Alessio Fasano M.D. on Gluten, Autoimmunity and Leaky Gut | RHR

Pioneering Researcher Alessio Fasano M.D. on Gluten, Autoimmunity & Leaky Gut


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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, and with me is Chris Kresser, health detective and creator of  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.

OK, well, Chris, I know you have a lot of questions to get prepped on, so keep working on those, and in the meantime, I’m gonna let the listeners know before Dr. Fasano gets on the air here that if you’re listening to this for the first time, if you’re new to the paleo diet, or if you’re just interested in optimizing your health, you’re gonna want to check out what over 10,000 other people have already signed up for.  What is it?  It’s Beyond Paleo.  Now, Beyond Paleo is a free 13-part email series on Chris’ top tips and tricks for burning fat, boosting energy, and preventing and reversing disease without drugs.  To get it, go over to, and look for the big red box.

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.  Please keep sending us your questions at using the podcast submission link.  If you have anybody that you’d like us to bring on the show, also send that to us using the podcast submission link.  And lastly, please head over to iTunes and leave us a review.

  1. Dr. Natasha Campbell McBride (who has had a lot of success treating autism and related conditions in children by healing gut dysbiosis) is very clear in her assertion that a healthy small intestine contains and depends on a thriving population of “good” bacteria. In her book Gut and Psychology Syndrome she goes into detail about this. But in this podcast I hear Dr Fasano say that only the large intestine should contain bacteria. How confusing!

  2. Fascinating information!
    As we’re in the age of acronyms, perhaps its time to create one for leaky gut/autoimmune
    How bout simple, IPBD, intestinal permeability biodysfunction? I believe the trinity condition
    would be covered with his acronym. Comments and other suggestions welcomed.

  3. Thanks so much, Chris, for interviewing such an interesting speaker and a fascinating topic. We learned about leaky gut in school but now I’m actually learning the mechanism for intestinal permeability. So incredibly fascinating. I must say that the drug that Dr. Fasano mentions sounds a little bit like a big band-aid (as drugs often are). Zonulin sounds like an intricate part of the puzzle but I’m not sure that a drug that blocks zonulin is the answer to the problem. I am sure it may help some people in the short-term, but does the drug truly heal intestinal mucosa and re-establish healthy immune barriers? Why are we getting an overdose of zonulin release in the first place? I’m not really sure that blocking zonulin is treating the underlying cause. When antibiotics and illnesses and stress and processed foods are all contributing to weaker intestinal health, I think there is more to be healed than just blocking a molecule or an enzyme. But I thoroughly appreciate reading this interview. Thanks!

  4. I don’t eat it often, I just notice no problems despite it being soy.
    Yes, if you have leaky gut LPS from anything other than anti-inflammatory probiotics could be tricky.

  5. Are you sure the fermented soy is not impacting you in some way? I can’t eat beans of any kind for nothing. Oh I tried. They would say if you eat a lot of them you body will adapt. In my case it would implode. I was a hopeless failure at eating beans.

    I could resolved IBS before many autoimmune conditions calmed down. To me this indicates that some foods cause bowels to explode vs some foods quietly cause your stomach to be sieve like and allow immune response. I don’t think they always go hand in hand. Some do though.

    I think food allergy seems to be different from autoimmunity too. I think Dr. Fasano had talked about this as I recall. Also fermented products were something us autoimmuners were told to avoid and my guess is because of the sieve like stomach tendencies. Those things that grow in fermented foods may easily pass through leaky gut and our immune system really doesn’t like living mold critters.

    If you have autoimmune conditions you may do better without fermented soy. The problem we have is we react to so many things and the sooner you make the diet simple the sooner you will figure it out for you.

  6. Yes, that dupont is getting in on the act is interesting! Weren’t they behind Love Canal?

    Aha, activeK is extracted from Natto.
    ActivK™ Vitamin K2 is a pure natural extract of natto – traditional Japanese fermented soya beans and the richest known source of the vitamin.

    Now, I am very allergic to soy which causes raised whelts, hardening and damage to my skin. But fermented soy products are fine. Tofu, soy milk are poison, a really nasty effect that ruins my week,
    but miso or preserved curd are A. OK.
    Of course my soy allergen may not be yours.

    This is MK7.

    • Ha Ha….My first reaction is anything Dupont is pushing should be cautiously approached. Second I can’t seem to figure out what it is actually made of, can you? This sounds like a Frankenstein vitamin that I would want to avoid.

    • I am not convinced I need it or in fact any of us need it.These studies just don’t speak to me who eats Paleo and especially me who is meat eater only now. They say that butter actually contains low amounts of K2 as well. But if did need to add K2 in diet, butter oil might be a great way for me to take it.

    • @ George thanks for the tip. I have sworn off all supplements. So many contain so much non Paleo stuff and preservatives in them that do me in. Since there is really no regulations with this industry, they disclose what they want and very little. Even the capsules are made of cellulose (grass of some sort) or gelatin and when you contact the manufacturers they have no idea what their capsule venders use in them and that can change overnight too. Even our illustrious fish oils all contain a distilled soy product from all fish processors as a stabilizer before they ship to pill manufacturers and they don’t disclose this properly for those with soy allergies. They think that once it is distilled 3 times that the proteins are all gone and no big deal.

      They call it Vitamin E d-alpha Tocopheral instead of soy. Hey last I heard all food manufacturers are required to disclose soy ingredient as one of the top 8 allergens but not so with supplements. I know some who have soy allergies who couldn’t figure out why they had a problem with their Carlson’s fish oil….well it could be the stabilizer. For autoimmuners who have to stay away from alcohol and vinegar that are also distilled maybe voiding that fish oil is something you should consider too. Next time you look at Carlson’s fish oil check it out. Their quality control science guy said he they should disclose this but some how I bet they still haven’t gotten around to that yet. Especially when you got Wolf and other Paleos pushing fish oil who haven’t a clue as to what is actually in and done to it. Some of these capsules are made of petroleum too.

      If I am going to get nutrients I want to get them from my food since then I know the source of the ingredients. The more I move away from processed foods the more I notice how sensitive I am to them. Those preservatives are either causing stomach permeability or messing up the gut flora or something or all of the above.

      I tried bacon last week and it did me in. But Paleos are big on bacon even though it has sugar except the Costco ones and tons of nasty preservatives and is the highest in AGEs at 90,000 for one slice I think. Talk about you inflammation bomb. But you don’t hear that and that is my reality and others with autoimmunity. When you are young Paleo with few health issues it is hard to relate but as you get older they can pile on and it just isn’t so simple.

      I also worked for one of these supplement companies long long time ago and briefly. They ended up on 60 minutes and never told the staff they were being investigated. I was stunned to see them rip this company apart about ingredient disclosure and started to look for another job since it all seemed rather unsavory. Bradely took three companies to task on this so it was common practice. I recall the third person from the top would down dropper fulls of echincea and swore about the health benefits when in fact no studies had been done. Ignorance is bliss and profitable. Finally in recent years they actually studied it and found out it does nothing to help protect you from colds and flues etc.

