Gluten proteins can transiently cause leaky gut in everybody. This is not a per-person experience — this is a known reaction. The gliadin protein binds a receptor in the gut lining called the CXCR3 receptor, which triggers the release of a protein called zonulin. It opens the gut barrier, like pushing on a turnstile to go through the subway. And as zonulin levels increase, you get greater degrees of leaky gut. And of course, the more frequently you eat gluten, the longer it persists, because you're constantly producing higher and higher amounts of zonulin.
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In November of last year, one of the biggest medical journals on the planet published a review that said something a lot of people in the gluten-free world didn't want to hear: most people who believe they're reacting to gluten, in properly controlled trials, react to gluten about the same as they react to a placebo or a sugar pill.
Now, before you go throwing out your gluten-free bread and going back on a gluten diet, stick with me — because that same body of research, and a stack of other studies from the last year, also confirms that plenty of gluten reactivity is completely real. It's measurable, it's mechanistic, and in some cases tangled up with your gut lining, your thyroid, and even blood flow to your brain.
The honest answer here isn't simply that gluten is poison, and it certainly isn't that gluten sensitivity is completely fake. It's a little bit messier than either extreme, and today we're going to sort through all of that.
Whenever I take on a personal coaching client, the first thing we do clinically is a diet review, and I get asked about gluten more than almost any other food-related topic. I have patients who are convinced that gluten is slowly destroying them, and I have patients convinced that cutting it out is a waste of a perfectly good donut. Sometimes both of those people are right, to be honest — and sometimes both are wrong. The only way to actually know which one you are is to understand what's happening in your body when you eat a piece of bread, not what an influencer or some elimination diet tells you should happen.
So here's where we're headed today. We're going to define what gluten actually is, because most people avoiding it couldn't really tell you. We're going to separate a true wheat allergy from a gluten sensitivity, because those are not the same condition wearing two different names. And we're going to draw a real line between celiac disease and non-celiac gluten (or wheat) sensitivity. Then we're going to dive into the last 12 months of research — what's new on gluten and your gut lining, blood flow to your brain, and gluten's contested relationship with Hashimoto's disease in your thyroid. And we'll finish up talking about the tools we can use to test for this properly, instead of guessing your way through elimination diets or a Google search.
Before we go any further, let's answer the question most gluten-avoidant people can't actually answer: what is gluten? Gluten isn't one thing. It's a family of storage proteins found in wheat, barley, and rye, and a few lesser-known grains. These wheat proteins are broken down into two subclasses — gluten proteins and non-gluten proteins — and about 70% of the proteins found in wheat are classified as gluten proteins. That category is broken down further into two subclasses: gliadin and glutenin.
When you mix flour with water and start kneading it, like you're making bread, gliadin and glutenin link up into a stretchy, elastic network. That network is what traps gas bubbles from yeast and gives bread its chewy texture and structure. If there's no gluten, there's no stretch. If you've ever made gluten-free products — especially in the old days, before all the new products came onto the market — you'd know gluten-free bread didn't rise, didn't stretch, didn't have the same mouthfeel. It was kind of a miserable place to be. That's why gluten-free baking is its own science project: you're trying to rebuild the scaffolding normally supplied by gliadin and glutenin with different materials.
And gliadin itself is broken down further into alpha-gliadin, gamma-gliadin, and omega-gliadin. For many decades, the only point of concern for medical doctors was the part of gliadin associated with celiac disease — the alpha-gliadin portion. So when somebody says "gluten," they probably mean one thing in their head, but the clinical and scientific reality is that gluten is a whole family of different proteins, and each of those proteins has its own subtypes.
Celiac disease was actually first described in antiquity, somewhere around the first or second century A.D., by the Greek physician Aretaeus of Cappadocia — but it wasn't until 1888 that Samuel Gee named it celiac disease. The word "celiac" is just a Latin word referring to the abdomen. But the trigger for celiac disease wasn't identified until a man named Willem Dicke, who worked with children who had celiac disease in the Netherlands during World War II, noticed something peculiar about his patients.
