Episode 168: Alessio Fasano discusses celiac disease and gluten-related disorders

Primary Topic

This episode delves into the intricacies of celiac disease and other gluten-related disorders, featuring insights from Dr. Alessio Fasano, a leading expert in the field.

Episode Summary

In this enlightening discussion, Dr. Alessio Fasano, accompanied by hosts Dawn Kernagis and Ken Ford, explores the complex world of celiac disease, gluten sensitivity, and the gut microbiome. Fasano, renowned for his groundbreaking work, shares insights from his research at the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital. Topics include the genetic predispositions of celiac disease, the impact of intestinal permeability on autoimmune diseases, and the promising avenues for new treatments beyond the gluten-free diet. The episode also highlights Fasano’s recent studies, books, and an international consortium project aimed at understanding celiac disease from infancy.

Main Takeaways

  1. Celiac disease affects a significant portion of the population, distinct from those who have non-celiac gluten sensitivity.
  2. Intestinal permeability, or "leaky gut," plays a crucial role in the development of autoimmune disorders including celiac disease.
  3. Dr. Fasano's research indicates potential new treatments for celiac disease that may complement or replace the gluten-free diet.
  4. The microbiome’s impact on health extends beyond the gut, influencing conditions like autoimmune diseases through mechanisms like gut permeability.
  5. Ongoing international research aims to predict and prevent celiac disease from a young age, indicating a shift towards more personalized medical interventions.

Episode Chapters

1: Introduction

Dr. Alessio Fasano is introduced as a world leader in celiac disease research. The hosts discuss his background and contributions to the field. Marcus Bauman: "Alessio is considered the world's leading expert in celiac disease and gluten related disorders."

2: The Science of Gluten Sensitivity

Exploration of the differences between celiac disease, gluten sensitivity, and wheat allergies, including their symptoms and treatments. Alessio Fasano: "Although just 2 million Americans have celiac disease, an estimated 20 million suffer from gluten sensitivity."

3: Advances in Treatment

Discussion on the latest research and potential future treatments that go beyond the traditional gluten-free diet. Alessio Fasano: "We are exploring several new treatments that promise to change the management of celiac disease significantly."

Actionable Advice

  1. Consider genetic testing: For those with family histories of celiac disease, genetic testing can provide crucial insights into personal risk.
  2. Monitor diet closely: Understanding how different foods affect your health can help manage or mitigate symptoms of gluten sensitivity.
  3. Stay informed on new research: Advances in treatments and understanding of celiac disease are ongoing. Keeping informed can provide options beyond current treatments.
  4. Engage with support groups: Many communities offer resources and support for those dealing with celiac disease and gluten sensitivity.
  5. Consult healthcare providers: Regular consultations with healthcare professionals can help manage symptoms and tailor treatments to individual needs.

About This Episode

Dr. Alessio Fasano, who is considered the world’s leading expert in celiac disease and gluten-related disorders, returns for his second appearance on STEM-Talk. Although just 2 million Americans have celiac disease, an estimated 20 million Americans suffer from gluten sensitivity.

Alessio is a professor and director of the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital. In addition to celiac disease and gluten-related disorders, Alessio’s research is also focused on the microbiome, intestinal permeability and autoimmune disorders, which he discussed in his first interview on STEM-Talk, episode 20.

Since Alessio’s first appearance on STEM-Talk in 2016, he has published two books, “Gluten Freedom” and “Gut Feelings: The Microbiome and Our Health,” which we discuss in today’s interview. We also talk to Alessio about an exciting new project that’s bringing together an international consortium of researchers and scientists for a long-term study that will follow infants who are genetically at risk of developing celiac.

Alessio is a researcher and physician who wears many hats. He is the director of the Center for Celiac Research and Treatment and chief of the Division of Pediatric Gastroenterology and Nutrition at Mass General Hospital. He also is a professor of pediatrics at Harvard Medical School and a professor of nutrition at Harvard’s T.H. Chan School of Public Health.

People

Alessio Fasano, Dawn Kernagis, Ken Ford

Books

"Gluten Freedom" and "Gut Feelings: The Microbiome and Our Health" by Alessio Fasano

Guest Name(s):

Alessio Fasano

Content Warnings:

None

Transcript

Stemtalk
Welcome to Stem talk. Stem talk. Stem talk. Stem talk. Stem talk.

Welcome to STemtalk, where we introduce you to fascinating people who passionately inhabit the scientific and technical frontiers of our society. Dawn is continuing to play hooky, so I am Marcus Bauman, and I'll be your host today. Joining me to introduce today's podcast is the man behind the curtain, doctor Ken Ford, IHMC's director and chairman of the double secret selection committee that selects all of the guests who appear on Stemtalk. Hi Marcus, great to be here today. We have Doctor Alessio Fasano here with us in the studio for his second appearance on STEM Talk.

Marcus Bauman
Alessio is considered the world's leading expert in celiac disease and gluten related disorders. Although just 2 million Americans have celiac disease, an estimated 20 million Americans suffer from gluten sensitivity. Alicio is a professor and director of the Mucosal Immunology and Biology Research center at Massachusetts General Hospital. In addition to celiac disease and gluten related disorders, Alicio's research is also focused on the microbiome, intestinal permeability, and autoimmune disorders, which he did discuss in his first interview on STEM Talk, episode 20. Since Alicio's first appearance on STEM Talk in 2016, he has published two books, one called Gluten Freedom and the other Gut feelings, the Microbiome and our Health, which we discussed in today's interview.

We also talked to Alicio about an exciting new project that's bringing together an international consortium of researchers and scientists for a long term study that will follow infants who are genetically at risk of developing celiac disease. Alicio is a researcher and physician who wears many hats. He's the director of the center for Celiac Research and Treatment and chief of the Division of Pediatric Gastroenterology and Nutrition at Mass General Hospital. He's also professor of pediatrics at Harvard Medical School and a professor of nutrition at Harvard's Th Chan School of Public Health. Before we get to our interview with Alicio, we have some housekeeping to take care of first.

Ken Ford
We really appreciate all of you who have subscribed to StemTalk, and we especially appreciate all the wonderful five star reviews. As always, the double secret selection committee has been continually and carefully reviewing iTunes, Google, Stitcher, and other podcast apps for the wittiest and most lavishly praise filled reviews to read on Stemtalk. If you hear your review read on Stemtalk, just contact us at stemtalkhmc us to claim your official stemtalk t shirt. Today. We have a follow up on our recent winning review that was posted by someone that goes by the moniker Canuck supporter when he wrote us to claim his t shirt.

Our Canuck friend added a few additional comments about Stemtalk that we think are worth passing along. His new review goes I was thrilled yesterday to hear my review was selected by the double blind selection committee. I enjoy listening to the podcast so much. My daughter got me into it. She is two years from completing her PhD in neuroscience and has turned me into a neuro nerd.

Your podcast is much more than that and touches on subjects that really interest me. I'm proof you're never too old to learn, even at 61 years old. Keep up the fantastic work. And by the way, 61 is not old. Well, Canuck supporter, please let us know the t shirt size of your daughter so we can send her one too.

And thank you very much for your kind comments and thanks to all of our other Stemtalk listeners who have helped Stemtalk become such an excellent success. Okay, and now onto today's interview with Doctor Alicio Fasano. Stem talk. Stem stem talk. Stem talk.

Marcus Bauman
Stem talk. Alicia, we covered a lot of your background in episode ten of SteM Talk. But since your interview in 2016, you've published these two great new books, Gluten Freedom and gut feelings, the microbiome and our health. Later in the interview, we will talk about each of these books. But first, I'm curious about when in your medical training at the University of Naples, did you become interested in both pediatrics and gastroenterology?

Well, pediatrics was first sight love. I realized from the very beginning, from medical school, that dealing with kids will have more fun and interesting involvement, both in terms of clinic and research enterprises. I was interested in research since the gecko of my medical school. And that's the reason why when I was offered an internship my second year of medical school there, six years in training in Italy for medical school, I decided immediately to become an internship in pediatrics. It happened to be there was a time in which of course, you have to choose also a mentor.