      Since they have yet to figure out what our genetic tolerances and intolerances are how can they say you need so much Vitamin K and in what forms and how much? I will check it out more but gut instinct is to really be very cautious about supplements and find it in food.

      • Adequate K2 in the diet comes from grass-fed beef, as cows convert the vitamin K1 in the grass to K2 in their rumen/intestines. If you have been eating grass fed, and mostly meat, this may have been a factor improving your Rosacea. Instead of butter oil, just go for grass-fed butter to complete the grass-fed meat and you’ll be sure that if you still have symptoms it’s not your K2.

        You can get uncured/untreated bacon, like canadian bacon or turkey bacon or pork bacon from places like trader joe’s (and maybe whole foods? haven’t checked). No sugar, so no AGEs, delicious.

        I wonder how healthy Mark Sisson’s fish oil supps are, then, if all that is true. Well, in my case I would argue that I need the omega-3 and am not sensitive to much (started out healthy, so no gut issues beyond being allergic to strawberries, cats, and the seasons -> pretty much cured now), so I will take Carlson’s or Mark’s or whomever gets the job done. In your case though, I totally see your point.

        As for your general health and carnivory, perhaps it’s the FODMAPs? Specific types of short-chain carbohydrates that can cause bowel/intestinal distress, which includes fructans and compounds issues with fructose malabsorption. Read these (flatulence may not apply, but maybe Rosacea and other generally bad reactions are connected to this, as well as the fructose/glucose ratio of meals – apples are particularly high in fructose): This one is similar to the first link, but read the “get bacterial overgrowth” link – could you have Crohn’s disease? Or just bad gut reactions in general, but not to the point of disease?
        This is also nice, about fructose malabsorption (though you probably are an expert on that now I bet, there may be some valuable info about the fructose/glucose ratio being too high per meal):

        Finally, again from Jamie, this is incredibly relevant. Basically, eat your medium chain triglycerides (coconut stuff you can eat, yeah?) and it’ll help with your possibly leaky TJ’s.

        I would agree that, over time, you will get healthier and healthier (as opposed to many people who follow CW, who continue to get sicker and sicker). I don’t know if probiotics would accelerate your gut healing or hurt them (the pill kind, ala GAPS, but you don’t like pills, yeah?). I would say try some of that stuff, especially the adding in of more coconut products as well as trying to avoid some of those other FODMAPs if you haven’t already done the elimination-test for all of them (maybe try them again in a few months, as your gut can take a very long time to fix itself from severe damage). Of what I’ve linked so far, though, I think this is probably the most specific and applicable link, from the GAPS diet (which you should try – basically paleo, but with more eliminations in the beginning to restore gut flora. Interestingly, the FIRST recommendation is to cut out all sources of fiber (go no-plant). Fruit has both fructose and fiber, last I checked, and pretty much all veggies do. Thus, you found they didn’t agree with you. This is actually more likely to be important than the FODMAPs thing I mentioned earlier, as it’s not the most health-relevant if you’re foregoing the non-paleo FODMAPs. You basically already started the GAPS diet, so find out where you are in their procedure and go from there. Let me know how it goes on here! 🙂

        • I would love to be able to afford grassfed meat but in this economy it just isn’t going to happen and meat prices are only going to even higher with drought and corn shortage too. I have already priced local ranchers too. Need a big freezer too. But I could find grassfed butter no problem at store and will try that out, heck I have tried so much already.

          I have experimented with bacon. Even made my own since either bacon has preservatives which wipe out my gut flora and/or cause leaky gut or some sweetener to replace the noncured bacon. Either way it is not Paleo. But don’t tell that to Wolf. I experimented with pork bellies and made my own just with brine. It tastes like salty fatty pork and I made sure I cooked it low and with water to reduce the AGEs since that is also key. It is not great and worth all the effort. But others may like or adapt to it better.

          I spend time in bathroom recovering from eating any processed bacon be it cured and not cured. Because they all have some sort of preservative even the non cured ones. I recall years ago wondering what was the big deal about preservatives since I thought they never bothered me. Well I now understand what the big fuss is about.

          This reaction also happens with trying to conform to the idea that us Fibromyalgia types need magnesium per Wolf et al. I have tried many types of magnesium and in the smallest doses possible like 1/8 t. and end up in the bathroom for 2 weeks. So is true of potassium sulfate which is used in dried fruit and other foods as preservative. One researcher said it was cause I got a bug in my food and I can tell you that that was not the case. I tested these things over and got the same responses. Makes you wonder about researchers if they are really paying attention or just too busy with proving their assumptions.

          I have checked out Sessions supplements before and even called them about them and they are formulated to be better than most in some ways and in other ways they are not. Expensive too. Wasn’t Mark in the pill business before? He knows all too well how to play the game. I think he could have made them better but didn’t and he also doesn’t disclose it all and who ever he has licensed to make them for him are not disclosed from what I could tell so when you can’t get straight answers from the old guy at Sessions no manufacturer to call to find out more. You may be surprised at who has making them for him.

          Before Paleo I didn’t have Crohn’s but IBS but can now control it with diet. I do not have IBS when my Rosacea flares with carbs. These are two separate issues. That is why I say it is not malabsorpton but leaky gut to fruit. No gas or the rest.

          As far as what is a disease you got me there and so many autoimmune conditions are suspected since no funding for research. When I look at so many autoimmune conditions they have very similar symptoms at times that most folks with autoimmunity are wondering if they have this or that since it is such a gray area. Autoimmunity to me is just different combos of reactions to food toxins. Depending on your genetics it will present it self one way and for others it will present it other ways or other combos if you like. I think they like to call it one disease when it favors a certain grouping of symptoms, but really I think that Fasano is saying hey all autoimmunity is created by what you are eating and other epigentics and when you take out those triggers it will stop. Doesn’t matter if you have MS or Lupus or ________. So he saying one approach works for all autoimmunity and this is big and no we don’t need various immune suppressing drugs. Drug manufactures love to divide autoimmuners and conquer. Make them seem special and unique and it is beyond their control and they just pulled the short stick of life. They are there to help you when nothing else works and you can still have a fun life and eat your mac a cheese….fade out.

          The further north you get the fewer the carbs they ate due to climate restrictions. Why is that abnormal? It isn’t. No they didn’t have fruit year round and why do you think my genetics require it? They also didn’t have lettuce year round either. But they did have meat year round and shellfish etc. What we need, are you listening Sessions, is maybe a pill that would make up for the lack of organ meats we are missing. Make them in frozen form. No need for preservatives either. But that is costly.

          There are certain populations like the Inuit who did fine on an almost carb free diet. There is a movie that many Native American’s recommend to watch to get a sense of their culture. It won awards too. It is about the Inuit. It is called The Fast Runner. They used real Inuits to play the roles and some of the acting is cheezy for sure but hey they are eating raw frozen meat. They even have a hierarchy of what part of the animal is considered the cheap cuts too and weave that in the story. I see no bowls of anything. I see them with a knife and cutting off frozen meats from their in ground meat locker.

