Ep 146 Celiac Disease: Rootin tootin gluten

my parents to take me to see my pediatrician. My pediatrician recommended that I go get blood work done. I was terrified of needles at this age and obviously did not want to hear this, but I do remember my pediatrician saying and passing that it could be Celiac disease, but that she was pretty sure it wouldn't be. After a very traumatic blood test for everyone involved, my pediatrician called my home a few weeks later to let me know that my blood work had tested positive for celiac.

I then had to get a biopsy of my small intestine to confirm this. The biggest thing that I remember from this period was being absolutely terrified of the biopsy. I don't even think it had even processed yet that I could have an autoimmune disease triggered by my favorite foods. I was a kid, so the idea of going to the hospital and getting an IV dominated my understanding of

the situation, and the biopsy was really hard. I drink an obscene amount of water beforehand to make the veins in my arms easier to access, but it didn't work and the nurse had to use the veins on my hand to get in the IV. I even had to be wheeled out of the hospital because it took a while for the anesthetic to wear off. But after all of that, the results came back positive and confirmed officially

that I had Celiac disease. Celiac is an autoimmune disease that prevents the body from properly digesting gluten, which is a protein that is found in wheat. The only treatment is to stop eating glutin, which is exactly what I did. The good thing is that within a month or so of going gluten free, I did start to feel better. I hated the new food that I had to eat because it was bland, but I could at least recognize that my body wasn't in nearly as much pain as

it used to be. I had more energy. The awful cramps that made me feel like my stomach was eating itself grew more infrequent. There was, however, a significant mental impact of Celiac disease that I want to highlight. I was diagnosed with Celiac right when I was hitting puberty as a girl in the early twenty tens, and even though I was only eleven, I was already acutely aware of the seeming requirement for people like me to be

small and thin. I was already self conscious of my body, and I want to note that Celiac did not cause all the issues I would develop with food and body confidence. However, it definitely exacerbated them. Suddenly, food, which I'd already had a tense relationship with, became really bad, and not just bad but harmful. Because of Celiac disease, food actually hurt me. It felt like I had been failed not just by food,

but also by my body. I received all of my early treatment and tests at a children's hospital, and this included a specialized meeting with the dietisation who explained celiac to my parents and me, including what foods to avoid, possible meal plans, and how to identify gluten in seemingly unsuspecting food products. Gluten can go by many terms maltodextrin, rye, malt name a few, so I had to get really good at reading the ingredients lists on foods. Unfortunately, the

calories were always right by the ingredients. Food became a point of stress. Eating was no longer fun, but rather a minefield that I had to navigate for every meal and every snack. I still can't really express how much this altered my perception of food and its relationship to my body. In short, food became my enemy. Unfortunately, I

also started to lose weight. During my first year post coeliac diagnosis, I did not gain any weight despite growing a few inches, and I actually remember proudly telling one of my middle school friends that I hadn't gained weight for an entire year. I was twelve, and I was so proud of that. I also grew really self conscious

about my eating habits. I hated having to ask for accommodations in restaurants or went over at a friend's house because I didn't want people to perceive my body as a problem, and I so strongly associated my body with celiac that any sort of conversation about food was immensely stressful. Again, while siliac disease did not necessarily cause my fractured relationship with food, it made it so much easier for me to continue to view food as my enemy. When I

went to college, Celiac became even more problematic. As with many people with as many people with food allergies and intolerances will know, colleges don't necessarily have the best reputation for dietary accommodations. The freshman fifteen, which is in and of itself a wildly problematic term, did not happen to me. Instead, I lost weight. I had to walk about ten minutes to get to the nearest campus dining hall, and then the only option for me was rice and bland vegetables.

It was really easy to skip meals and supplant that with going to the gym, and I became anorexic. This continued through COVID, when suddenly I was living back home and cooking my own meals, I rapidly gained weight. Within the first few months of lockdown, which in and of itself was terrifying. But that's what happened when I finally started eating three meals a day and making food that I actually wanted to eat. It's been about three years since I was able to acknowledge how much Celiac disease

negatively affected my relationship with food. I had to see a therapist that specialized in eating disorders, as well as a dietician who had experienced working with clients like me who had food intolerances. I would love to say that this all immediately solved my problems, but that wouldn't be true. I am, however, better at eating gluten free meals that are filling and nutritious, and although it's not perfect, I do have a better relationship with food now than I

did as a teenager. When I was first diagnosed with Celiac, it seemed like a relatively easy thing to treat. I thought all I had to do was stop eating bread, and I wasn't the only one who thought this. I actually remember people sort of brushing my diagnosis off or saying that they were thinking of going gluten free to lose weight. After all, I was diagnosed with Celiac right

when it became a sort of trendy dieting fad. I didn't realize how much it would influence my entire understanding of food as a necessary component of my life that had seemingly become very, very evil. I would love to see more support offered for children, especially girls, who are diagnosed with food related intolerances and diseases at young age. With Celiac specifically, it's never just bread that you have

to cut out of your diet. Rather, the diagnosis means an entire shift in your understanding of food as the thing that is supposed to help you but seemingly only manages to hurt you instead.