The mentor is somebody that will really impact your professional life for the entire span of its journey. And this gentleman was somebody that just came back from University of Chicago that spent some time there to study diarrheal diseases. I thought that was unglamorous. I said, you know, I want to save the world. I want to do something on cancer or HIV.

That was at that time, at the beginning, beginning of the journey. And it just educated me that at that time, every year, 5 million kids would die of that real disease so if I want to do something impactful, I better focus on that. So that's how the journey started. That makes perfect sense. You moved to the United States in the 1990s and spent 20 years in Maryland at the center for Vaccine Development in Baltimore.

Ken Ford
While in Maryland, you founded the center for Celiac Research in 1996. Then in 2003, you accepted an offer to join Massachusetts General Hospital, which was quite an undertaking, as I understand it, because you essentially had to move your entire lab there, or a big chunk of it. How did that move come about? And what was that all like? It was a military operation, actually.

First of all, the reason why I moved to Maryland from Italy is mainly because I decided that, you know, in this study and the interaction between a bug that makes you sick with diarrheal diseases and the host, I learned a lot about the host. I really had no idea how microorganisms will eventually exploit their capability to interact with the host and create condition like diarrhea diseases. So that was something that I definitely need to fill as a gap of knowledge. And my mentor said, you know, there is only one place in the world where I think that will be worth it to go, and that's Baltimore, and that's at the center for vaccine Development. They do vaccine development for enteric pathogens.

That was the beginning of the era, genomics, to manipulate the genome of this microorganism and so on and so forth. So that's the reason why I moved from Italy to United States. In Italy, I was also involved in Celia disease because University of Naples was a hub of the situation there. I was supposed to move to Maryland for two months and end up to be there for 20 years. And then I was offered a job at mass General Hospital.

And the first time that I was offered a job, I turned that down because, you know, as Ken was mentioning, I would have been moving a pretty large operation. And I thought, this is unfeasible. Plus I'm not a really competitive guy. Comes professionally. I thought that, you know, Harvard was going to be a too, you know, inquisitive and, you know, a professional, aggressive environment.

And I said, I'm not going to drive there. So I first offer a pass and, you know, a few months passed by and a month in a year, and then they continued to come back. And then I realized that, you know, at that point, stay in Maryland, the science can only be incremental and not transformational because we didn't have the critical mass of people around. And for that reason, I spoke with the people in lab, and we had a general discussion. And finally, you know, we decided to dive in and give it a try.

So 21 people and two trucks moving from Maryland to Boston in a military operation. Because, you know, as you realize, when you have a deep portfolio science, you can't afford to be, you know, a year without doing anything. So we had to shut down the lab on a Monday in Maryland and prepare to have the labs on in Boston, you know, within the same week. And it really took, you know, a lot of organization, but eventually we made it. So, early in your career, as you began to study cholera in the early nineties, as you were working on cholera, you discovered the zonula occludens toxin that the toxin producing bacteria, vibrio cholerae uses to cause intestinal infections.

Marcus Bauman
Can you talk about the key insights you gain by studying the zonula occludens toxin? This is an interesting question that has been asked me over the years, many, many times. And the answer is, there are two ways to address your question. One is the quote unquote sanitated, you know, version. So that, you know, I say, oh, I was thinking about this.

I was smart enough to hypothesize that cholera was using, you know, different tricks to achieve its biological goal and so on and so forth. And so there was all planned. But that's absolutely not true. And you can read that, you know, in the papers that we published for this toxin, the reality of the story is much less glamorous, but serendipitous. That, by the way, is my favorite english word.

There is no such thing in Italian to really encompass what serendipity is all about. Anyhow, long story short was when I moved to the United States from Italy, as I mentioned before, to learn about bacteria pathogenesis and how microorganisms interact with us and talk with us and so on and so forth. I dig in immediately in a project to develop an attenuated live cholera vaccines. Again, cholera was claiming a lot of lives in pediatrics, and the idea of the people at the center for vaccine development was, you need to have a live vibrocolor to induce an immune response that will protect you, but you need to take the weapons out because otherwise these people will be sick. Of course, the only weapon that we knew at that time was cholera toxin, very powerful toxin.

Just to quantify this, if you go on the beach in Pensacola and you take three grains of sandstone, that would be enough to give you 40 liters of diarrhea, if that was pure cholera toxin. So, you know, that was the time in which I also had the opportunity to talk with, at that time, recent Nobel Prize, that discovered the restriction enzymes to cut and paste these genes, to cut the genes that encode for cholera toxin out. And bottom line, after a year and a half trying all this, and in the meantime learning about, you know, microorganisms, I developed what I thought was a heck of a vaccine. The cholera toxin genes was out. Cholera was still alive.

I gave this to the animals. The animals were happy, didn't got any sickness and so on and so forth. So at that point, you know, you got to try and the real deal volunteers that at that time were students at Maryland School of Medicine, and, you know, they got the possibility to participate with, you know, three arms, one placebo, you don't get anything. So you got your money for free. Two, you got my vaccine.

Also, you're not gonna get sick because I was very confident that you were not gonna get sick. Three, you got the real deal, but we will take care of you. Don't worry about it. They had to be locked in a facility because of course, you can't spray this color stuff around for a week in exchange of $250. That was heck of money for them, but not that much to go through this aggravation of being locked in a facility for a week.

Well, long story short, the placebo didn't get nothing. The folks that got the real deal, they got, you know, purging diarrhea. We took care of that, but unfortunately, the vaccine did not work, was not like the real deal, but there was still residual diarrhea that made that not, you know, feasible as a vaccine. So literally a year and a half flushed in the toilet, no pun intended. Now, this is the split between different kinds of scientists.

You know, there are people that, you know, give up and say, this is it, I failed, and move on and do something else. Well, the inquisitive mind said, why that happened? You know, what is all this about? So after two, three days, they got completely wasted because I got drunk. I didn't show up in the lab because I was very frustrated about the entire deal.

I went back to the blackboard and tried to reason, and I said, you know what? Gotta be something else. And that led to the discovery of this toxin that you were mentioning, this zonal occludens toxin. Zono occludens is the latin name for, you know, this tight junction, this sort doors in between cells that were just discovered a few years before by a japanese group, because in the past until then, the space in between cells was considered like sealed by cement. So everything that negotiates the exchange between the environment and us has to go through the cells of these single layers of cell and intestine, but not in between.

So it was a pretty new concept. Now we find a toxin that exploits that device, that is this sort of door to open it up to induce additional diarrhea. Now, why cholera wants to do that is pretty obvious. It was pretty obvious to me. Cholera doesn't like to live in the gut.

It's too hot, it's dark, there is not enough oxygen. Cholera likes to live in a pond out there. And if a fellow will drink that water and get cholera into the gut, the first thing that cholera wants to do is to get out of there. And cholera is very famous to be a great swimmer. Matter of fact, cholera is a microorganism with a tail that swims very fast in the water environment.

And to swim out of there, you need the element water. And that's the reason why cholera toxins are there. But being a smart pathogen, it didn't put all the effort in a single direction. It said, if something goes wrong with the cholera toxin, to purge diarrhea, I have a backup that is open these gates in between cells and have fluids get into the intestine, and I will be washing out of there. So that was the first time that a mechanism, other than the typical mechanism to endure diarrhea was found.

And again, it was surprising to us. It was difficult to publish something like this, because it was out of the ordinary. Of course, nobody believed that you can make the intestine leaking so much so with the toxin. But eventually it got on. A very prestigious journal, the preceding National Academy of Science published this stuff.

And the next step was why we have this machinery there just to be target of a bug that make us sick. And we, the few years that follow, focus on what is machinery for why we have all this, and who is the actual physiological modulator of all this, because it can't be just this zonal occlusion toxin that is doing this. It's most likely that Fibria, during evolution, learn the physiology of the host and mimic a modulator of this permeability. And that's led us to what I believe it was another transformational discovery, the eukaryotic counterpart, zonal occluding toxin. That is zonalin, that was discovered in 2000.