          I know what I am telling doesn’t jive with what you understand. Not one fruit or fruits works for me. Not one veggie or veggies seem to work for me. When I take out all fruits I do better but not perfect by any means. As I back off of veggies it improves.

          Yes I could eat them when I was younger but hey didn’t have autoimmune issues then. Maybe when you get older and lose hormones and systems less efficient the body’s ability to bounce back from eating the wrong things just isn’t there anymore. It say’s enough and not going to do anymore.

          I have manna and coconut oil and will test those out again. Yeah I am not sure if probiotics will help or hurt. I respect Dr. Fasano enough to give it a try. I see his group had tried VL#3 which has several stains at high amounts. Pricey dude and needs a script. But so far I can’t find any info that says this strain or these strains are the ones that work to heal gut. They all notice that probiotics has an anti inflammatory affect on cancer but don’t understand it enough yet. Some say take one strain at a time would be a better approach to see which ones helps your genetics. But they tend to make combo pills. That is why I wanted Chris to ask a follow up question on this, frankly I am surprised he didn’t ask it himself.

          To Chris’s defense I guess he was taking a beating at AHS with starchy carbs and last night I was thinking I may not be able to handle fruits and veggies but how about rice a little bit since it is just glucose? I am going to test that out. Also thought about your butter idea with that. Maybe not eat it a lot but it sure might break up the tedium of meat only.

          I found that Dr. K pushes DHEA for Fibromyalgia and then I found researchers who actually tested this out in Europe. Turns out it does nothing for those patients. But Dr. K is on a roll. Yes I have looked at FODMAPS and GAPS closely. Hey they don’t know either. So many of those foods are what I react to. Do you hear Fasano pushing GAPS? No.

          His science is pretty darn good in my book compared to so many out there. He get’s autoimmunity which is something that so many gloss over and pretend to get. While they wait for his science to come out with real answers the rest tinker with FODMAPS and GAPS and PALEO.

          That is why I was THRILLED to listen to this podcast of Dr. Fasano. It you have an autoimmune condition Fasano is the guy to keep your eyes on. Even Chris here is giddy and for good reason.

          • Ah, sucks about the grassfed, but I can definitely relate to the crazy prices (student >.<). In my opinion, "uncured" bacon is still Paleo for the vast majority of the population because it's as close as we are going to get in this neolithic world (at least commercially), short of killing the animals ourselves and eating them raw on the spot. If it doesn't work for you, you shouldn't have to go to all that trouble for so little reward – that's your N = 1, a point which I think you understand full well 😛

            With respect to magnesium, I think most everyone agrees that magnesium can help with fibromyalgia, but not necessarily that it WILL help for everyone. In the comments, it mentions a Wolf podcast where Chris talks about the mechanisms of fibromyalgia and how magnesium could help (or anything that helps glutathione or mitochondria). Emily wonders, however, whether the improvement in magnesium studies has been because of the improved sleep effect – if you were already sleeping well, then it may not help you as much. Your N = 1 says it didn't work, so back to diet and your specific needs. I'm sorry about the researcher, just keep telling yourself he's probably non-paleo and is thus inferior healthwise 😉 . In defense of Wolf and Sisson and authorities, I believe most people really do want to help. I think (as mentioned in Emily's link) most people assume that everyone else eats a poor diet or did something wrong, in sort of an egocentric view of "it has to work, so you made a mistake". You are clearly not in the typical "I can eat healthy things and reverse all my diseases in 6 months" kind of paleo story, and that's fine. It just means it's going to take more time and/or work. Despite some shortcomings, I believe Wolf and Sisson are truly there to help (even though Sisson sells supplements – he's upfront about it, and if it helps him spread the paleo word you can even treat it as a paleo advertising agency that needs funding to support the cause). I would write emails/blog posts detailing your needs to a bunch of these smarty paleo people, to see if they have any additional recommendations they can flesh out for you – if it's not sleep, thyroid, magnesium, etc. then it must be _____. (Personally, I would expect it's either gut flora or intestinal permeability and intestinal health – no ulcers or anything like that? Perhaps both of those at once).

            On that same track though, I agree 100% that drug companies suck. They're so large that treating people like ants is quite easy to do, as the drug creation process takes so much money and so much time that when push comes to shove they need to sell it all like it's the only treatment for a condition that ever existed (and they might have to believe it themselves, too).

            The peeps at whole9 totally agree with your seasonality idea (at least in reference to fruits/veggies): As for the carbs, I think it isn't harmful to get more carbs than your ancestors might have gotten in colder climates – regulation of blood sugar and hormones beyond melatonin aren't tied much to length of light cycles, so I would put greater emphasis on tying in your carb intake to your activity level (unless you are fairly overweight, in which case limiting starchy stuff is best).

            The no fruit/veggie thing does jive with what I understand, because from what I understand humans are physiologically capable of consuming these foods. Any deleterious effects from doing so are either because of messed up hormones (thyroid? that seems to be implicated in everything) or a messed up gut. That severity of food intolerance is NOT genetic, and cannot possibly be so. Susceptibility to unhealthy gut flora or more leaky tight junctions might be genetic, but I have no doubt those are epigenetic and as such can be changed by lifestyle factors (not necessarily fixed, because even though genes are on/off there may be multiple genes controlling your zonulin and thus your improvement may exist on a continuum of your ability to fix some or all of those genes). How long have your fruit/veggie elimination tests gone on for?

            I realize that Dr. K isn't perfect. I know that the GAPS diet does not work for everyone, because of things like specific genetics (maybe you are a low-carb person for life, whereas others will enjoy higher-carb, talking after-healed-gut here, and it's all part of the paleo template, as Chris would say). If you look at the introduction diet (the more restrictive diet) of the GAPS, you would see that it's practically no-plant and is certainly no-fruit and is definitely no-starchy-carb. It seems to me this is exactly what you are eating, no? She says: "Some people have to follow the introduction diet for up to 18 months… before moving into the Full GAPS Diet. This is usually the group of the most severe people such as those with chronic fatigue syndrome, fibromyalgia.." and "I have patients who have done best on a completely no-plant diet". Even if she made an oopsie with the DHEA, it seems the diet is flexible and applicable to your situation. I would try to follow it for a while and see if you can add veggies/fruits back in as the timeline for gut-healing dictates (could be year or more, she said, but again I don't know how long you've been tweaking your diet and such). I know you have an inherent distrust of authorities or people who think they have the "one answer", but I think that if you try them all, one of them is bound to work – the GAPS diet already seems to be working for you as your N = 1 diet, so why not try it in its entirety? Of course, you would ignore foods you know you have a reaction to that are "ok" on the diet – this is mentioned in the "sensitivity test" section online. The way I see it, you have nothing to lose.

            I don't know if a no-plant diet is the best for you forever, but if you try the GAPS (probiotics included) and it doesn't cure the fruit/veggie intolerances, then I would say stick to your guns.