I really enjoyed doing the non traditional format anyway. But this is a really interesting topic with so much to unpack in terms of evolution, in terms of diet culture, in terms of stuff like that, and like I just as a forewarning, I'm not going to get into every last bit of all of that. But but also Celiac is just a really fascinating topic. There is really so much to unpack, and I don't know really anything about the biology, as per usual, and so I'm excited to tell.

of your small intestine cells. That's like the end result. So let's get into the steps of how kind of this all happens. And to do that, I think we have to start with, like what is gluten.

gives bread that chew if you're eating bread. When it comes to celiac, it turns out that it's one part of this gluten complex, specifically the gleodin proteins, and there's different subtypes that people react to in celiac disease. And it's also a different subset of these gleodins that if you have a wheat allergy that you end up reacting to in a different way. Allergies are totally different than autoimmunity,

so fascinating. And there's an enzyme in our body that will become important later called TTG or tissue trans glutaminase that helps to break down these proteins in our guts, and this becomes important in coeliac because spoilers, this is the enzyme that we end up making auto antibodies against.

the same antibodies as glutens. So even though it's similar, it turns out that most of the time, oats are pretty well tolerated and considered safe for people with celiac. I'm not your doctor. If you have celiac, please talk to your guest ventrologists, et cetera. But yeah, so that is what gluten is. It's just like these combinations of proteins that are present in some of these grains that why do they make a person with celiac start attacking gluten?

That doesn't make sense. Why would that happen.

Celiac disease, the genetics become super super important. Over ninety nine and I think it's really close to one hundred percent, but all of the statistics just say, like over ninety nine percent of people with Celiac have one of two HLA markers HLA DQ two and HLA DQ eight. What do those mean? Because they're all over the Celiac literature.

Vaccines episode season two. Yeah, it's been a minute, but these are cells that help our immune system by bringing stuff that they find to are lymph nodes or other areas where a bunch of immune cells are congregating, and they present stuff to our immune cells specifically like our T cells and our B cells to activate them to

start an inflammatory reaction. So they are the cells that go out and gather up things that they find that might be foreign particles in our body, viruses, proteins, gluten, whatever it is, and they bring them and say here, I have presented something to you. Tell me if it's dangerous or not right, and then then our T cells, which are British, always, oh always react to those things

if necessary. Everyone has a variety of HLA proteins. You get half of your HLA proteins from your mom, half from your dad, and then that makes up your HLA component. The two that are involved in Celiac, Dq two and Dq eight happen to have an affinity for glutent specifically for gleodin proteins, so they have the ability in your guts because remember from our tonsils episode that our guts

have their own entire immune system. So these HLA proteins in our guts find some of this gluten bring it over to pire's patches in our guts where immune cells are congregating, and they're like, hey, T cells, what should we do with this? And if you have Celiac disease, or if you develop Celiac disease, your T cells are going to see that gleodin protein and be like we'll I'll destroy them and go hogwild.

I don't remember. But they're in your guts.

don't know, over twenty five feet long or something. It wiggles back and forth in like the whole center of your abdomen. If you look at like a picture of guts, it's the wiggly part in the whole center. Your small intestine has multiple other parts. There's like the duodenum and then the jujunum, and then it goes down into the ilium, which is the last part of your small intestine. Your small intestine is mostly responsible for like the continuation of

digestion in the first part and then absorption. All of your nutrient absorption is going to happen throughout your small intestine, and then it passes through the iliosecal valve, which is the last part of your small intestine, and that goes into your colon. That happens right in your right lower quadrant where your appendix is, because that's like a little beep that hangs off the edge kind of where your

intestine and large intestine combined kind of. And then your large intestine goes up your ascending colon on the right side, and then it goes across the top that's called your transverse colon, and then down your descending colon on your left hand side, and then it wiggles around and that's called your sigmoid colon, and then into your rectum and out your butt. Your colon mostly is reabsorbing water. That's like the main function of what's happening in your colon.

There's some nutrients that also get reabsorbed there in your colon as well, but that's like the main thing that's happening throughout your colon. Does that answer your question?

we were not even in the duodenum. No, so your T cells are going to respond and start causing damage to your small intestine. It's a little bit more complicated than just gluten being presented because I mentioned already this enzyme called tissue trans glutaminase. And this is where I'm not going to get too too deep into the weeds, because while there is a lot that we know about the nitty gritty path of physiology that's involved here in

this intestinal damage that's mediated by this autoimmunity. I'll link to a paper about it. It gets just too detailed for us here. But what is important is that there's this enzyme called tissue transglutaminase. This is something that we all have that helps to break down gluten in our bodies.

