stay on a regular diet and enjoy the diet.
Chris Kresser: It doesn’t seem like there’s much downside to trying anyways if you have that predisposition.
Dr. Alessio Fasano: Yeah.
Chris Kresser: Dr. Fasano, thank you so much for joining us. It’s been an honor to have you on the show, and I wish you the best of luck in your future endeavors.
Dr. Alessio Fasano: I appreciate very much to be on your show, guys. Thank you so much for having me.
Chris Kresser: Take care.
That’s so great. Best show ever!
Steve Wright: All right, so we’ve got Chris on record saying best show ever. I would agree. I want to thank you, everyone, for listening today.