            G'luck 🙂

            • Hi Adam,
              I have a big problem with “expert” Paleos when they start giving advice to folks like me when they are just guessing at autoimmunity. To say Fibromyalgia folks CAN do better with magnesium is like saying I CAN do better standing on my head. Yeah maybe I could but no science to back it up. Hypothetically it could possibly happen….I have already emailed to some of those shamans and got such responses and followed such baloney advise and realized much like the king they have no clothes and we need to speak up so others will take heed. I now look for answers in published research before I fall into the trap of this online shamans. I have big problems with what Mark and Wolf do and others who market such off the wall advise for chronically ill folks like myself. It is one thing to tell healthy folks to eat bacon and such but whole different ball of wax to start telling sick folks to play round with this or that without any supporting research or cherry pick it to sound like they found some new take on it.

              Must they really make money from giving crappy advise to the sick ones too? That is where I draw the line. But lots of physicians do this every day in clinics so are they any worse? No, but I tend to lump them together. I used to give them more leeway on this since they were getting the basic Paleo concepts out there but realized you can do that in other ways and they do cross the line. They like to try to straddle the fence on all of this but really don’t. They are really not that into chronically ill folks and for good reason. We will debunk their baloney time and time again or ask to support it and they come up short. Haven’t you ever read their postings where they go out on the limb and say this or that and then back paddle their way in the same article? Nearly every time.

              New research is coming out all the time and these Paleos are constantly changing up the recommendations and that concerns me too. Now they act like there was no such thing as a so called Paleo diet per se so they are even now back paddling the tenets of Paleo? This in its self is remarkable and why folks are not saying “hey wait a minute what about that cookbook or those recipes weren’t they outlining a specific diet by the recipes alone”? I think we all inferred that was the diet.

              Testing out foods for close to two years now and have tried so much so not new to this by any means. I am trying out rice but not too much and so far it seems to be ok for me but it needs more time. I do not think I am that unique but maybe just another casualty of what happens when you eat SAD along with having taken antibiotics with a genetic makeup that was used to more limited carb diet.

              I used to eat tons of carbs before but now it is so messed up with epigenetics too that so many of us face the possibility that we may never ever be able to go back to carbs again. I do know healing for us takes years. We have so much to repair and figure out it just takes way longer. That is why we are very frustrated with all the baloney.

              There are a few studies I have tracked down some I can’t read the full text of that indicate that fructose is very common in intestinal permeability in animals. Horses for instance and rodents. On a diet of like 30% fructose too. I know I have eaten 30% fructose in the past.

              Just as insulin hormone becomes messed up with too much fructose and leads to some permanent diabetic issues then perhaps other hormones that regulate intestinal permeability could also be impacted irreversibly by fructose. Fructose has a toxic impact on so many of our hormones like knowing when you are full. Why not the hormone Zonulin?

              When a diabetic eats fructose well the body reacts strongly even if they have been avoiding it up to that point. It is hyper sensitive to the toxin now. I wonder if that is also the case with leaky gut too. How it works I am not sure and several theories are being offered. Such as probiotics but I found several studies that taking those could be more harmful than helpful.

              To advise taking probiotics would mean something like the bacteria caused by fructose is causing the intestinal permeability and that could be one way or it could be another way. That is why I wished to heck that Chris would have ceased the moment and asked Dr. Fasano why he is suggesting probiotics. If you are into this topic of autoimmunity you would have keyed in on this. Just saying….

              But drug companies probably already know where this is headed thus they are pushing Metaformin as their short term answer much like auto suppressing drugs. It think there is already research out there that can give us more than theories but real clues to this.

              But the studies are so limited right now and lay person has a difficult time understanding this. That is why I am soooo disappointed in the Paleo gurus for not actually digging into this with their fancy Phds and B.S.s. or have resources to get those investigated, Mark. Instead they talk about how “Play” is important or doing podcasts with lots of yuck yuck yucks. They have painted themselves into the media hungry online venue and have to fill up dead air time. I prefer quality over quantity. Maybe when I feel better I can afford to be amused more by their antics.

              More enter the arena like Dr. K and just when you think maybe someone with some intelligence has actually entered you find out he ain’t any better than the rest and again some of his shtick is just really bad advice hence DHEA. But folks don’t spend the time it takes to figure this out. He counts on it. But he got tons of interest and then of course Mark wants to get in the wave of this and wants to write a book with him. Arrrgh.

              Don’t get me started on Mercola either. Whole9 really is about more healthier types and exercise unless they have switched recently. Emily Deans I have checked out and but found it to be off topic for my immediate needs and she endlessly tinkers with something she has no clue about. She regurgitates what they all do and so many make the same type of stupid conclusions much like T. Colin Campbell does by following one track thinking. It is a total waste of time. That article is about Fibromyalgia and the focus is on magnesium which I cannot tolerant and there are forums full of us who can’t handle it and why is that? We are not some small group, but growing group who is getting louder out of total frustration. Much like they labeled Celiacs as too small to justify much research etc. it now turns out it is a multi billion dollar industry, gluten free food industry, today but just a few years ago it was like pulling teeth to get them to listen to consumers. So if Celiac just one form of autoimmunity is a multi billion dollar industry then if you do the math with diabetes et al how can we be a small insignificant group to address in Paleo?

              Focusing on one symptom as generic as sleep does not make a good argument for a supplement. I see this all the time. She comes up with a “sensible” approach which for me is like “whatever” based on much about nothing. I have much confidence in much better research that doesn’t isolate one or two or three symptoms but comes head on to immunity with Dr. Fasano. If you got nothing better to do Emily makes for light reading.

              If like me you go googling on line you will see countless so called experts trying to explain fructose and which ones you should avoid. OMG this is so crazy out there and on one list you will see this food is ok and on the other list it is not. You could spend years on this merry go round testing it out. I shun such things like GAPS and FODMAPS because it is also just more tinkering and leading folks on more wild goose chases and autoimmuners have spent decades doing this already. Enough already.

              So taking out all carbs and testing back in one at a time would seem a more effective approach. Don’t get hung up on one list. Some say fructans, some say free fructose, some say high GI fruits, some say _____ etc etc etc. There is not one place to get good info for us at this point.

              There seems to be more and more interesting research and no one is actually connecting the dots well at all and that includes Cordain.

              It bothers me to no end that autoimmuners are suffering big time. Some folks die from this and it is not just about Eczema either. This is serious stuff and Paleo just doesn’t get it or really care because if they did I would be seeing much better out there. They are all racing to get those google SEO numbers higher and planning for their next book release full of more regurgitated junk IMHO.

              It is rare when you get serious researchers to do an online interview and listen to their passion and dedication and thoughts separate from their official findings to really figuring this out. I am pretty tired of reading regurgitated fluff from professors who dabble in this and are not really focused on cracking the codes and seem to be merely publishing for publishing sake to meet their University’s requirements or to look relevant. Their half hearted attempts do not impress us anymore.

              Why didn’t the AHS have Dr. Fasano speaking? So many better who could have weighed in on this and it just makes us move further way from Paleo and at a faster clip. The Paleo community is so enamored of its self that it lost its way.

              So kudo to Chris for actually providing some substance with this podcast.