But what happens in the case of celiac disease is that as gluten is bound to TTG, what ends up happening is that it makes this gluten protein even more available for presentation to T cells, and then those T cells that are.

So what's really in resting about coeliac disease compared to most other autoimmune diseases is that we know that specific trigger so specifically, I guess not to use the same word over and over, But for most autoimmune diseases, we think, or we know in some cases that there are environmental exposures as well as genetic susceptibility, right, But with celiac, we can pinpoint that gluten is necessary for the development of coeliac disease, and gluten is the trigger that continues

to perpetuate and cause damage. But it's not just those two things. It's not just this genetic susceptibility and exposure to gluten. There's also a third component, something else, And that's something else we don't fully understand. It's involved with tissue transglutaminase and creating these auto antibodies against tissue transglutaminase

and other enzymes as well. It's just this one, but there's some other trigger that has to happen that then leads to the eventual presentation and development of auto antibodies against gluten but also against your own cells and your own enzymes that end in this immune activation and damage to the small intestine. Now that third point, the trigger besides gluten, we don't know what that is. We don't

understand it. Something like twenty to thirty percent of people have these various HLA types DQ two and DQ eight. Almost everyone is exposed to gluten. Right. Gluten is in wheat, rye and barley across the entire globe. Populations depend on these grains, and I know erin you'll talk a little bit more about that from an evolutionary perspective, but it's a very small subset of people who then end up developing seliac disease. So there is some other environmental trigger

that we don't fully understand. There are a lot of ideas on what this can be. There's some data that perhaps exposure to gastrointestinal infections, including rotavirus, might be one of those triggers or one of those things that puts you at higher risk spoilers rotavirus vaccination might help protect against the development of coeliac disease.

body disease. So let's get into what this all can look like. The most classic quote unquote symptom that's associated with celiac disease, and it's also now called classical coeliac is diarrhea, and diarrhea can be pretty profound because again, what's causing this diarrhea is that your small intestine kind of gets destroyed. Like I mentioned that because of your wonderful question, Aaron, that your small intestine is where we have to absorb all of our nutrients. The way that

your intestine does that is they have inside. If you look in your small intestine, these beautiful, wonderful things called villi that are kind of like these anemone tentacles lining your whole small intestine. They make this incredible amount of surface area for all of that absorption to be able to happen. In celiac disease, you develop what's called enteropathy, which just means damage to that small intestine specifically and

blunting of these villi. These are just fancy medical words to say that all of your beautiful gut anemonies.

like anemia, and not just one type of anemia. Yes, you can have iron deficiency anemia from not being able to absorb iron, but also other vitamin deficiency anemia is like B twelve deficiency, full late deficiency, and especially in kids, and a lot of the time celiac develops in young kids even if it's not diagnosed until they get older. You can then see growth failure because of how much

malabsorption you have. On top of that, you can end up with other symptoms or other entire diseases like osteoporosis, which results from not being able to absorb enough calcium. Another common sign is abnormal liver testing, which we don't have an exact mechanism for, except that that TTG enzyme is also present in the liver. So is it because of damage to the liver from that? I'm not one

hundred percent sure. But then with all of this overall malabsorption and literal damage to the small intestine, you can have a lot of abdominal pain and bloating. Sometimes you end up paradoxically having constipation because of just how much overall damage and dysfunction and dysregulation really that we see in the guts.

a bloody diarrhea, but not nes necessarily. It's not like characteristic of coeliac or anything the way that it would be for an inflammatory bowel disease, which we'll do eventually on this podcast, But that's something like ulstertive colitis or crones, which is causing damage not to the small intestine but the large intestine, asterisks, et cetera. But in general, those are associated with more bloody diarrhea, which you would expect to see a little bit less of with celiac, but

it's not impossible. So no, there's nothing that makes this diarrhea special I guess or very specific. Diarrhea is a very non specific symptom. And while it is classic, it's not necessary to have coeliac disease. Not everyone with celiac

is going to present with diarrhea at all. And in addition to these intestinal symptoms, there are also extra intestinal they're outside the intestine symptoms and not just all of those complications from malabsorption that I already mentioned right, the osteoporosis and the there are also a few specific extra intestinal manifestations that we see relatively commonly there's a condition called dermatitis herpetiformis no idea where it got that name.

It's a weird name, but this is a skin blistering condition that is associated with celiac disease, and it's directly related to gluten consumption in someone with coeliac disease who may not have any other symptoms that they know of of coeliac, meaning no intestinal symptoms except for this rash.