Ken Ford
Yes. And speaking of zonulin and cholera, you discovered that molecule, zonulin, which is present, as you've said, in the gut of humans, and whose function is to control gut permeability. Can you give us an overview of how this research led you to investigate celiac disease and its trigger, which is gluten? Yeah, I mean, you know, another act of serendipity that was not planned because, you know, again, at that time, I was working on two parallel, apparently completely disconnected routes. One, the clinical interests of CT disease, and the reason why I was interested, because I came from an environment, and I Europe, which serious disease was extremely frequent, to another environment like United States, which pretty much was considered nona to be existent.

And at that time, we knew that there were at least two elements to make your risk for cd disease. The genetic predisposition that we share between Europe and the United States. An ingestion of gluten containing grains that we also shared, and yet one was present, the other one was not. So that, you know, induce my intellectual curiosity, epidemiologist speaking, why this is happening. On the other hand, I was following this route of the communication.

At that time, microbiome was a term that was not created yet, but how microbes communicate with us and for which reason, and using vibrio cholera as a paradigm, and as I mentioned before, discovering that it was miming something that we do with this molecule of zonalin. From there, I also realized through the epidemiological data of CT disease, that genetics and exposure, environmental trigger are necessary, but not sufficient. The reason why this was discovered, because we start following people at risk for Ctrl disease, for which we know that, again, the risk is ten times more than a general population. And interestingly enough, we saw that there were people that were eating gluten for 10, 15, 20 years, and now getting sick. And then all of a sudden, they eventually developed the problem.

Yet the two elements were there. They were born with the genes, and they were eating gluten containing grains forever. But some people, they were able to tolerate this gluten for that long. And we ask ourselves how that's possible. That led to a revisitation of what it really takes to develop any chronic inflammatory disease in humankind, including autoimmunity.

Like CT disease, genes and environment are necessary, but not sufficient. These two worlds are segregated by barriers. The most evident is the skin, because we see it that protect us against, you know, stuff that comes from the environment. But the largest interface is definitely the intestine. If you spread the intestine of an adult on the floor, you cause a double tennis cord.

And it's very complex, the ecosystem there as friends and foes, nutrients and pathogens, and you have to distinguish between friends and foes to decide what to do with that. And all this is due to segregation, this barrier there, if you lose that barrier function. So in other words, the intestines become leaks and you don't segregate, like for the color toxin business that we were talking before, the zon occluding toxin, then you have a consequence. Stuff from your body can go out, like for, you know, what happened for the zonal gluten toxin, but stuff from outside can come in and can instigate inflammation. Then we realize that the fourth element has to be an immune system that becomes hyper belligerent.

And the fifth element to explain why I can eat gluten for 20 years and then I cannot anymore, is the microbiome that epigenetically put in motion genes that I'm born with but are not expressed or repressed. That starts my march from genetic predisposition to clinical outcome. But without losing that barrier function, all this will not happen. And that's how we linked celiac disease with an exaggerated production of zonalin that eventually created a shortcut for undigested gluten to come in and instigate the entire process. That leads to brick intolerance and then the onset of disease.

Ken Ford
That's a great explanation. Thank you. I wondered about that, actually, some aspects of that over the years. You know, historically, celiac disease really didn't seem to be taken too seriously by most of the medical community, perhaps especially here in the United States. But, you know, I remember friends having celiac and having a tough time with the medical community taking it seriously.

Why do you think that was? Well, because, again, if you have a definition of something that doesn't reflect the reality, you may overlook it. You know, if I've never seen an elephant, and I am in a zoo and there is an elephant there, and say, do you see an elephant here? I would say, no, I do not, because I don't know what I'm talking about. At that time, the definition of seedy disease was, one, it's a pediatric condition.

That's the reason why most of the experts in the field, including myself, are pediatricians. Two, it's a gastrointestinal disorder. You know, this implies a inflammation in the gut, and therefore you have to have gastrointestinal symptoms. And three, these symptoms should be the typical symptoms of chronic diarrhea, weight loss, muscle wasting, and so on and so forth. If that's the description, the physicians at that time were correct, there was no such a thing.

You know, it was extremely rare to see kids with the big belly and, you know, muscle wasting, like the malnourished kids that we see now in the third world country. That was not the way that, you know, disease was present itself. Little we knew at that time that CTA disease is an inflammation in the gut, but it's a systemic disease. There is no organic tissue that can be spared. And when we did in 2013, this huge epidemiology study that involved more than 16,000 people in United States, we learned the one.

This is not epidemic conditions. Any age you can be involved. Two, gastrointestinal symptoms are frequent, but not the most frequent of all. Matter of fact, the most frequent way disease presents itself, both in kids and adults. Now, anemia and fatigue, no GI symptoms whatsoever.

And that's explainable because, you know, the gut of an adult is roughly 20ft long, and if you have 1ft over 19 that is inflamed, you don't have GI symptoms, you don't have diarrhea or stomachache, because the rest of the intestines subsidize. But if that foot involves the part where we absorb iron, that is absorbed only in a very few inches, no backup, you will have anemia and nothing else. But then you can have also any other symptoms, like joint pain, headaches, you can have short memory loss and infertility, and so on, and skin rash, and so on and so forth. So when you see the entire spectrum, then you realize that this was not rare here, it was just present itself in different ways. But the other thing that is fascinating, my humble opinion, that like any other immune disease, if you embrace a worse than lifestyle, it's increasing over time in terms of prevalence.

In other words, serial disease, double every 15 years in the United States. And I think that, again, biocerendipity, working on one hand on cholera and discovered zone, and the other hand on epidemiology of seeded disease, brought this together to answer the key question. What is accelerating this process of autoimmunity that we see in the western hemisphere? Meaning this is the same destiny for MS, type one diabetes, multiple sclerosis and so on and so forth. And serial disease turns to be a phenomenal, phenomenal model.

To answer this question, because of all, chronic inflammatory disease on autoimmune basis, is the only one for which we know the trigger there is gluten. We don't know why people got sick with type one diabetes and Ms. It really answered a lot of questions that we were not able to answer with out of modals, sort of going. To the opposite end of the aging spectrum. This is very interesting to me, this zonulin and these sort of gatekeepers between cells, because as we age, there's evidence that we get a leakier gut, right?

Marcus Bauman
And you can study this by looking at the levels of microbial DNA in the serum, in the blood, and that's actually highly related to the chronic inflammation associated with aging. And so this sort of reverse flow right from the gut into the bloodstream is interesting amongst those who are aging. And I wonder how much of that is actually linked not so much to the biological aging process, but to an adult lifelong dietary habit and other insults that might lead to a leakier gut. So we were talking weekend about this, and we would take a different podcast, but to make a long story short, is that there are strong evidence, as you mentioned, of an involvement of changing the biology, particularly in controlling antigen trafficking with aging. Aging is an irreversible, common process that we always go through.

It's something that we still do not have a capability to manipulate. However, talking about regenerative medicine, contrary to what we believed before, even at advanced age, we have the capability to regenerate tissues, cells, pathways, metabolic signaling. What is the process of aging, if you define the biological terminology of aging, is when the steady state between destruction and construction goes off of balance. We all, from birth to death, have that steady state in which 100 cells are produced. 100 cells will be killed by a programmed death, what we call apoptosis.

And we maintain a seedy state. For example, our bones, when we finish to grow, seems to be static. They are not. They continue to be remodeled. There are some cells that are called osteoclasts, that chew them.

And there are other cells, osteoblasts, that will produce them. The shape will stay the same, like a 3d printing. You have a program, and you need to maintain the femoris in certain dimensions, and so on and so forth. Then what happens? That you start aging and the process of chewing will continue, if not increase, but the process of building will be less efficient.

And typical friability of an elderly person is osteoporosis, because the bones are not produced and maintained in a seedy state anymore. What is now clear, Mark, as you mentioned, is that this process implies that you lose this compact remedialization with the external world, so that you have, first of all, a different microbiome composition. You have a load of endotoxin that's higher, and you have less efficient maintenance of this barrier. So when this happens, you have a flow of this endotoxin. The immune system does its job seeing an animal, we fight, and that would generate inflammation, what we call inflammaging.

And that starts to spiral down of destroying more than reproducing. To finish up with the zoning business, two elements that I believe that would be nice to say. Fruit flies predicting when they are dying is not the chronological age of the fruit fly, but when they lose the beta function. When they do, they know it's highly predictable when they will die. And if you manipulate the genes that control their gut permeability, you can double their life expectancy like that.