              • I think you’re being a little unfair here to these ‘paleo experts’. Diet is easier to prescribe than diets for those with medical ailments, especially if said blogger is not an MD or PhD. Last I checked, 95% of paleo blog posts include citations, and if they do seem wishy-washy it’s because there isn’t enough evidence out to definitively say autoimmuners should do X alternative therapy to fix everything. Guyenet links studies. Mark links studies. Emily links studies – the fibromyalgia article was a study showing magnesium helped patients with fibromyalgia. Chris talks about research on it in the podcast with rob wolf, and emily has another post about magnesium and brain health that mentions a comprehensive review/hypothesis that magnesium may help those with fibromyalgia. Clinical studies take time and sometimes you don’t want to wait 15 years for a drug to come out (like the one that’ll fix zonulin). So they say ‘try this’ not on a whim, but because there’s factual evidence that it may help, yet not proof. They don’t make money off of magnesium sales…

                As for tinkering, that’s basically what GAPS is. But it’s tinkering with a plan, with expectations of what should happen and what should work or not, and with specific probiotic supplementation. Did YOU know why you couldn’t eat veggies, that the fiber was feeding pathogenic gut flora that increase intestinal permeability? This kind of insight is helpful, and the process of the diet is nuanced and scientific in ways you or I could not think up off the top of our heads. I just fear that you think your ‘add random things back in’ plan is better than a plan created by a licensed MD who is on the paleo up-and-up (that’s street cred, there).

                Anyways, let’s talk more specifics: fructose is a carb, and carbs promote proliferation of specific strains of bacteria (i think yeast and clostridium, in the view of Dr. K), and may out-compete healthy gut flora. The correct ‘lists’ on what fructose containing things are ok or not would be the ones that rank the foods from more to less fructose… I.e. fact: even though you don’t eat fruit, you really shouldn’t eat apples. Not rocket science there.

                Why didn’t Fasano speak at AHS? Idk! Schedule conflict, either side not interested, whatever. I certainly would’ve liked to see that! I don’t think it’s because the paleo community hates researchers.. Many of the speakers at the AHS events WERE researchers – even Wolf was at some point, as a biochemist. Don’t write off the community so soon.

                Lastly, Chris’ paleo-template idea is something you should support. The idea is people have different preferences as well as genetics. Thus, there is a perfect diet for you and one for me, with the same concepts but maybe with some differences based on activity (starchy carbs), intolerances (nightshades, etc.), protein, and so on. Why do you think this is a regression?? It’s clearly and advancement to this one-size-fits-all approach to diet (even from the one-concept-fits-all paleo community – though the concept is evolution so ofc it fits us all). Another example, Mark wrote a post on ‘is wheat addictive’ and you KNOW he’d love to say yes and convert more to paleo and have them buy more supps etc. But he didn’t. The science wasn’t there. He cares about more than alarmist statements that support his own views/business. Open your eyes, and see that the world isn’t such a myopic place.

                • I wish I was wrong about this. It would benefit me and others if there was better out there in Paleo land. I have looked under all the Grok rocks for answers and it took me a long while to come to these conclusions. BTW I don’t recall finding any research papers by Robb or Mark, let me know when you come across them.

                  Oh anyone can use citations. I think T. Colin Campbell did a lot of that and it means nothing. Just because Emily cites Fibromyalia and magnesium supplements doesn’t mean it works for so many. The problem with these is it sets a lot folks up for failure basing recommendations on a symptom of a broader problem of autoimmunity. If you understood more about autoimmunity you would see that they have many of the same symptoms and they over lap a lot. But some present as MS or Lupus or ______. The flaw here is that no one gene pushes MS. Studies have shown that different genes activate for instance. If all autoimmunity is activated through leaky gut as one aspect but if affects different genes to turn on then to say all MS patients should take A for a certain symptom is kind of short sighted at best. But then I am following autoimmunity not some short sighted study on sleep which encompasses an even broader topic than autoimmunity which is broad enough. I have a big problem with that approach.

                  It is like trying to put a bandaid on someone who is hemorrhaging. Yeah but all the studies say this is what you should do most of the time with you have a cut. This is what you should do if you can’t sleep. Oh and use dark blinds too.

                  Much like folks who had ulcers were told they ate spicy food and they are too stressed and ______. The put the burden back on the patient that they were doing something wrong when in fact it turned out two weeks of antibiotics cured it. That is shamanism medicine and I see that over and over with the approach to autoimmunity.

                  Factual evidence shows I and many others cannot tolerate any magnesium supplement in any form. In the news daily they have pop medicine where it you drink coffee or wine it will improve or make this worse. It changes everyday on this but it is based on generically approached studies. Should I believe them too?

                  For Fibromyalgia for instance there is so many snake oil products and treatments and you just get so tired of it all. Many based on so called factual evidence. You become a bit jaded and I am sure that is true of so many other autoimmune conditions. So many conditions have yet to be researched enough to even be classified at autoimmune.

                  I totally disagree with you about they don’t say it on a whim. I think they do since they don’t bother to really dig into it. Take an asprin for a headache, take magnesium for Fibromyalgia. Well maybe that headache is more than a headache? Maybe taking an asprin does nothing or causes stomach permeability and adds to the discomfort like for me running to the bathroom for two weeks. Not life threatening but not close to accurate and has a negative impact.

                  Well that tinkering with GAPS is all over the place too. When you have leaky gut just trying certain things is a big commitment and we get more and more careful before we just dive right in on trying more tinkering from bloggers with or without PHds or BSs because I now have to commit myself to a bathroom for two weeks if they are wrong. You do this enough times and you get pretty myopic for sure.

                  No they do not make money off of magnesium sales but they do try to seem like their magic works so that the google numbers climb. If they said hey I don’t know how many would come back? Not as many. But they just can’t help themselves and just have to say something otherwise why would anyone bother to come and ask again and help them sell their books et al.

                  Tinkering with a plan…..well I have no idea why I can’t eat fruits and vegetable carbs without Rosacea reaction. But I am digging for it since the shamans default to things like magnesium for Fibromyalgia which doesn’t work. IF I can dig up better research then it begs the question why aren’t they? Because they have a busy blog to run and empire and it is all about keeping the Paleo plates in play and spinning and make it look like they know what they are doing.

                  Folks get sucked into the vortex of it all. Must be working since so many are coming and and asking questions and they are answering them. Must be working. Well it isn’t for many. They don’t hang out but move on and that is what folks don’t see. Plus their comments get moderated out if they don’t play nice and tow the Paleo line.

                  I love this part. So if the person has an MD behind their name that is when I should drop everything and listen to their advice as to how to eat? Well that is what got into this problem in the first place and for DECADES only proceeded to get worse. I went to so many specialists to ferret it out and spent tons of money only to get more bad SAD eating advice. Now I am suppose to just listen to these Paleo MDs when they are wrong about basic things like magnesium for me and other stuff? NOT. If you are older you can appreciate how experts can be very fallible and when you noticed problems with their advice you need do some critical thinking about where they are coming from and why? They may have good intentions but I have had many experiences with docs that have an agenda that is not in my best interest.