And this rash looks like incredibly itchy, fluid filled blisters and vesicles, mostly on like extensor surfaces, so like the front of your legs or the back of your arms, or on your butt or your trunk, and they're super super itchy and look kind of like little teeny tiny blisters everywhere. And then there are also a handful of neurologic complications of coeliac disease, the most well known of which is gluten ataxia. We've talked about ataxia on this

podcast before. A Taxia is a movement disorder where you lose the ability to coordinate movements, especially walking, because of damage to the cerebellum or the bottom part of your brain. And this is a neurologic manifestation of coeliac disease. For these extra intestinal manifestations, we don't fully understand them or like why exactly are you seeing these or what exactly is the specific like cause in consequence kind of a thing, which is not surprising, But we do know that these

two things specifically are related to celiac disease. And then there are other disorders or diagnoses that we might see at higher rates in people with celiac that we don't know if they're causal or not, and that's things like migraines or depression.

tolerance to gluten and therefore develop coeliac disease. And what I mean by that is that someone might have no symptoms and if they are followed for long enough, let's say, in studies where they're looking at kind of like higher risk populations, so either someone who has a known HLA haplotype that's associated and a first degree family relative or

something like that. Right, so they're in these studies where they're trying to look at when do you develop celiac, they might end up with these antibodies that we associated with seliac disease even before they have any symptoms of

coeliac disease. On the flip side, someone might have symptoms for years before getting a diagnosis, and then that turns out that all of those symptoms were related to celiac, or they might not have any symptoms, get diagnosed, and then look back and realize, actually, no, maybe I did have these symptoms, but I just didn't realize that they were symptoms, if that makes sense. So there's not a

good answer really to your question. And I think that that's part of what one of the challenges is in trying to understand what are the points at which and what are the real triggers aside from the genetics and aside from the gluten that are associated with the development of celiac disease. We don't really know, and so we don't know when someone is going to develop disease from celiac or not, but when it comes to how do

we end up diagnosing them. For a long time, biopsy was considered the gold standard, and that's really to look for those specific types of damage in the small intestine that we see associated with celiac, both like visually and histologically. Because biopsy is invasive and not available to everyone and expensive and time consuming and all these things, especially for children, people are kind of moving away from biopsy, though it is still kind of like, especially if the diagnosis is

in question. One of the important parts of a diagnosis. But there are other tests that are getting better and better as our technologies develop. That are zero logic tests, so looking just in your blood for antibodies against TTG, so specifically ttgiga, and those are antibodies that you make primarily in your mucosa, So these are the antibodies that your guts are making against this TTG enzyme. And then there are few other types of enzymes that we can

test for antibodies against as well. None of these are one hundred percent perfect in diagnosis, and a lot of times they rely on thresholds of like how high the tighter is of these antibodies to be able to make

a definitive diagnosis. One of the challenges with all of the types of testing that we have for diagnosis, including biopsy, is that if someone is already adherent to a gluten free diet, you can't diagnose coeliac disease because you're going to have healing of the damage and a reduction in these TDG antibodies, So a negative test doesn't rule out

coeliac disease. If someone is already on a gluten free diet, they actually have to be exposed to gluten for these tests to be accurate, if that makes sense.

that we have is a gluten free diet. The majority of people, and some studies say like up to ninety five percent some studies say even higher than that, will have a complete or near complete resolution of their symptoms of coeliac as a result of a very strict gluten free diet. But only about forty percent of people have complete healing of their mucosa. When you go back and do another biopsy. What are the characteristics that are going

to determine that. I don't know. It's a really good question, but it's something important because a lack of complete healing like this continued inflammation in your small intestine can put people with celiac disease at risk for certain cancers, especially like lymphomas T cell lymphomas, because it is your T cells that are primarily being activated it as part of this immune process. But it can also put people at higher risk of things like osteoporosis and hip fractures over time,

even if they are very adherent to that gluten free diet. Okay, yeah, yeah, so that I mean that is coeliac disease in a nutshell.

coeliac disease specifically. There are at least two other entities that I think, in like common parlance, get conflated with celiac disease, and that is wheat allergy, which is something totally separate, and non seliac gluten sensitivity, which is kind of a nebulous term that I'll talk a little bit about. Wheat allergies are an allergy, and I cannot wait to do allergies on this podcast. But allergies are IgE mediated, so these are antibody mediated responses to an environmental exposure.