You know, for a man, for a human, you go from 80 to 160. The other elements associated with zoning is that if you look at the level of zoning in ultracentric, is extremely low compared to 40, 45 years old folks, that they have myocardial infection, that the zone level is much, much higher, and the zone level is inversely proportioned to agility. So the more zonal you have, the less agile you are by the measurement agility, and it's directly proportional to cognition decay. The more zonal you are, the more your condition. Really?

Ken Ford
Due to the effect on the blood brain barrier. It is due to a variety of conditions. One, as Mark was mentioning, this flu and the toxin, and two, the blood barrier starts to suffer. So you have neuroinflammation. That is another common denominator, by the way, zombie control.

Also the blood barrier you mentioned, the rapid increase in the rate of diagnosis of celiac. How much of that do you think is an actual manifestation of increased disease, and how much do you think is attributable to a better appreciation by clinicians of celiac? And they're taking it seriously and diagnosing it more frequently. Do you think it's a mix, or is it more one than the other? It's definitely a mix.

It was much more increased awareness at the beginning, but now everybody knows and is much more now a true increase in prevalence as we see for all chronic inflammatory diseases. If you embrace a western lifestyle, this. Is actually really a transformative idea when it comes to aging. It's fascinating. Thank you for overviewing that.

Marcus Bauman
You covered a lot of this in your book. Gluten Freedom, which you co wrote with your colleague Susie Flaherty, came out in 2018, and the Celiac Disease foundation refer to this book as a must have work, an excellent reference for those with gluten related disorders. In reviews of the book, some readers have referred to it as a life changing book. You must be pleased with the response you've received. Well, yes, I am.

But, you know, once again, to be not glamorous, but factual. The reason why we end up to write that book is because there was a lot of confusion at that time. We went from an obscure, obsolete condition to very fashionable. And we had people that claim to be experts in the field making some statements that were not defendable. You know, there were books that start to be, you know, popular out there that will, you know, suggest that we all have to go gluten free as a human species.

Otherwise we'll be extinct. And others that, you know, continue to say, listen, the only reason why you have to be gluten free is if you have serious disease. And if that is ruled out, you have no business to be on a gluten free diet. So to be factual and being open minded, we decide to write this book and say, well, you know, what's the state of the art and knowledge that we have that? One, it is not true that gluten is offensive for everybody.

Two, is not true that the only reason why you can be in trouble, clinically speaking, what is posted to the gluten serial disease. We're talking about a spectrum of gluten related disorders. Now, CT disease being the autoimmune form with allergy being the allergic reaction, and then this gluten sensitivity on celiac. Gluten sensitivity to be this third element that you mentioned before that seems to affect many more people that, you know, celiac disease. So.

And that was the impetus to write the book. Very interesting. So, as of today, even though there have been many attempts, genetically and otherwise, the only available treatment for people with celiac disease, really the only viable treatment, is a gluten free diet. For a long time, pharmaceutical companies were not interested in celiac disease. But today, there are more than two dozen drug therapies in development, according to the Celiac Disease foundation.

Marcus Bauman
Can you talk about the progress that's being made in these potential therapies other than just diet manipulation? So the impetus to a gluten free diet alternative stems from a couple of observations. One, that the gluten free diet that was considered to be extremely efficacious to control CT disease seems to not be the case. So the efficacy of the diet is, you know, not even close to what we believed before. And secondly, because the gluten free diet impose a change in lifestyle for you or your family, for life, and that really has a negative impact on the quality of life.

Imagine teenagers, for example, that need to adjust their lifestyle. They tend to blend with your peers, and now you are different because you have to act differently. And so on and so forth. The second impetus for this is that since we start this journey, the knowledge of the steps involved in, you know, from the very beginning to the brick of tolerance and develop serial disease now much more in depth understood than before, meaning that you have targets for a possible alternative or complementary approach to the gluten free diet. So, as you mentioned, there have been many, many clinical trials.

Many are still ongoing. If you go to clinicaltrials dot gov and you put disease keyword there, you will find more than 200, you know, clinical trials. Many are ongoing as we speak. We have four of them ongoing at our center for severe disease and treatment in Boston. They go from using microorganisms that can completely dismantle gluten.

We don't have the digestive enzyme to do so. And therefore, these undigestible peptides can induce an immune response to inhibitory zoning. So you stop the trafficking to, you know, other drugs that target other steps, that leads to the presentation of gluten to the immune cells so that they can fight and create inflammation, to the migration of activated cells to the gut so that you prevent the damage. They are in different stages of development. One of them, the zone inhibitor, got to phase three trial, and then, by a flocking design, in my humble opinion, didn't go the next step.

But now there is a revitalization of the trial. Other they are in phase two. Either they are repurposing drugs already on the market, approved for other indications that can be useful for severe disease. So there is a lot of interest in the field right now. Something else that's been ignored for a long time is gluten sensitivity.

Ken Ford
You know, we hear a lot about celiac these days, not so much before, but a lot of people have really serious gluten sensitivity issues. It's estimated that 20 million Americans have a sensitivity to the gluten protein, and yet these people don't test positive for celiac. This is somewhat seen as a nebulous kind of condition. When you talk to the average physician, it's kind of not taken seriously. I would say somewhat dismissed.

Can you talk a little bit about that and explain for the listener what really is involved in this disorder? Let me elaborate on the skepticism first. Anything that is novel is acquired with skepticism. You know, novelty has very few friends, and I experienced first hand this when I, for example, published for the first time the epidemiologist study of cd disease. That was an environment which the people say you're trying to sell, you know, refrigerators in the.

There is no such thing here and now. Nobody will dispute that same story with the zone on it. That was voodoo science at that time. I said, you know, leaky gut or leaky guts in the way that typically people describe that loss of barrier. It's stuff of voodoo, complementary alternative medicine, and not streamline science.

And now we know by genome studies that that's the same story that is well accepted. Nobody will dispute that same story with the non CDA gluten sensitivity. Gluten sensitivity for short. A lot of skepticism at the beginning, but now people are growing into the idea that that's a real deal. And I have to say that at the beginning I was also skeptical, and again, to be factual, so not to be appearing smart, that we thought about this, and therefore we discovered this new entity.

The reality of the story is very unglamorous. We had people coming in our center from all over the world, and they believed that gluten was creating problems. And we did this typical test for CD disease, and they were negative. And as typically would have done is said, listen, you have no business to be on a gluten free diet. You have to see somewhere else the reason of your symptoms.

And then eventually they did. And then they said, you know what? I tried everything under the sun. The only thing that makes me better is going gluten free. So call me whatever, but I'm going to stick with gluten free diet, even if I'm not celiac.

And that one became ten and ten hundred, a thousand. And at that point, you need to ask yourself, am I seeing this by myself? Or this is a real deal? Or people, they went all nuts, or this is all placebo effect. So you still to talk with your colleagues all over the world, and they start to say, you know what, we do see this kind of stuff as well.

And then you have the first consensus conference, and then a second, and so on and so forth. And that led to the description of this new entity in which, unfortunately, not having a biomarker, you can't make the diagnosis. Like for sea disease, we have a biomarker, you do the blood test and you can eventually suspect that. Or it's the same for wheat allergy, but we don't yet. And for gluten sensitivity, and a lot of people are working on it.

But the reality of the story is that, again, the confusion also stems that, you know, the state of mind was for CT disease, 100% of people with CT disease, they have a gluten reaction and they react gluten. But just to name one of the many conditions in which gluten sensitivity has been involved. Let's say irritable bowel syndrome. It's a condition that, you know, translated in English means irritable. Your gut is irritated bowel because it's your gut to be the object syndrome.

I don't know what I'm talking about. That's what syndrome means. Once in a while, we pull stuff out of there, meaning that people that have stomachache, bloating, changing their bowel habits, and so on and so forth, we find the cause. And 1015 percent of people with IB's, they have gluten sensitivity. And those are the ones that when you go on a gluten free diet, they feel better.