During the war, food — wheat particularly — was rationed and in short supply for the general population. Dicke noticed that during this period, the kids he worked with actually got better. Then, when the war was over and wheat became a staple again, their celiac disease got worse. Shortly after, scientists isolated the alpha-gliadin subtype of gluten that actually causes celiac disease.
That discovery dominated gluten-related research for decades. The focus was so hyper-focused on the alpha-gliadin portion alone that the other types of gliadin, and even glutenin, were largely ignored as potential causes of wheat-related complaints. So much so that even today, many conventional doctors only test for celiac disease — and in their minds, if you don't have celiac, you should be fine with gluten. That's not necessarily true.
We've known for a couple of decades now — and it seems like only those in the functional medicine space really understand this — that gluten reactions don't have to manifest as celiac disease. Celiac is only one part of the entire spectrum of what we call gluten reactivity.
I mentioned in the last episode that it takes about 17 years, on average, for information to trickle down from research to clinical practice, so that your doctor knows it too. Gluten was understood to be made of gliadin and glutenin in the early 1900s, and the distinction between the gliadin subtypes — alpha, gamma, and omega — was made by the 1980s. But it wasn't until 2011 that the medical establishment coined the phrase "non-celiac gluten sensitivity" for people who reacted to gluten but didn't have celiac disease. That's about 30 years from research to formal medical recognition.
Since then, researchers have discovered a handful of non-gluten proteins in wheat and other grains that can cause the same complaints — but that will be missed entirely by a conventional gluten sensitivity test. That discovery led to the replacement of "non-celiac gluten sensitivity" with the broader term "non-celiac wheat sensitivity," because unless you run state-of-the-art gluten testing — like I do in my practice — it's anybody's guess why someone has a problem with wheat.
Among those non-gluten wheat proteins that can cause immune reactions, the research says whether someone reacts or not is dependent on the person. We can't say everyone in the world is gluten sensitive, and we can't say everyone in the world is sensitive to non-gluten wheat proteins either. But here are two universals you can trust.
The first: gluten proteins can transiently cause leaky gut in everybody. This is not a per-person experience — it's a known reaction, due to the nature of the gluten protein itself, specifically the subtype called gliadin. The gliadin protein binds a receptor in the gut lining called the CXCR3 receptor, which triggers the release of a protein called zonulin. If you've listened to any of the leaky gut content out there over the last few years, you've probably heard about zonulin — it's a protein that, when your gut releases it, opens the gut barrier, like pushing on a turnstile to go through the subway. As zonulin levels increase, you get greater degrees of leaky gut. And the more frequently you eat gluten, the longer it persists, because you're constantly producing higher amounts of zonulin, which continues to promote a transient leaky gut. This connection between gluten and leaky gut does not require you to be gluten sensitive. No matter who you are — sensitive or not — when you eat gluten, you get a transient leaky gut. That's universal number one.
The second universal comes from the non-gluten protein side of wheat. On that side, there are several other non-gluten wheat proteins that act like gluten, in that some people react and some don't. But there's also a family of proteins called amylase trypsin inhibitors, or ATIs for short — and this is the second universal that doesn't depend on the person or on whether or not you're gluten sensitive.
ATIs do one thing we don't want, and it can get complicated quickly, so let me simplify: ATIs bind to what's called the TLR4 receptor — toll-like receptor 4 — part of your innate immune system's cell-signaling network. ATIs bind to TLR4 on certain innate immune cells, and these are the same cells, producing the same chemical response, that your immune system generates when it reacts to LPS (lipopolysaccharide) toxin from bad bacteria in your gut.
The net effect: this triggers its own inflammation. Worse, it amplifies any pre-existing inflammation already present in your gut. Second, it remodels your microbiome in an unfavorable way. And finally — just like gluten causes zonulin release and a transient leaky gut — so do these toll-like receptors that ATIs bind to. So when you eat wheat, even if you're not gluten-sensitive, you can count on two universal responses: a transient leaky gut, and a greater inflammatory load in your gut that may go systemic.