They are not autoimmune disorders, so there's no formation of antibodies that are attacking yourself in an allergy. There's the rapid onset and release of antibodies that are pre formed against the environmental exposure. In this case, specific and separate gliodin proteins that are present in wheat that trigger an over active hypersensitivity response. So that is like a totally separate thing. And like specific to gliadin proteins that are

present in wheat. And there's a lot of really interesting things about allergies, especially like that are different as it relates to coeliac disease, like exposure when you're young, and the development of disease for allergies versus coeliac disease that I think highlight that allergies are separate from autoimmune diseases, if that makes sense.

bad cramping, abdominal pain. And sometimes with noncoliac gluten sensitivity, we can see other non specific intestinal symptoms that tend to start hours to days after eating food with wheat or gluten or like from rye or barley, and tend to get better when gluten is eliminated from the diet.

But in nonciliac gluten sensitivity. In people who have this disorder, there are no identifiable auto antibodies, and endoscoped does not reveal damage to the small intestine, and so this is considered something that we essentially don't have any markers for, and so it's often grouped under the larger classification of kind of functional bowel disorders that are very real in terms of the symptoms that people are having and experiencing, and sometimes people can identify, for example, gluten as a

trigger for them. Sometimes people also when nonciliac gluten sensitivity, do better when they have what's called a low FODMAP diet. And that's a whole beast that we don't have time to get into. But I suspect that someday a lot of these diagnoses that are now under these big umbrella terms are going to be separated out into multiple different syndromes that have different potential causes, if that makes sense.

not good yep uh. Probably that's putting it mildly. And while it can be incredibly challenging to find gluten free options in some parts of the world or to ensure that no trace of gluten is in your food, you know, thinking about like having dinner at a friend's house and maybe they don't know that soy sauce has gluten, which like, there are so many things, so much have gluten. That's

like why does it? But like there are so many kind of random things like rice crispies have gluten apparently, huh how so apparently like the packaged rice crispies are not gluten free because they have a malt flavoring. Wow, so and so many things have malt in them. Like it's there's just a lot that gluten free is not, like, oh, don't eat bread and pasta. It's right, so much more than that, yeah, but yeah, and then like you're traveling

all of these things. But in theory, depending on where you live, many people with Celiac disease can get a decent handle on their symptoms by avoiding gluten right and I know that that can be really difficult, depending on where you live, depending on you know, a lot of the times it's difficult, it's more expensive to eat a gluten free diet, all of these things. But as restrictive and difficult as this diet can be, coeliac disease is fairly unique, I would say among autoimmune diseases for this,

for having this relatively straightforward way to manage symptoms. It's like, we know the problem, we pretty much know the mechanism, we know what's making you sick, and we can do something about it. And again, I know this is a general rule. I know that there are exceptions and that a gluten free diet is not a breeze. But having this option, or even knowing that this option exists, is actually pretty recent in the history of celiac disease.

a minute. And although there has been some discussion of rates of celiac disease increasing, and the evidence is mixed, like the rise in prevalence could be attributed to better diagnostics and general awareness, although there is some sig congestion that the more recently developed wheat strains may contribute to have like different types of gluten or more immunologically sensitive or triggering types of more iminogenic yeah, immunogenic. Yeah, there

we go again. It's not clear. But in any case, celiac disease is certainly not a modern disease, and it has been present for thousands of years of human history since grain farming began, because like, celiac disease probably didn't begin before grain farming, because there would have been no trigger for.

even fatal consequences if left unmanaged. And yet for thousands of years, people didn't apparently know that it was gluten that led to their symptoms, And therein lies a mystery, an evolutionary paradox as I've seen it described. What do I mean by that? Like, what's the paradox? The paradox is that coeliac disease is common in populations that have a long history, again talking thousands of years of farming

wheat and other grains containing gluten, like Ryan Barley. Given the potentially severe outcomes of unmanaged coeliac disease malnutrition, reduced fertility, even early death, and the fact that Celiac disease is highly heritable, meaning that it runs in families, you might expect that as grain farming began more prominent beginning around ten to twelve thousand years ago, when the Neolithic Revolution began, coeliac disease would become less prevalent, as people with the

disease in areas where grain was a large part of the diet probably would have had fewer kids, They likely would have died younger, had more malnutrition, which would have made them more susceptible to infections, and since celiac is to a large degree heritable, that would all mean fewer opportunities for those HLA genes to be passed down.

But to me, it seems like a lot.

and processed foods stuff like that. That makes sense, Yeah, And I'm not sure if we know enough about ancient grains to make that comparison, or even if there was a difference, whether it would have been big enough to have an effect. Maybe it's a contributing factor. But we also know that people with Celiac disease in ancient times did get very sick. So, for instance, we have this quote from Aretaeus of Cappadocia from the second century CE.