However, if I have to do a trial, because I want to answer the question, is gluten fuel IB's? I take all 100 people that have IB's, put all of them on a gluten free diet, and 15 out of 100 will respond. The answer would say, no, gluten doesn't have anything to do with IB's because the vast majority did not respond. But if I preemptively identify those 15, if I had a biomarker and I would put only those 15 on a gluten free diet, that efficacy will go from 15% to 100%, and you will have a different kind of attitude toward that. What I try to explain is, what is the concept of personalized medicine?

And that's what we need eventually to understand who differently are the people that have problems with gluten, having gluten sensitivity and trying to help their lives in implementing a gluten free diet? Yes. You see that phenomena of the way much research is conducted, it blurs out the individual differences, and it makes it seem like an intervention is not effective when, as you said, it would be, in this case, it would be remarkably effective for the right people. Absolutely. And you see that in so many areas of medicine and science in general.

Well, you know, consider that the most effective drug that is on the market has a 50% efficacy, the best. Meaning there's a 50 50 chance. So that really exemplify another concept that is very dear to me. Any kind of disease that you want to discuss, gluten sensitivity, you know, cd disease, rheumatoid arthritis, whatever, are final destinations. How you got there is very different from one division or another.

And if you have to stop that journey or start to slow down that process, there is no magic bullet that will fix them all. Got to be personalized. Yeah, I agree 100%. I mean, even in what we do. For rehabilitation focused efforts, precision or personalization is the key, because regardless of the treatment, I always say, you know, it's at least a 30% to 35% non responder rate.

Marcus Bauman
Right. And you've got to figure out how to tap into that. What differentiates these folks, and how can you address that 30 to 35 to make them a better responder, right? Absolutely. So, as you've talked about, celiac disease is a genetic disorder, certainly has genetic linkage.

There are a group of genes called HLA, DQ and Dqi, genes involved in the development of the disease, and about a third of the population actually inherits these genes, but not everyone ends up developing the disease. Can you talk about this? Do we really understand why that is? We do, actually, as we were mentioning before, one of the five key pillars, together with environmental exposure to gluten, the leaky gut, the immune system that becomes hyperbelliger, microbiome, genetic counts a lot. And, you know, like many other autoimmune diseases, there is a certain penetrance of HLA genes.

What is another peculiarity, beside knowing the environmental trigger in CTD disease? That the penetrance of these genes is unparalleled. So almost the totality of people with CT disease, they must have either DQ two and or DQ eight, these two alleles of the HLA histocompatibility genes, but 40% of the general population, 35, 40%, they also have these genes that will never develop CT disease. How you explain this, this a piece of a puzzle. You know, these are multifactorial conditions, so there are many genes involved, and those are a must.

Without those, you cannot develop CT disease. And the other peculiarity, we know why because these genes are sort of documentation on a specific immune cells called antigen presenting cells. So when gluten leaks through the barrier and comes in, our body needs to be accommodated on this docking station, these dock, HLA DQ two, DQ eight, on what we call antigen presented cells. And when they dock, then they are presented to other immune cells that will create the damage. If you don't have the doc, you can't develop the problem.

That's the reason why you got to have either. Both of these genes, but having the dock station, but not the rest of the machinery that genetically will lead to the presentation to the, you know, immune cells that damage the intestine would not do the trick. So the presence is necessary, but not sufficient. There are many other genes involved. That's really interesting.

Marcus Bauman
And you talked a lot about this in your book, gluten freedom. And as we talked about folks at the Celiac Disease foundation refer to the book as a must have and an excellent reference book for those with gluten related disorders. The best compliment that I got from this book, from our reviewers is this was written for the general readership to the point in which one of the reviewers said, this was like a romance or a thriller. I cannot put down the book until I finish from, you know, the beginning to the end. It's very conversational, but factual, and in which we discuss many things, including this genetic situation, including, you know, the evolution of epidemiology, speaking of the knowledge about celiac disease all the way, the role of the microbiome and epigenetic and so on and so forth.

Ken Ford
You worked with Bob Pryor at MIT Press in publishing this book. That had to be a good experience. It was an interesting experience. Again, I want to be factual. Bob approached to me and said, listen, it's time to write a good book on microbiome.

And I said, bob, I appreciate and I'm flattered, but there is no way that I would do that. And he said, why? It's an impossible mission. What are you talking about? Well, if I have to write a book in which every month on its subject, in which every month there are 700 papers published, this will be obsolete by the time that I finish it.

And Bob, with his sour fare, said, listen, you just set the rules. Of course, you know, the dynamic will change, but something that would never change are the rules of the game. You know, what can be done, you know, working on the microbiome, something that factually will not change over time. And it's also interesting to know the history of how we end up to move from the single microorganism mechanism that interact with us to the entire community, and what this does in terms of our clinical destiny, so to speak. So at the end, I capitulated.

And again with Susie Flaherty, that is a very smart scientific writer. I said, susie, this is an almost impossible mission, and we got to do this in a year. So let's start writing this using, you know, Bob's direction, and we start to write the book. And, of course, you know, you got to the chapter three, and then you have to go back to chapter two, because something really impactful was published the week before and so on and so forth. Then Bob said, I want this book by this date.

You cannot touch, other than cosmetically, this book anymore. And we eventually end up to, you know, fulfill the request. We gave the book to Bob, and guess what? Covid came on board I said, bob, I can't give you the book without mentioning Covid and what this is doing to the microbiome world. So he gave me a pass for another two, three months.

So we had to really scrabble to put this stuff in there in the midst of the pandemics. You know, it was an art of love, but, you know, honestly, it was one of the most difficult enterprises that I have to go through. But I had a lot of fun because I also had to rely on interviewing colleagues that are much better than I am in understanding the world, the microbiome, the history, how we got there. Fascinating. Yeah.

Ken Ford
He's a very accomplished editor. And you do realize who indirectly caused you that pain? Yes, indeed.

Stemtalk
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Ken Ford
One of our associates here at IHMC ended up in the intensive care unit of a local hospital because of a lower GI bleed. When he asked his gastroenterologist what he thought was going on, leaky gut was offered as a likely possibility. I understand, and I think I understand why that you're not a particularly big fan of the term leaky gut. I don't like it at all. And again, leaky gut, or leaky gut syndrome has been used and abused over the years to explain everything that goes wrong in the world.

You know, if you have a flood in Pensacola, it's due to leaky gut. So the election went wrong as the leaky gut. So, in other words, that term was vilified. I think even the concept is the same. I rather prefer, you know, gut barrier dysfunction, for example, or impaired gut permeability, but not leaky gut.

But, you know, again, one of the major challenges in the world of the role of gut permeability and antigen trafficking is that we did not have a good biomarker to study this. That was one of the limitations with the discovery of zoning, and many companies start to generate, you know, testing to measure zonal in the blood, in the stools, and so on and so forth. Now, it seems yesterday, but again, thumbs fly. Zoning was discovered 25 years ago. There are thousands of papers out there now using zoning as a biomarker.

And I can go through the lists of from aging again to neurodevelopmental disorder to neurodegenerative disorders to autoimmunity, to cancer, to metabolic disorders like type two diabetes and, you know, non alcohol effect, liver disease to GI bleedings and so on and so forth, the common denominator being inflammation. So your associate, you know, may have been blending in the ICU because of this massive passage of endotoxins due to a sudden increase of antigen trafficking that can translate in a situation like this. Interestingly enough, you know, these biomarkers of gut permeability are routinely used in Europe now and not prime time here in United States yet. But I think that is a question of time. Again, as I was saying, you, transformational science would take time to get that kind of, you know, streamline acceptance, so to speak.

Ken Ford
I think you're right. I absolutely think you're right. Back in 2018, you gave a talk at the Institute for Functional Medicine's annual international conference. The talk was titled Autoimmunity and the Interplay of Genes and the Environment. You began your talk by pointing out that medicine is still relatively ignorant about human biology in some regards.

And you talked about how and why people get sick. Can you expand on that and tell us a little bit about your talk and that experience? So, in the past, we were convinced that if I'm born with the genes for colon cancer or Alzheimer's or, you know, sarcopenia, whatever, it is my destiny to get there. There's nothing I can do about it. And, you know, little we knew that that's not the case.