Let me cover one more concept — and I think what I'll end up doing is breaking this episode into two shorter ones, because otherwise we'll be here for a couple of hours. I've already used the term "gluten sensitivity" several times, but I want to help you understand the difference between sensitivity, allergy, and intolerance.
Let's clear up the most common mix-up first: a wheat allergy and a gluten sensitivity are not the same disease with two names. They're two different branches of your immune system doing two different jobs. And an intolerance isn't an immune response at all — it's usually an enzyme deficiency. The classic example is lactose intolerance.
With lactose intolerance, someone lacks the enzyme lactase, which breaks down the sugar (lactose) found in dairy products. If someone can't break down lactose, eating dairy leads to bloating, distention, pain, and osmotic diarrhea — what we jokingly call "disaster pants." So remember: an intolerance is not just another word for sensitivity or allergy.
People say "I'm gluten intolerant" all the time, and that's really incorrect terminology — sensitivity and allergy aren't the same either, even though they're both immune reactions. Let me say it one more time, clearly: an intolerance is not an allergy, and it's not a sensitivity. Sensitivity and allergy are two different things, but they're both immune responses — they just use two different branches of the immune system. One uses the IgE branch, and the other uses the IgG branch.
A true wheat allergy is mediated by an E-type immunoglobulin — IgE, for short. In this case, your immune system flags a wheat protein as dangerous. It arms your mast cells with IgE antibodies specific to that wheat protein, and the next time wheat shows up, those mast cells dump histamine within minutes. That typically leads to hives, itching, swelling, and wheezing — and in the worst cases, like with peanuts or shellfish, anaphylaxis, requiring a shot of epinephrine. It's fast, it's dramatic, and it's confirmed with a skin-prick test or a blood panel measuring IgE response — it either lights up or it doesn't. Same culprit, completely different crime scene.
Gluten sensitivity doesn't work that way at all — it's a different branch of the immune system. There's no confirmed IgE mechanism (that's an allergy), no mast cell explosion, no massive histamine release. What you get with a sensitivity response is a much slower, murkier immune and gut response: bloating, fatigue, brain fog, joint pain — and all of these can show up hours later, instead of within minutes.
Allergies, by definition, are immediate-onset responses that always show up the same way, regardless of the person — they're reproducible, and the same from person to person to person. A sensitivity, which comes from the IgG branch, is a delayed-onset reaction that's entirely person-dependent. If two people are allergic to peanuts or shrimp and eat the same thing, they both get the same hives, itching, and wheezing. But if two people are sensitive to gluten and eat it, one might get gut symptoms, another might get fatigue and brain fog, and a third might get joint pain or feel depressed.
In other words, allergy symptoms are universal from person to person regardless of the food, and sensitivities are tied to the individual's own response — because they invoke two different parts of the immune system. Think of it like the difference between a smoke alarm and a slow gas leak. The smoke alarm — the allergy — goes off the instant there's a problem. It's loud and unmistakable, and everybody in the house knows exactly what triggered it. The gas leak — the sensitivity — has no alarm at all. You just start feeling a little worse every day, and it takes real investigation to figure out where it's coming from, because nothing obvious set it off.
That distinction changes how you test and how you treat — and I'll save that for Part 2 of this episode, where I'll help you understand the differences between celiac disease and gluten sensitivity. As a teaser: everyone who has celiac disease is gluten-sensitive, but you can be gluten-sensitive without having celiac. In Part 2, we'll also go over what the research says about how gluten can — or can't — cross-react with your thyroid, especially important if you have a family or personal history of Hashimoto's, and how, for some people, eating gluten changes blood flow to the brain, and not in a good way.
I'm going to cut it here. Thanks for listening — and if you want help sorting this out one-on-one, you can reach out with the contact information in the episode description. See you next time for Part 2 on the Inflammation Nation.