This is the first known description of coeliac disease. Quote emaciated, an atrophied, pale, feeble, and incapable of performing any of his accustomed works. But if he attempts to walk, the limbs fail. The veins and the temples are prominent for owing to wasting. The temples are hollow, but also all over the body the veins are enlarged. Not only does the disease not digest properly, but it does not distribute

that portion which the digestion has commenced. It appears to me, therefore, to be an affection not only of digestion, but also of distribution. End quote. So he's like, you're not absorbing any food and you're not getting nutrients. That's kind of what I'm interpreting that is. So we've got that description, and then we've also got possible archaeological evidence. So there's a paper from twenty ten that describes the skeleton of a woman who died aged eighteen to twenty and lived

around two thousand years ago in southwestern Tuscany. The economy of the city where she lived was based on wheat and olives, and she seemed to come from a wealthy family given certain aspects of her tomb, like there was like gold and stuff like that, and this suggested to the authors, to the researchers that she would have had

a good amount of wheat in her diet. But despite the evident wealth, she died of malnutrition and her skeleton shows possible signs of Celiac disease like shortness, anemia, dental enamel hypoplasia, osteoporosis, and a deformity of the hip. And I'm not sure how conclusive the like, how vague those symptoms are, or how many other things they could possibly be,

but the authors suggest Celiac is a strong possibility. Okay, So that was a long winded way of saying that it's probably not that coeliac disease was mild or historically, or just that we eat more gluten these days. So onto the next hypothesis. Does having coeliac disease provide a health trade off? So, for instance, does it give added protection against certain infectious diseases? This has been suggested for

lots of autoimmune diseases like celiac. Essentially, the idea is that our immune systems evolved under much different circumstances than most of the world faces today, Where infectious diseases were

a constant threat and oftentimes a killer. Thanks to vaccines and antibiotics and public health, it's not so much the case these days, and as a result, without that persistent threat, our immune systems have become overreactive like hygiene highypothesis fi Yes, right, or a more specific example would be something like sickle

cell disease and malaria. So is it possible that celiac disease stuck around despite gluten because it helped fight off a more pressing threat like infectious disease, which was becoming in general more common during the Neolithic Revolution as population

size and density increased. Perhaps we don't fully know classic classic There isn't a whole lot of direct evidence that people with Celiac disease are more resistant to certain infections, but there does seem to be some association where the genes or alleles linked to celiac disease, like those MLA ones that you mentioned, are also involved in inflammation and general immune function. Yeah again, I know that's super vague, but it's hard to draw firm conclusions from these types

of studies. And remember, we are dealing with a decently complex disease involving multiple genes or even networks of genes. Yeah. Yeah, we know a good amount about the underlying genetics of Celiac disease, but we don't have the complete picture, especially when it comes to environmental factors, right, And like I.

is kind of a side effect of evolution. As one paper put it, essentially, since there are multiple genetic risk factors for Celiac disease, each one of those factors on its own might not be harmful, might not lead to symptoms of Celiac disease, And in fact, each of those on their own might be beneficial in immune function or something like that, And so it stuck around, it was selected for, it was maintained, and that could have been what happened for different parts of the Celiac disease like

genetic risk network. So those factors helpful on their own, so they stuck around, or maybe they were just kind of they're not helping, like not good enough to keep around, but not bad enough to like, you know, be selected against.

I guess, not helping, not harming neutral in any case, because of the way that Celiac disease is caused by this network of genetic risk factors, that means that Celiac disease as a whole may not have been selected for or against, but instead that evolution may have acted on the individual parts. Right, hence the idea that it's a side effect of evolution. Does that make sense?

It's not like it's not directly heritable like one to one, and like like I mentioned, like twenty to thirty percent of people have one or both of these various HLA types, and the vast majority of them, something like fifteen or so percent of people with high risk capitalotypes are in studies go on to develop Celiac disease, Like, that's not that high compared to everyone who has that h those haplotypes. So it's it's complicated.

or less. And the last hypothesis all throw out there is that what if the environmental trigger the big question mark remaining in Celiac divise if that has increased in frequency all the time. I again, we don't have we don't know enough about the rates of Celiac disease over millennia, but that is something that I think is a possibility. So yeah, hopefully that was still interesting enough that even though meaning even though I don't know was the punchline.

I'm pedantic, so I had to self correct. Probably other people wrote about it or recognized it, but their descriptions maybe their descriptions were lost to obscurity, or maybe they weren't precise or clear enough to gain traction, or it was people who were not in a position to be writing medical text that were noticing these links and just managing it on their own right. It's possible, but anyway, in terms of medical literature, entered doctor Samuel Jones Ghee in October eighteen eighty.

but watery, more bulky than the food taken. Would seem to account for pale in color as if devoid of bile, yeasty, frothy, and appearance probably due to fermentation, stinking stench, often very great, the food having undergone putrefaction rather than concoction end quote.

no light upon the nature of the coeliac affection. Nothing unnatural can be seen in the stomach, intestines, or other digestive organs. Whether atrophy of the glandular crips of the intestines be ever or always present, I cannot tell. End quote. But he did have a suspicion. Quote. If the patient can be cured at all, it must be by means of diet. End quote. Gee suggested, among other things, a diet consisting solely of muscles.