Again, lesson learned from celia disease. There were people that for 40, 50 years were able to tolerate gluten, and then something happened that made them to lose that luxury, despite all the elements were there. And that led to the conclusion, in my humble opinion, that, you know, the presence of the genes is simply a predisposing factor. If this translates in clinical actuality, it really depends how you play your genetic cards, meaning your lifestyle, you know, and that brings also another concept that is very clear to me and very dear to me, that is epigenetics. So playing genetic cards means if, why, when, and how I put in motion these genes to start my journey from genetic predisposition to clinical outcome.

And if I understand that journey, if I understand, for example, what we've been doing wrong in the western hemisphere to justify the surge of chronic inflammatory diseases, we will have strategies to slow down, if not reverse the process. And this knowledge can be applied also to something that we thought that was not negotiable, like aging, in a gracious way. I don't have the ambition to live 200 years, but I would love to leave whatever is my genetic plan in an independent way so that I would not be a liability rather than a resource for the society. With an aging society, that's important. All this to say what we have been doing wrong in playing our genetic cards.

And if you just go through the process, the reality is the following. Anything that manipulates the microbiome in the wrong way so that our interaction is not in a friendly relationship, but is more on the belligerent side, translates in deviation deriving from what was the plan of evolution. That leads me to play my genetic cards, you know, at my disadvantage. That's the long and the short. I understand that you consulted with Claire Fraser as you began writing your book.

Ken Ford
She's wonderful, and she's been a pioneer in the microbiome, in genomic medicine, and was our guest on episode 32 of Stem Talk. Just for curiosity's sake, how did you folks meet? So I was in Maryland. She was with Craig Venter Institute, because at that time, they were married. And she was very much involved in the human genome project when she moved at the University of Maryland.

And as soon as she moved, we got acquainted because of our shared interest. And Claire is a fascinating individual, very, very smart. And we start reasoning about the entire human genome project, what that meant, what was the premise and the expectation of that? Remember, that was two parallel approach. One was the public approach, the NIH approach to this big genome project.

The other one was Craig's approach, the fast approach of a very entrepreneur person, controversial in some aspect, but smart enough to surround himself with very good people. And Claire was one of them. And when the genome project was completed and was unfortunately not leading to the expectation, so they said, okay, we find the key of the reason why we got sick. And by doing the human genomics, and we realized that genomically speaking, we are very rudimental, made only by 23, 27,000 genes. We end up talking very often, what else is going on here?

What is the key of the elements? How modern nature can create such an unbelievable machine like a human being based on only a handful of, you know, genes that translate in products, that is, proteins, and what is the rest of the stuff, what we call junk DNA at that time, that is useless. And, you know, Claire and I, you know, again, spend a lot of time reasoning about all this. And, you know, once again, and this also in the book, Claire, you know, remind me, the beginning, the Human microbiome project, it was all, you know, how we recycle all the knowledge, all the technology, all the hardware and software that was used to do the human genome project so that will not be trashed. And that's how the human microbiome projects were started, but was not appreciation at that time.

How revolutionary this could be in terms of understanding the basic of epigenetic transformation and therefore, the impact of the microbiome on our clinical destiny. When I started to write the book and I decided to go to the source of facts, Claire was on the top of my list, and she was kind enough to accept the invitation. And I believe her contribution to the book has been instrumental to be very, very factual. How the field of human microbiome really started. This is actually a great lead in to some of your current work.

Marcus Bauman
One of the relatively new projects you've been working on is called the Celiac disease genomic, environmental microbiome and metabolomics study. The project features a team of physicians and scientists for a long term multicenter trial that will follow infants from birth through childhood in an effort to better understand the many factors that contribute to the development of celiac. Some of those you've touched on already, it's your hope, to my understanding, that this study will lead to a historic new conceptualization of how we identify, predict, and prevent celiac disease. It's quite an ambitious project, isn't it? That's an understatement.

And then, Marcus, again, I'm, in general, very humble, but I'm very proud of this, because when this was conceptualized was more than 15 years ago, we were at the dawn of the microbiome field. And what I realized at that point was, you know, it is a multifactorial component that dictate our clinical destiny. You need to know who genetically you are. You need to know who you are dealing with in terms of this ecosystem that we co evolve with. You need to have the metabolic understanding of this interplay with this translated metabolic pathways that can dictate the balance between tolerance, immune response, that is, health and disease.

I also realized that the only way to do this right was to follow a quart prospectively, because all the stuff, the microbiome, all the stuff that is out there, including our stuff, it's very descriptive. So I can take, you know, 100 people with Alzheimer and 100 people metaphor, whatever you want. There are controls. And I find a different microbiome and lipophyta. I say, okay, they got Alzheimer's because the microbiome difference.

What about the other way around? Because I have Alzheimer eat differently, therefore my microbiome is different, or I have different physical activity, and therefore, this will change my microbiome. The only way to mechanistically link the microbiome to disease pathogenesis is to follow a quartz from birth, ideally, and I'll tell you in a moment why from birth and see the dynamic before, during and after the onset of disease. How this really change and how mechanistically can be linked to the clinical outcome. You can't do this with Alzheimer's because you can't follow people for 70 years.

It's unfeasible. So you need to choose a disease that materializes rather early in your life. And once again, Celia disease was, you know, our target. The other thing that you want to do is to trick the system to your advantage. If the prevalence of CD disease in the general population is 1%, you need to recruit 100 kids to gut one with severe disease.

And we require a huge number of kids to be followed. But if you take kids at risk because somebody in the family has CD disease, you enrich your population ten times because the risk is 10%. And that's what we did with the cd gem study. Now fast forward in 15 years after we've been following these kids for, you know, ten years now. We recruited more than 600 families because of course we also do studies on the rest of the family, including the probant, that is the ones in the family, mom, dad or brother sister that have severe disease.

We know everything about these kids. One of the key elements that surface by you know, study the microbiome. It's like to look at egyptian geographic without knowing the key. If you don't have metadata, so in other words, clinical data, you need to know mom's style. If these kids was born by c section of vaginal delivery, where was the vaccine calendar?

What these kids have been eating the first year of life, a number of infections, pets in the household. And you can go on and on and on because all this dictate the change in the microbiome. The other thing that we learned through this process was something that I find simply fascinating. The first thousand days of life, from conception to two years of life will be instrumental to dictate your clinical destiny because that's the time in which we have to find that nice compatibility between the host and the microbiome. You know, the microbiome is primarily dynamic.

It's not that once you got it, it's there. And there are a lot of elements that can disturb that ideal symbiotic relationship to find each other. If you look at the microbiome of these kids at the of all we realize that engraftment starts before birth. We start to see a blood microbiome and then the placenta microbiome of these mothers, that has a sort of signature, so to speak. Then we realize that at the beginning, from birth until two years of age is completely chaotic.

It seems to be chaotic. So some folks, they come in, they leave, they are substituted by others. Then you start to introduce baby food. Once again, there is another shift and everything quiets down. Around two years of age, that's not chaos, it's dating, searching each other.

The host, that is the baby, analyzed the microbiome and said, you metabolically can be compatible with me. You can stay. You, on the other hand, you're not. You got to go. Conversely, the microbes got there and they found a good biological niche.

They stay. But once they consider that biogenic to not be appropriate for their survival, they will leave. Imagine, during this delicate time, elements that were not planned by evolution. Use of antibiotics, pollution in the air, you know, stressful mother bottle feeding, that's more, is not part of cease action. Of course, they were not part of the evolution.

And that will derail that delicate time in which you have to search each other. And why this is so important for our destiny. I mentioned this before, you know, 2 million years ago, when we started our journey on the face of earth, our life expectancy was 1415 years. And there are two ways that you finish your journey. A dinosaur will eat you, or an infection.

You didn't have time to develop cardiovascular diseases or cancer. Luckily, it wasn't a dinosaur. Luckily, if you were lucky, because infection you can survive eventually, but not with a dinosaur. So the immune system was generated to fight only one enemy, infection. And in matter of fact, what is inflammation?

Nothing else. That generates a very hostile environment for microbes to grow. It's too hot. There are chemicals like cytokines, will kill you. Immune cells that will eat you.