                  Last years AHS had everyone but the dog catcher speaking. This year it was tightened up but still I want to hear from the serious researchers rather than listen to Robb or Mark blab on. But maybe for Paleos they can’t draw the crowds for the serious topics. Maybe they can’t draw the serious researchers to align themselves with these shamans either. Maybe doing in August folks are on vacation.

                  But we do agree on this that it would have been stellar if Dr. Fasano was a speaker and on panels to answer questions. I can think of other researchers that who are doing other great work on this and would have provided a much more interesting science talk on this than many that were invited to it this year. AHS has mirrored the problems we have online in Paleo land. More crazy bloggers and everyone trying to cash in.

                  I think this is a regression due to the fact I have several autoimmune conditions. To any reasonable person that would be considered a negative. To eat so dramatically different from even your basic Paleo is not a plus in anyone’s eyes but my reality and others. I am also insulin resistant and even cheating is something I can’t do without having to deal with days or weeks from the fall out from that. I cannot just eat something sweet now. Yeah that is a big regression for most folks. I am now painted in the food corner and I am upset to say the least. But I do it not based on anything any Paleo has given advise on since they don’t understand nor do they want to understand this. I figured this out by going against what docs have told me and what Paleos have advised and digging for research since Paleo land glosses over this. I used critical thinking here to get me to where my face is not hideous from Rosacea. This is frustrating to me since no one is talking about this. The autoimmune protocol is a baby step towards this and when those who fail on it leave Paleo it does discredit it all. Same is true for weight loss to. Paleo failo came out of total frustration with the indifference that was shown to folks who didn’t fit in the Paleo square peg.

                  Hey for that matter maybe the whole lectin and saponin thing might be wrong or just part of the story and since wheat has fructose and so does saponin group and that is another angle as it relates to intestinal permeability.

                  Robb hasn’t a clue and goes around to autoimmuners and asks them how they got better with autoimmune condition. He asks them what is their protocol so he can check it against his. This is how he researches and tries to do short cut to this all. He was a biochemist years ago and then ran a exercise gym. Yeah it could be a stretch that the gym was his lab of sorts. He does know the science babble and he uses this very effectively to make it sound like he is on top of this all. I do not find he is.Seriously cite me some of his published research or has he finally opened a lab some place now?

                  I can’t even take your Mark statement seriously that he is not a full time marketing machine. For example, since there is a lot to point out here but to play along with this…shall I cite you some of his recipes in his very expensive cookbook I bought that has soy based soy sauce as an ingredient and other basic non Paleo ingredients? I think he had this gal write it for him and then he puts his primal stamp on it.

                  He is in full throttle marketing mode on this and sloppy as all get out. Yes I catch all the details on what they do and it does make me pause and to look closer. Those details can derail autoimmuner. I don’t hang out at Mark’s store front so I can’t speak to all of his musing on whatever. He lost credibility long ago with me.

                  However, there is a place for Mark and he is like those fashion magazines or Cosmopolitan for Paleo. Trending and hip and all. He looks good and fun with the surf board and many will gravitate to that. He fills that need. For us with real serious health issues he does not fill that need.

                  I think you need to use a bit more critical thinking here with this. I think if you had serious autoimmune conditions for decades you would be much more critical of how these guy operate since you get how wrong they are for you and others with similar conditions.

                  I really wish there were better in the Paleo landscape. I have optimistically bothered to keep looking. I have looked for two years and it doesn’t exist, at least not yet. Myopic I am not. Realistic and searching for answers, yes and finding them despite all the wild goose chases the Paleo gurus have sent me on.

  7. Hi Chris,

    Great podcast. Three questions, I’ve often heard Robb Wolf say that he believes that most all autoimmune disease is caused by Celiac’s. As a type 1 I have been hounding my PCP and Endo to diagnose me, but to no avail. Dr. Fasano mentioned leaky gut as being present in the autoimmune conditions they have tested, but didn’t go as far to say that Celiac’s and gluten cause most all autoimmune diseases. Am I chasing a ghost on this one or misunderstanding? Is there any plans to do a podcast on Type 1 diabetes? If someone wanted to interview you on a podcast what is the best way to arrange it?



    • @Daniel,
      I used to follow Robb in the beginning with all my AI conditions and found so much he advised didn’t work. Robb is guessing like the rest of us. But he talks a good game.

      I think with all the variety of genetics, that gluten can be one of a few or even many that causes autoimmunity. I eat Paleo and AI protocol but only helps so much. For me fructose is toxic not just malabsorption. The more fruit and veggie carbs I took out the fewer autoimmune conditions remained. I tried to isolate certain fruits to find the culprit and couldn’t. All fruits went out the door and AI conditions improved but not gone.

      Then tried to figure out which veggies were the culprit. Got down to trying one veggie at a time and still Rosacea hung on. Could not find one veggie that didn’t cause issues. Only when I took out all veggies did Rosacea calm down. So maybe some common component in veggies and fruit is causing this and fructose seems a likely candidate. No test or doc is going to ferret this out for you. Only you can do it in your kitchen. Your genetics drives this so what I found out may not apply to your genome.

      I am also insulin resistant and that is another reason why fructose is not my friend.

      I also have a dog that is diabetic and vets say dogs can only be T1. I have learned a lot working with him. Dogs are domesticated wolves. There has not been one peer reviewed published paper done on diabetic dogs and their natural diet of raw meat. Nearly nothing about diabetic dogs in general either. But vets warn against raw meat due to compromised immune system based on zero research and ultimately what dog food manufacturers spoon feed them. Plus there is a huge conflict of interest since diabetic dog food can only be purchased with a script. If you feed the dog the diabetic dog food which is primarily grain carbs you will only have a diabetic response. So maybe this is why you only have T1 diabetic dogs but since they have done nearly nothing in research anything they say is just a guess at this point.

      My dog didn’t get diabetes drinking pepsi or eating fruit, he got it from eating dry dog food. I do think when you combine grains with fat this makes for a bad combo. I heard Lustig say this too.

      Did you know that blood glucose meters can be off by 20% and still be working correctly? Only One Touch from what I can see is being honest about this and making a meter that gives a range not a set number. Tight regulation can be fleeting with such a meager testing method.

      Did you know that the pin prick method of testing BG is a poor method and taking sample from vein is better but it still is just a snap shot and not the full story of how the glucose is pooling in other parts of the body?

      You are probably well aware of diabetics you post on forums about how they took 2 or 3 BG meters, all tested to be working properly with the drops, and then they compared them with using the same blood from the same pin prick at the same time and will get different BG numbers from all of them. These meters are good for checking for big high swings but for tight regulation they are not so good. Not only don’t you want diabetes because of all the health issues that come with it but the way we manage it is just not so good at all. Kind of scary stuff. But you see tons of happy diabetics in commercials now making it look like it is something ok to live with.

      I was insulin resistant but my BG was in the middle of the normal range. Only eating Paleo and cheating with sweets did I get gout. I was flying under the BG meter for probably many years this way since my BG stayed the same number for several years. I was consistant. My body figured a way to adapt and tried to keep a lid on it all.