Over the first couple decades into the twentieth century, people continued to try to unravel the mystery of celiac disease and got so close to solving the puzzle, but ended up sad and frustrated like GF. Still, who was rightly convinced that it was a digestive disease due to diet,

and even recognized that quote. Unfortunately, one form of starch which seems particularly liable to aggravate the symptoms is bread end quote, something that even Aretaeus hinted at nearly two thousand years before, but did still try a bread free diet, not that I could tell.

demonstrated this link. In the winter of nineteen forty four to nineteen forty five, food shipments were blocked to the western part of the Netherlands by German forces, leading to a famine, affecting millions of people with ultimately around twenty

thousand deaths. Estimates vary. The availability of wheat and rye dropped to near nonexistent during this time, and one Dutch pediatrician, Willem Carl Dick, noticed that his patients with Celiac disease actually improved during the famine when they did not have access to wheat and rye, and then when Swedish plains dropped bread into the Netherlands to help relieve this food shortage,

those same kids experienced a relapse and got worse. And so Dick put two and two together and realized that it might be wheat and rye and barley that was causing the problem, and later showed that it was wheat flour and not wheat starch, ultimately pointing towards gluten as the causative factor. Yeah, but apparently so kind of when we're talking about, like, well, how did people not realize this?

Maybe they decided on an individual level. Apparently years before in nineteen thirty, Dick had a patient who's had coeliac disease whose mother told him that when she removed bread and biscuits from her kid's diet that they got better. So I feel like probably.

the other parts of the puzzle. Over the second half of the twentieth century, many of those parts were found or were put together by research teams all over the world. And I'm not going to go into the nitty gritty of the history of discovery of those but instead what I want to do is wrap up this history section and talk by talking very briefly about the gluten free tree friend that really took off around twenty ten or so. As with most health related things that make headlines or

become trendy. It's a mix of fact fiction and people wanting to make money. We should honestly do a full episode on the gluten free diet. It's not clear to me what initially propelled this gluten free diet to the wild popularity that it achieved. But around this time around you know, twenty tens or so, is when non celiac gluten sensitivity was finally recognized as a real thing by

much of the medical community. And following that, we're a bunch of articles and books that perhaps took this and ran with it a bit too much, overstating the extent to which a gluten free diet could improve the health of those who do not have a diagnosed gluten disease or sensitivity, saying things like, you know, eliminating gluten will make you live longer, it will improve your brain health, it'll improve of your relationships, it'll you know, like everything right, everything,

And it's what we see with so many diet fads. It's what we see with so much health trends, like it's a constant.

points because first, so here are the fair points. First, there have been studies that show that people who do not have gluten intolerance or sensitivity can experience nutritional deficiencies with this restricted diet, like it can actually impact your health negatively if you do not have gluten sensitivities or intolerance. And secondly, it has led to the spread of or unsupported pseudoscientific claims about the link between gluten and overall health,

again for people without diagnosed gluten disorders. The spread of those claims and sort of this like, oh, well, this one trick. You know, doctors hate this one trick.

be the issue part of the issue for you. Secondly, a gluten free diet does bring about huge health improvements for those who can't eat gluten necessary, like it is absolutely necessary. And Thirdly, it has done a great deal to raise awareness I think of gluten intolerance and sensitivity, and it has led to increased availability of so many more gluten free products which prior to twenty ten were

not nearly as numerous. And again with the caveat that this is not globally, this is in certain regions of the world. But I do think that that raising the awareness and we still have a long way to go, you know, just the fact that, like when I was researching this, there are so many products that have gluten that I'm like, but why does it have to have gluten?

in the twenty tens. Coeliac disease, which has in many people's minds been conflated with other forms of gluten sensitivity, has this perception that it's only a disease of like the Western world or something, and that's not true at all. The overall pooled global prevalence of coeliac disease is estimated at around one point four percent. That's like most paper site around that number. There's a little bit of variation, and it's hopefully not surprising that there is estimated to

be some variation of this across the world. Prevalence is estimated, surprising to me, to be a little bit higher in Asia at about one point eight percent, and a little bit lower to about the same as the global prevalence in South America at one point three percent, and then the European and North American prevalence, as far as I can tell, is about equivalent to the global prevalence of

one point four percent. Okay, I also want to say, and this is what's fascinating to me when I read this, because I still don't quite understand how the first time, and I think six seasons of making this podcast. The main paper that I read for these epidemiology numbers said that they thought that these numbers, this one point four percent, could be an overestimate. What I know, right, I've never seen overestimate.