You destroy the tissue, so you pay price, but you save the organism. So it should not come as a surprise as the microbiome that program, like a computer programmer, the immune system to decide if, when, why and how to generate inflammation and when to stop. Because generate inflammation when it's controlled, is a good thing. And it's good thing that you will stop the inflammation when the enemy is being defeated. So that you know you have a repairing situation there in the evolution plan.

A good programming of the microbiome of the immune system will lead to healthy immune system that does the job. Now we are born more a c section. We eat junk foods, there is a lot of stressors, pollution and so on and so forth. The microbiome programmed the immune system to put the bar of inflammation way too low, and it's a matter of time that on a specific genetic background, this will translate to the clinical outcome of an inflammatory condition like CT disease. That's what we learned through this project.

But most importantly and dramatically important is that following these kids, over time, we were able to identify microbiome signature years before that were predicted with almost 90% who develops CD disease, who does not. Of course, this is all AI generated information. So in other words, you have 32,000 genomic data from the human genome, millions of genomic data, the microbiome that is modifying all the metabolism, profiling all this metadata, and you feed the system and say, I have a court of kids that they start from the same start line, this went left and develop CD disease, this went right and not segregate them. And tell me, AI wise, what are the minimal denominators that we predict? And again, to make a long story short, there were systematically the loss of protective elements of the microbiome of those that developed cEta disease.

That led to five strains, only five strains, all of them, they are probiotic strains compared to the ones that did not develop it. We took these five strains, we do the whole genome sequence. In these five strains, we find 2% of mutation compared to the reference strains in some key elements that we knew pathogenically important. Genes that control the host's body function, genes that control the host programmed death, apoptosis, genes that control the innate immune response and the adaptive immune response. And finally, to close the loop of epigenetics.

If you take biopsy from these kids and you make organoids like small intestine in the tube, now, you can do that because, you know, the intestine has, you know, these stem cells that regenerate very fast all the time, and you make organoids and you expose these organoids to gluten. If you have serial disease, three things will happen to you. Gluten will make your cell to die very fast, so increase the rate of apoptosis. Gluten will increase your gut permeability. You lose, you know, this tight junction because you, gluten induced overproduction enzyme.

Gluten induce a battery of pro inflammatory cytokines. If you take the same organoids and you predict these organoids with these protective bacteria, they are lost by the kids that develop CD disease. They epigenetically reprogram the epithelium on those elements. Cell turnover, barrier function, innate and adaptive immune response. So if exposed to gluten, you will respond like a normal individual, meaning nothing.

You do not have increased apoptosis. You don't have increased gut permeability. You don't increase the production of pro inflammatory cytokines. Long story short, if those strains are there epigenetically, the epithelium is programmed to tolerate gluten. When you lose it, you lose that capability, and you start your march.

And that's the reason why you can develop serial disease in your fifties, because you may lose those protective elements later on. Well, thank you for that description, Alicia. The study we're discussing really is a remarkable study. So many ways. And you had participants not only from the United States, but also from Italy and Spain.

Ken Ford
Could you tell us about that, and how did that come about, and what was the rationale? I can. I think I know, but I want to ask you. Yeah, I mean, you know, these three sites, genetically, they are very similar, so we didn't expect difference there. What we expect, on the other hand, is the environmental factors that can be at play, and that's the reason why we decided to do that.

And compared to United States, kids in Italy and Spain, they lose tolerance earlier. So, in other words, we see that the average onset of seeded disease in United States is three, four years later than in Spain and Italy. And now looking at the metadata, we try to understand what are the elements that makes these kids to lose tolerance earlier, because that's another information that can help us intercept the disease. That is the only real study. So is the overarching goal of this project to pave the way for personalized prevention of celiac disease?

It's exactly that, because now, by making all the omics and with AI analysis, this is what we learn. The first thing that happens is dysbiosis. You lose this protective element that I told you. The second thing is the ozone start to raise, increase over time, a few months before the onset. So the antigen traffic increases, and only those that are destined to develop see the disease.

The third thing is that you break tolerance. So you start to see the biomarker, that you develop an immune response against gluten and so on and so forth, and then you develop disease. So with that in mind, our idea, if this will be confirmed in large numbers, is, you know, surveillance of the microbiome. When we see that this biosis of these people that eventually will have this loss of protective elements, we can supply those elements because we isolate them. And therefore, there are now strains that we can give to kids.

And we use biomarkers like Zolan and the biomarkers for brain intolerance. To see if this indeed is intercepting the disease or not. CD Gem really is a gem. I have to say, not very many projects in science are of the duration in a cohort study. It's really kind of amazing.

Marcus Bauman
Let's talk about some of your other work as well. Last year, you published a paper in the American Journal of Gastroenterology titled early antibody Dynamics in a prospective cohort of children at risk for celiac disease. The aim was to identify possible serum biomarkers that could help predict celiac disease in at risk children. Can you tell us about this study, a little bit about the design and what you found? Yeah, same story.

We exploited the CD GEM study. So in a prospective cord, and what we found that some antibodies that are called deamidated antiglanin antibodies, they are biomarkers of brachial tolerance. Again, gluten, they surface a few months before the onset and they follow, you know, the other two steps that I was mentioned before, the dysbiosis and the increased zonal. So what we understand is the dysbiosis cause zonal upregulation, because this has been demonstrated by many others beside us, and that increased antigen trafficking, gluten, and that gluten will induce these deaminated antibodies that are biomarkers that, unfortunately, you went over the threshold of tolerance and the next step would be the onset of disease. Interesting.

Marcus Bauman
CDGEm will produce many, many offshoots, I would imagine. Yeah. I mean, again, as you mentioned, these are very difficult cords to maintain for so long. We have dedicated research coordinators every year. We have the lab coat, you know, ceremony.

So we have this one, two years old kids, they come to the lab, they got the lab coat, and they do the tour of the lab, they look at the freezer where their poop is in there, and they're very excited about all this. A study you published earlier this year in the journal Pediatrics looked at Zonulin. We've been talking about Zonulin now for hour and a half. This study evolved from the observation that increased intestinal permeability seems to be a key factor in the pathogenesis of a variety of autoimmune diseases, including, of course, celiac disease. It's unknown, however, and I think this is really interesting, whether increased permeability actually precedes the onset of celiac disease.

Ken Ford
So please tell us about this study. I think this is really interesting. Yeah. I mean, as for the microbiome, when you do the studies where the horses are at the barn, so that the people, they already have the disease, same story with zoning that a lot of people have been in. The zoning that is elevated in a variety of conditions.

But you don't know, again, if the cause of the consequence, an epiphenomenon, so they are not related. The cd gem and the study that you mentioned allow us really perspectively to see that indeed it's an indicative part of the story that precedes the onset. So we see this rise of Zonalin way before that these kids develop, see the disease. And interestingly enough, the slope of this increase of this rise increases with the number of antibiotics that these kids have been taking the first few years. The more antibiotic, the more steep is the curve, meaning that, you know, there is a close correlation that we knew already between the zoning and the microbiome.

Ken Ford
Thank you. That really clears it up. So as a pediatric gastroenterologist, you also work with autistic children. In addition to social challenges and repetitive behaviors, there are a number of other symptoms related to autism spectrum disorder. Can you talk about experiences in working with these children?

I think as a pediatrician, working with kids with autism spectrum disorder is one of the most frustrating experience. You know, it really drains you out. And the reason why is, one, we don't understand really the intimate mechanism why this is happening. Two, we are in the midst of an unbelievable increase, way more impactful than any other chronic inflammation that we see increasing in western hemisphere. Just to quantify this, we went from one in 10,000 in the mid seventies to one in 36.

One in 36 now. And last and not least, when you make a diagnosis like this, you are telling to the parents the following. Your child is lost, is in a parallel world, and I don't know how to bring him or her back. That's pretty much the sentence. And there's been this till the recent past.

You know, this is kids that they. You mean there are verbal kids and nonverbal kids. So there is a degree of severity of the condition. But these are kids that really. They live in a parallel world and you can't communicate with them.