      Our understanding of what is insulin resistant and what is normal is archaic. I now can see why folks who are doing the due diligence with BG meter and in normal range then they just go unconscious driving down the road. I can also see why folks like me who had the SAME normal BG for years can end up in the emergency room when it just crashes one day and either end up with full blown diabetes or dead.

      My dog is doing better on raw meat diet. So many things improved. I experimented on him since no place to go to get good answers. I monitored him closely too. I think our understanding of insulin resistance is rudimentary and wrong at times. Our methods for testing for it and monitoring it is just not there yet.

      If cats who use different insulin can go into remission with diet and tight regulation and humans can do this like Steve Cooksey with T2, and if dogs and humans can use the same insulin since there are no pet specific insulins, then maybe dogs could go into remission under the right circumstances in some cases? If I wait for research on this well both my dog and I will be dead by then.

      Dr. Fasano new conclusion states :

      “Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer.
      This new theory implies that once the pathological process is activated, it is not auto-perpetuating. Rather, it can be modulated or even reversed by preventing the continuous interplay between genes and the environment.”

      There is hope for us, even possible remission if we figure out our triggers. Since it will be decades before they can tell us genetically what our individual triggers are we have to figure it out on our own. I would be happy to tell you want I learned with my dog.

      • I had Rosacea like dry skin on my nose and face and read in a paleohacks post that a lot of people where giving up mint including in their toothpaste. I tried it and sure enough it cleared up most of the redness on my face. I still get a little at times but I suspect it is either due to cross contamination or I ate something that had mint in it without realizing it.

        • Well I gave up herbs long ago and that helped. Well I am using toothpaste and it does have minty taste to it but my Rosacea is calming down big time with zero carbs. With Rosacea I noticed there are different levels of it. I also had the bulby nose which I got used to and didn’t realize it until one day I was looking in the mirror and it was narrower as I was eliminating more carbs. I couldn’t figure out why my nose was smaller. Even my husband had to agree on this one. Then I found out Rosacea can cause this. As I recall my father also had this but didn’t know what it was. As I took out more carbs the Rosacea became less and and would be gone from certain areas and then there was just certain areas were it would still hold out. You are right you can stop the bumps but then still there is red skin it is just still slightly there ready to pop out in a bigger way with the right trigger. It drove me nuts trying to figure it out. I just think my stomach is a sieve right now and it doesn’t take much to set it off. I will keep the toothpaste mint thing in mind.

          • Your Rosacea and most likely your vegetable intolerance is caused by SIBO. Both can be fixed.

            This study demonstrated that rosacea patients have a significantly higher SIBO prevalence than controls. Moreover, eradication of SIBO induced an almost complete regression of their cutaneous lesions and maintained this excellent result for at least 9 months. – Clin Gastroenterol Hepatol. 2008 Jul;6(7):759-64. doi: 10.1016/j.cgh.2008.02.054. Epub 2008 May 5.

  8. For 3 decades I had colitis attacks ,finally I had 15 silver mercury amalgems removed by a non ADA dentist using Hal Huggins protocols and the colitis vanished.Much of the population have this mercury installed. Isn’t it possible that mercury is a factor in Dr, Fasano ‘s studies that he is not factoring in? By the way would love to hear you interview Hal Huggins DDS retired. Also Boyd Haley.

  9. Can you ask Dr. Fasano followup questions? If so I want to know more about this statement he made:

    “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.”

    Is he suggesting probiotics, and which ones?

  10. All I can say is WOW! This was a great interview and the best one I have heard from Dr. Fasano for the general public. Some how we got to keep the funding going for his research and specifically for this new drug that could be out as soon as 3 years!!! The ramifications when a such a drug does come out is…. well mind blowing. If in fact all autoimmune diseases are affected by Zonulin then this could mean that so many conditions will actually have a real treatment that actually works. This could upset the health care apple cart in a big way and I can see why they would want to delay this drug.

    Chris what can the public do to help this this drug along?

    Do we write to the FDA and those who fund the research and donate or demand it be put on the fast track? I know the FDA has changed some rules and offered some deals to drug manufacturers if they do this or that they will fast track some of their drugs.

    What is key about this drug is that it works no matter if we have not figured out ALL the Zonulin triggers yet. I think fructose maybe complicit too. Whatever the causes or the cascading circumstances are we now have something to tide us over until we figure all of this out.

    Dr. Fasano is a total rock star and has been for many years in my book. And yes I remember a time when leaky gut was bantered about before any proof and I too found nothing to back it up and discredited as did the professionals and for good reason. The term is too gimmicky and I don’t like to use it. Intestinal permeability or stomach permeability is what I use and I love the clueless looks on doc’s faces when I use it. Educate one doc at a time is what I say.

    • Intestinal permeability is a valid and accurate term; “stomach” permeability however, is not. It is the small intestine that becomes permeable, not the anatomically separate and distinct stomach. (Just a hint, if you want to continue to get a positive response from the use of the term).

  11. Why create a medicine (larazotide) to combat the effects of eating something we didn’t evolve to eat in the first place and that the body treats as a toxin? That’s like the recommendation for diabetics to eat what they want, as long as they take enough insulin to counter it. Even if zonulin is upregulated after refraining from gluten, the symptoms of celiac or gluten sensitivity disappear when you stop eating the offending toxin. The law of unintended consequences predicts that if you block zonulin, something else will go wrong in people who have celiac or gluten sensitivity and continue to eat gluten.

    • There are some of us who are just more problematic than others with all of this. For me any vegetable causes problems. I do best just eating meat now and that is boring as hell. Genetically other foods or fructose may cause increased Zonulin. Some of us feel very broken with many autoimmune conditions and just taking out gluten is not enough. Taking out so many things is not enough. Cross contamination is a big issue too and if you had this drug then you would prevent this from happening. So many reasons why this would be helpful. Sometimes you are stuck and can’t find gluten free everything and you still need to eat then what? I wish it were that simple. Also avoiding so many foods also can have unintended consequences too. We got this way eating the wrong things or with bacterial issues from previous treatments etc and that was not natural and maybe for some of us there is no natural way back but a drug bandaid to keep us going until they learn more. I have eaten Paleo and AI and beyond and I have tried to eat my way back to health and it is not enough for some of us.

      • Thanks for this perspective, Turnip; it hadn’t occurred to me. I wish you success in finding a path to recovery.

      • If you have leaky gut and any inflammation you will have slight “allergies” to food you would normally not have any to. No human should have problems will all vegetables, in my mind this is a sign your system is still overwhelmed and most likely clogged. Watch this video, even though the subject matter is radiation he explains the process of all healing.

        • What video?

          Yes I agree with you about the food allergy stuff. My husband could not eat shellfish any longer as an older adult much like his mother. But after going Paleo shellfish is no problem for him. I had no such obvious food allergies prior to Paleo. But I did notice how my non rhinonitis allergy symptoms didn’t need prescription nasal spray or generic zyrtec any more. I also could breath better and no need for cpap. No more problems swallowing either.