So who knows. It's somewhere between point seven percent and one point four percent globally fascinating. But one thing that is consistent across all of the studies and in all the geographic regions, and you mentioned this, aaron incidence does seem to be increasing over time. This one paper from just a couple of years ago estimated that the pooled incidence worldwide is increasing like seven percent per year, So that doesn't mean like seven percent globally, It just means

like compared to each year. And because celiac is a chronic disease, there's no cure for it, an increase in incidence necessary really means an increase in prevalence. So we have new cases being diagnosed and therefore more people are living with coeliac every year. Does that mean that the true number of people who are developing celiac is increasing? We don't know, because it could just be that we are getting a lot better at diagnosing and recognizing coeliac disease.

But at this point we don't have enough data to necessarily disentangle. Are the rates of disease truly going up or are we just better at detecting it and so we are seeing an increase in rates because of this increase in detection wit or not. Yeah, But what is still true today is that there is often a real delay in diagnosis, and hopefully with better and better diagnostic tools and more and more awareness, this delay kind of

decreases in time. I don't have perfect numbers on this, but there was a survey in Finland that reported at least a three year delay in diagnosis for about half of people living with coeliac disease, and three years compared to some other autoimmune disorders that we've talked about, might not seem that long. What was endometriosis like ten years, twelve?

I think it's gone down in recent years. Yeah, Yeah, But three years of not absorbing your nutrients, three years of worsening anemia and osteoporosis like that, that's a very long time, especially because a lot of people do develop symptoms of coeliac disease when they are kids, like underage ten, which means that you have kids that are not growing, that are failing to thrive, and that are having delays

in their diagnosis. And adults too, because really a lot of people don't develop symptoms of celiac until they're adults, so it kind of is both ends of the spectrum,

which is really interesting. Yeah, in terms of the pathways forward for coeliac disease, there of course is a lot of research being done on what other factors might be in terms of triggers and how we prevent celiac disease, But one of the biggest areas of research is in therapeutics and specifically in trying to find therapies that don't require a strict gluten free diet, because while a gluten free diet might be easier to achieve today or easier

for some people that for others, there's really nothing easy about it. Like wheat is present globally in so much even if you don't consider that, it's also hidden present in so many of our standard American foods and in

packaged foods. Right, So not only is it expensive and difficult to stick to it, but also can be socially stigmatizing and like we heard in our first hand account, it can lead to these unintentional difficulties in terms of people's relationship with food, yes, and with Celiac disease especial, even unintentional really small amounts of gluten can trigger severe disease relapse. So there's a lot of interest, understandably in

developing other therapy options. As of today, twenty twenty four, there's nothing that's like out there, there's nothing available, But there are a few big buckets of research that I wanted to just kind of highlight that people are looking at in terms of different strategies. So one is what's called like tolerance induction strategies, and so this is exposures in various ways that try and trick the body into developing essentially tolerance to gluten rather than having this really

strong reactivity. There's various types of exposures and exposure to certain proteins and things like that that people are trying. We don't have anything yet, but that's an idea. Another idea is using gluten degradation think like LACTASEE for gluten. Yeah, using these gluten aces, okay, so that people can break down the gluten more efficiently to therefore expose it in the same way to your T cells and not trigger

this inflammatory response. So that's another option. Another really interesting idea is inhibiting that TTG, so inhibiting the tissue transglutaminase enzyme, which then prevents the activation of those T cells and reduces your inflammation because you're reducing the autoantibody formation essentially. And finally, monoclonal antibodies, which more generally are targeting like cytokine and inflammatory responses that coeliac triggers rather than like

specifics of coeliac or gluten itself. If that makes sense. There's lots of different options out there. None of them exist for humans today. There's a lot of them that are in either preclinical or in some cases like phase one and two clinical trials, So they're moving through the process. And I think that in the future, like in the next few years, we will likely see some of these come to market and it'll be really interest to see who gets access to them and how much they end

up helping people. Yeah, so that is coeliac disease today, Aaron.

in Humans. Then for the history Pavely from nineteen eighty eight, From Aretaeus to Crosby, A History of Celiac Disease, and then about the gluten free diet by Newberry at All from twenty seventeen, Going Gluten Free The History and Nutritional Implications of Today's most popular diet.

Another paper by someone that I have worked with in gastro andrology here in San Diego, which was really exciting to see the fame of someone you know. They don't know me, but anyways, that was Celiac disease from the Annals of Internal Medicine from twenty twenty. We have so many more papers from this episode and all of our episodes on our website this podcast will Kill You dot com under the episodes tab.