They have their own behavior that or idiosyncrasies, one of the most frequent. You know, they eat always in a stirred up way, or they really want a certain environment. And if they are outside of that, they got extremely agitated. When they are in pain, they cannot communicate. So they change behavior that is communicating pain.

In other words. I can only imagine putting myself in the mind of these kids how scary it could be that you are physically there but not capable to communicate with the surrounding world. And how frustrating is for the families knowing that your child is there, but it's not there. So it's becoming my crusade, if you wish, at the stage of my career in which, if I want to do something impactful, I should spend time to try to understand all this. And this is in a smash of what we call the gut brain axis.

That the brain communicates with the gut has been known forever. If you're nervous, you have stomachache, but that the gut can communicate with the brain is a relatively new notion. And once again, not to be monotone, but the microbiome seems to play a huge role in all this. And we have a similar project now that we have for cd gem. It's called Gemma for autism, that is trying really to get to the root of this.

And again, I know the animals are not humans, but, you know, we have a component, this project in which you eventually take, you know, a mouse, humanize this mouse with tools from an autistic kid, and you resemble in this animal, some are stereotype, you know, conditions that seems to suggest the neuroinflammation, the different pruning of the synapses that happen in kids without this. It's also not only, it's also dictated by a relay from the environment that is the microbiome. Remarkable. And I think the impact of the microbiome is so broad and so amazing. I particularly like it as a way of understanding how a super complicated creature, like a human, you mentioned this earlier, can be assembled out of only 23,000 genes.

That's right. And again, not to be politically incorrect, but, you know, there is another concept that is to be very clear, and it's the concept of one healthy. The microbiome is extremely dynamic. It's not that once a choir stays there, I share my microbiome with you guys if I touch anything here, but definitely also, you know, my stools are going in the ground and, you know, eventually in the water and the soil and in the vegetable that somebody else would eat, it's a circle of life or the livestock that I eat. So if I have an environment is polluted, if my soil, my air, my water is polluted, everybody suffers.

So I think that the challenge of the 21st century is to take good care of our microbiome. We cannot overlook how important it is for our clinic destiny. And that goes through taking care of the environment, because it's a one health. Mm hmm. That's for sure.

Ken Ford
When we last talked to you, you were involved in renovating a 13th century monastery in Salerno. Italy, which is your hometown, after all. Salerno is home to the school of Medica Salernitana, which is considered the world's first medical school. And this dates back to the 9th century. You and your colleagues have really transformed this former monastery into the European Biomedical Research Institute of Salerno.

Can you give us an update on the institute and its continuing development? Yeah. The initial rationale to have this institute there was because this monastery was abandoned and there was some, you know, funding for European Commission that they were going to use for a museum. And at that time, Mayor Nanao is the governor of the region there. Want to do something more impactful?

Also, in connection with the reopening of the Scola Medical Serenitana, that was closed for two centuries because was moved to Naples and then was reopened. And then, you know, he decided to invest this in this research institute. The focus in institute is on nutrition and health and how the nutrition can impact the microbiome. And now it's an institute that has almost $45 million of funding, mostly are involved in nutrition and gut brain access. So the two are, one is on autism and the other one is on depression.

But we also have some very cool project that will be more in the realism of the IHMC rather than us. The last one that is very ambitious that we just got submitted, is a project in which we use 3d printing of biological material to regenerate tissues. So the idea being to use AI guidance and organoids and different biological scaffold to reconstitute a piece of gut or a lung or a kidney or a liver so that you have a transplant of your own organ. This is just to give an idea. And this, of course, relies also on epigenetic information that you have to put into the equation to make this compatible with the host through the microbiome study and then other projects, for example, optimization and triage of people that they got a stroke and they are in an ambulance.

So that's, you know, again, through three AI algorithm to decide in which hospital to go to optimize in the outcome. This is just to give you a few examples. How different is now from the original concept civilization. So, matter of fact, now we have a microbiome core that, of course is a heart and soul, what we're doing, and an immunological core that is important. But we have an AI core that does a fraction of what you guys do here, but specifically these projects.

So all this to say, I see the future of personalized medicine and preventive medicine and healthy aging. As a corollary of how AI and biology needs to work hand to hand in order to do this right. And, you know, for what I heard, you guys are really pioneering this kind of concept, so I'm so glad that you really invest in that direction. Well, thank you. This sounds like a real hub of innovation.

Marcus Bauman
So congratulations on the new institute. Sounds like rapid progress in a short amount of time, so keep it up. That's exciting. Since our interview with you in 2016, your son Stefan has joined us here at IHMC as a research associate. I know that you have always enjoyed Pensacola during your visits here to give lectures, but now you must really enjoy Pensacola to come visit Stefan.

How is he liking it here? You know, I am the kind of father that I want to stay back and not pushing, you know, my kids in any direction. I never conceptualized I will have a rocket scientist in my family. But, you know, and I remember, and I don't know if Ken remembers that when I came here, one of the first time to give a talk, I brought Stefan with me, and Stefan spent, you know, half a day in the, at that time, very early stage, your robotic lab, and he got so untangled that I believe that that's really imprinting that desire to eventually sport this direction. And when he graduated from the space engineering program at University of Maryland, among the other places, he applied here, and he didn't tell me.

And then, you know, he told me in his typical way, guess what? I'm going to Pensacola. Is it to do what? Well, I've been accepted there. And, you know, of course I was thrilled.

I don't think that I mentioned this to Ken because I didn't want to get into the dynamic of the matter. And, you know, he's my younger kid, of course, so I was a little bit trebidant. It was the first time that he was by himself and so on and so forth. I have to say I'm very proud of him, first of all, because he really entrenched in the community here, so he showed me around that kind of stuff. But also in this community, he really, really likes the philosophy of the place.

He said, you know, there is no chain of command. You're allowed to really exploit your creativity here. And it's not that, you know, people will eventually impose you one direction or another. Of course there are boundaries, you know, that is all of normal. But, you know, he said, this is the place in which I can see myself growing professionally.

This is also a kid that, when was in kindergarten, was terribly bored because was not enough stimulating, and we decided to put him in Montessori to try to simulate him a little bit more. But I said, you know, this is waste of time. He definitely has other kind of state of mind, and he find, in other words, the perfect environment here. My only thing that I really would like to see him doing is to progress. Has to take an MD, I mean, a PhD or a master, to move on, because I believe that, you know, he has that capability.

But, you know, again, as we mentioned before, you need to be aspired. And he has this extremely luck, you know, contingency to have a very, very good mentorship team. So he should take full advantage of that, right? He would be great in the PhD program. Agree more.

Marcus Bauman
So, yeah, absolutely. We love having him here, and I'm glad he's found a scientific home that he can grow in. This has been great fun. Alicia, I have one last question for you. Will there be another book?

And if so, what will it be about? You know, I don't like to do this kind of stuff, but if. If I could do it, I would like to write a book for microbiome for kids, something at that level. Because the next generation, really, the sooner they got on board of respecting your own microbiome, the sooner we will start to reverse off this trend. So, an illustrated book for kids.

Ken Ford
Wow. To explain the microbiome. If I got to. If I'm obligated to write another book, that would be my choice. That'd be pretty cool.

Marcus Bauman
Yeah, that'd be very cool. Shorter? Oh, yeah, yeah, yeah. The span attention of kids. It's very short here, go.

For 600 pages a book, definitely not. Well, it's been great fun, and thank you for joining us on STEM Talk. I appreciate the invitation.

Marcus Bauman
When Alicia first appeared on STEM Talk back in 2016, gluten free pizzas and other gluten free options were not common on restaurant menus. But now, restaurants and consumers are much more aware of celiac disease and gluten sensitivity. And that's partly due to Alicio's role in identifying gluten sensitivity as a serious issue affecting more than 20 million Americans. Something else that wasn't widely discussed back in 2016 was the microbiome and its critical role in human health. Thanks to researchers like Galicio, we are in the early stages of unraveling one of the myriad mysteries of human biology.

Ken Ford
Recent developments in microbiome research are paving the way for personalized and precision medicine that may 1 day become standard and provide us with novel treatments and therapies. Well, this is Marcus Bauman signing off for now. And this is Ken Ford saying goodbye until we meet again on Stemtalk.

Stemtalk
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