          So many things cleared up and so much inflammation in feet and legs etc went away. Since my autoimmune skin issues still presented themselves no matter which carb I used but the fewer I had the better I got.

          For instance when I took out apples the Rosacea was not as bad where as I could eat a lot more of another type of carb and not get the same harsher reaction. So all carbs are not apples to apples but what about apples did it not like even more? It seemed like fruits gave the worst reaction. So what sets them apart from other vegetable carbs?

          Fructose is one major one. Also I am insulin resistant and fructose is a major antagonist for this. So many vegetables have some fructose in it from what I can tell. It wouldn’t at all surprise me if fructose upregulates zonulin thereby causing my stomach to leak when I eat carbs and causing autoimmune response.

          Also another reason I say this is if you have a leaky stomach then why wouldn’t the bacteria in my stomach cause immune response when I eat meat only? For that matter if I have a leaky gut why wouldn’t any foreign particle from the meats annoy immune system? But I see my skin calm down when eating just meat. So perhaps the meat particles are not passing through leaky gut? If so they my leaky gut isn’t leaking then? Maybe so.

          So that naturally makes me look very suspiciously back at carbs and their components. I tried to see if maybe they had high lectins and saponins and maybe that would explain it but I tried so many types of fruit and they just didn’t work at all and were worse. Then tried so many types of vegetables and they were not as bad but still some reaction to them. I was totally frustrated with all of this. That made me stand back and say hey there is no great carb for me at this point.

          Granted I should be eating vegetables based on logic but maybe my genetics has another strategy. I am 1/2 Icelandic and 1/4 Swedish and 1/4 English for the most part. I am predominately Nordic and there are no lemons and lots of fruit where my ancestors came from. If there was it was for a short time in late summer to bulk up before hard winters. This may explain why I am so reactive around fructose and sugar in many ways. I can just smell sweet stuff and feel it on my hips. I may have burnt out my regulatory systems, insulin resistance and leptin resistance by eating way too many carbs and particularly ones with high fructose content. All systems highly sensitive and annoyed and messing up. Thus the now permanently leaky gut. Perhaps once I lose more weight and become leptin sensitive and have better control of insulin resistance as a result of that my ability to have normal levels of zonulin in my stomach may improve?

        • Hi, Ryan. The link to the video of healing from radiation last year was (perhaps automatically) deleted from your comment. Could you tell words to google that those of us interested may find it? Thanks! 🙂

      • As someone replied to you above, if you’re reacting so bad on all vegetables and fruits, then your body is deranged and it overreacts. The way you wrote your replies over here is like saying that “even veggies/fruits are toxic for me”, but in reality, your body has undergone such damage over the years because of gluten/sugar/whatever, that now it overreacts on almost everything. But that doesn’t mean that veggies/fruits are toxic. If you’re not very old, you might be able to reverse this by doing the diet you currently do for 1-2 years, AND by adding fermented foods (e.g. home-made goat kefir should help a lot). Then, you add veggies one by one, slowly. Then fruits.

        • The above was not a medical advice to you btw, but rather what I would do in your case. I would definitely try to get the right vitamins for example, if I was off veggies. I wouldn’t live off on only meat, that would be impossible because as you said it’s boring, and it’s missing so many vitamins. As someone else said below, FODMAPs is something to look into, there might be some veggies you can tolerate.

        • I have to say I did try kefir and it caused blood shot puffy eyes in one day. I do think it has more to do with gut flora imbalance and just adding any new flora willy nilly can be problematic. All fermented foods are not beneficial. It depends on what strains you have. They don’t know yet about which strains we need and how much. The Human Microbiome Project is just winding down and finally we may some concrete answers on which strains and how much we need. Supplement makers have just been guessing on this. I am old and with that piles on the health issues. I have been mostly Paleo/ketogenic for 2.5 yrs now. Yes I have already tried adding one carb back in at a time too and this is how I found out I was reacting to so many veggies and fruits. Been there done that.

          • Have you tried a formal elimination diet? It sounds like you are doing a sort of elimination process now, but a more structured approach could give you better, clearer information on what foods are “safe” vs. problematic.

    • Regarding your comment about the problem going away when you take gluten away… this is not the case with myself. I have taken gluten away with much improvement but certainly not total improvement. I am still having problems. Also, gluten is used in so many sneaky ways these days that it is almost impossible to be 100% free of it. I have learned it is used in lipsticks and glue recently and in clarifying some wines. I am very excited to speak to my specialist about Zonulin now that I have found this information as he has not been able to fix my problem since seeing him in 2006. I have had pain and cramps after eating all of my life so I think for some people who have other problems with this other than purely gluten sensitivity, it is a wonderful blessing.

  12. Brilliant interview.
    The junctions need to be dissolved when cells are being replaced, which happens often in the gut?

    Interferon is a trigger for development of gluten sensitivity and temporary sensitivity is seen while viral infections last.
    Bifidus reduces this interferon response to gluten peptides significantly.

    I suspect the increased variety of grains we eat is part of the problem. mixed grain breads with sesame seeds quinoa maize (cornflakes and toast) and also the use of modified starches and flavouring extracts from grains in processed foods and added gluten in bread making.
    None of this happened before.

  13. Chris: Great episode. Dr. Fasano states that the tight junctions open, if only for a few moments, in those without Celiac upon ingesting Gluten. I’d like to get more understanding and wish you would follow up with some more analysis (maybe in an upcoming podcast?) on what is or could be present in the small intestine and get thru to the body (and be missed in the clean up) and what the results could be. In a sense it seems like one is playing Russian Roulette by eating Gluten and having the tight junctions open. Also, when are the junctions supposed to open? Is there where the single amino acids and sugars pass thru?

  14. The elephant in the room that Dr. Fasano is avoiding here with regards to the sudden uptick in rates of celiac disease is actually more likely to be the current omnipresence of GMO wheat, which now accounts for approximately 90%+ of all commercial wheat sold worldwide. The women who were able to tolerate wheat well into their 70s are now eating a completely different wheat than the grain they grew up with.

    • I’m not for GMO’s. But stuff like this is just.. ignorant. There are more places in the world than the US. GMO’s are primarily present in the US. Celiac disease is rampant all over the western world.

      • Yes, the real problem is what Dr. William Davis points out: that the wheat that is consumed world wide is the variety bred in Mexico in the middle of last century to stave off world wide starvation that is a higher yield wheat that also is short enough to be able to support the larger seed head that produces the higher yield.

    • There is in fact no GMO wheat in the global food supply. Even William Davis, who cherry picks his data like crazy, admits that.

      This kind of knee-jerk pseudoscience is what keeps people from being able to make good decisions.

    • I have diverticulitis. I have major gut pains and joint pains, but to follow a diet is very expensive on top of knowing exactly how to eat correctly.please help?

      • I’ve been dealing with diverticulitis for awhile, I’ve gotten the flare ups almost to nil – I use prebiotic rich food and lots of resistant starch, study up on SIBO and maybe try adapting a SCD diet to work through, but I think the biggest thing that helped me the most was using resistant starch – so really dig into and their work and understanding of resistant starch, good luck!

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