RHR: Is Non-Celiac Gluten Intolerance Real?

In this episode, we discuss:

• The difference between celiac disease and non-celiac gluten sensitivity
• What the science really says about wheat and gluten intolerance 
• Diagnostic criteria that have been established over recent years for non-celiac wheat sensitivity
• Why conventional testing is limited in its scope, leaving sensitivity to gluten and wheat underdiagnosed
• How to test whether you’re sensitive to wheat, gluten, or both

Show notes:

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Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. In this show, we’re going to talk about non-celiac gluten sensitivity and discuss whether it’s a real condition or [if] it just exists in the minds of people who claim to be gluten intolerant. That’s, indeed, the impression that you get if you follow the mainstream media on this topic or talk to your primary care doctor about it.

I’ve found, from talking to patients [who] come [to] see me in the clinic, [that there’s still a common impression] that gluten intolerance is imaginary and the only condition that [actually exists] when it comes to gluten is celiac disease. If you are one of [the] people [who] suffers from gluten intolerance and you don’t have celiac disease, you know exactly what I’m talking about. You may have been ridiculed or criticized by people in your family, your friends, or on social media. As I think you’ll come to understand by the end of this show, that’s not only unfair, [but] it’s [also] completely out of alignment with the current scientific evidence base. We’re going to review some of the studies that support non-celiac wheat sensitivity, which [is what] I’ll refer to [non-celiac gluten sensitivity] as in this show, because it turns out that people can be sensitive to multiple proteins within wheat, not just gluten, which is only one of those proteins. The recent statistics that we have suggest that this condition affects up to 18 million Americans, or about 5 percent of the population. So we’re not talking about something that affects a small handful of people. This is something that affects a large number of people, and the impact can be significant, equaling, or, in some cases, even surpassing, the impact that celiac disease can have.

In this podcast, I’m going to share research on non-celiac wheat sensitivity and, I hope, show you convincingly that it most definitely does exist, and it contributes to a shockingly diverse range of conditions, from depression to schizophrenia, epilepsy, type 1 diabetes, osteoporosis, dermatitis and psoriasis, Hashimoto’s [disease], hypothyroidism, [and] peripheral neuropathy. Ready? Let’s dive in.

Celiac Disease vs. Non-Celiac Wheat Sensitivity

Celiac disease and non-celiac wheat sensitivity are two distinct conditions with a few major differences. Celiac [disease] is an autoimmune disease characterized by an inflammatory immune response to wheat, rye, barley, and other gluten-containing proteins. It results in a significant disruption of the normal structure of the tissue in the gut, including atrophy of epithelial cell projections called villi, and an enlargement of intestinal crypts where new epithelial cells form from stem cells. Celiac disease is strongly associated with the genetic haplotypes DQ2 and DQ8 of the [human leukocyte antigen] (HLA) gene. There is a very strong genetic predisposition and heritable quality [to] celiac disease. In terms of blood biomarkers, the transglutaminase-2 (tTG2) autoantibody is considered the most sensitive marker for celiac disease. But that testing is not perfect and can be problematic, as we’ll discuss later on.

Non-celiac wheat sensitivity, on the other hand, is a term that’s applied to people who experience symptoms in response to eating wheat or gluten, but who lack the characteristic markers of celiac disease. The list of signs and symptoms can be incredibly broad, ranging from [gastrointestinal] (GI) discomfort to fatigue, neurological issues, skin rashes, [and] even paralysis, in some cases, although temporary. These people tend to improve on a gluten-free diet, but, as I said in the introduction, they’re often mocked or ridiculed for avoiding wheat and gluten and told that their sensitivity is all in their head. In response to claims that have been made over the last few years, I’ve written several articles on non-celiac wheat sensitivity on my blog, and I will link to those in the show notes. If you want to check them out, you can head over to my website, but the gist is that non-celiac wheat sensitivity is indeed a real condition. It’s supported by numerous studies in scientific literature, and it can, like I said just now, be as serious or even more serious than celiac disease, in some cases.

You’ll find that those who claim that gluten sensitivity isn’t real often cite a study that attributed any negative reactions that people experience to gluten to [fermentable oligosaccharides, disaccharides, monosaccharides, and polyols] (FODMAPs). This is a class of compounds, most of them complex, long-chain carbohydrates, that people with digestive issues have trouble breaking down. The low-FODMAP diet is often used in that context for people with [irritable bowel syndrome] (IBS) or other GI problems to help reduce symptoms. There have been a couple of studies [which] have shown that some people who thought they were gluten intolerant actually had FODMAP intolerance. When they were given purified gluten in a capsule, outside of the typical foods that [contain] gluten [and] are also high-FODMAP, they didn’t have any reaction. Whereas, when they [ate] high-FODMAP foods, they did have a reaction. And I don’t doubt that’s true for some people. I see FODMAP intolerance a lot in my practice. A lot of people with digestive issues can’t tolerate FODMAPs. Again, I think it’s at least plausible that some people who believe they [are] gluten intolerant are actually FODMAP intolerant.

Studies Supporting Non-Celiac Wheat Sensitivity

However, there have been a few studies done since then, which I think are a better way of getting at the question of non-celiac wheat sensitivity. Even with that one particular study, the researchers chose whey protein for people in the control group, which is a terrible choice, considering that many of their subjects likely had inflamed guts and multiple food sensitivities, including dairy products. I don’t think [it] was a well-designed study, and I [certainly] don’t think it answered the question definitively. A much better study was published a few years ago in BMJ Gut. Researchers at Columbia University Medical Center enrolled 80 people with self-reported gluten intolerance, 40 people with celiac disease, and 40 healthy controls who [had no] known response to gluten. The patients with gluten intolerance were excluded if they showed any of the characteristic diagnostic markers of celiac disease, like alpha-gliadin antibodies, tTG2 antibodies, or any history of celiac-like structural changes in the gut. They wanted to have a clean sample of people who claimed to be gluten intolerant but had no evidence or history of celiac disease.

They took blood samples and intestinal biopsies from all of the people in this study. The blood samples were used to look for particular signaling molecules and proteins in the blood, while the biopsies were used for tissue analysis in the gut. In addition to comparing those measures between the different groups, they also took a subset of 20 patients with gluten intolerance who had adhered to a strict gluten-free diet for six months and compared their blood and tissue samples before and after gluten avoidance. What did they find? Well, non-celiac wheat-sensitive individuals had leaky gut. Big surprise. They showed increased intestinal permeability when compared to healthy subjects. That shouldn’t be a surprise because we know that gliadin, which is a component of gluten, can affect tight junction proteins that help regulate intestinal permeability. In addition, subjects in the non-celiac wheat sensitivity group had evidence of systemic immune activation. Their blood levels of lipopolysaccharide-binding protein and sCD14 were significantly elevated in comparison with people who had celiac disease [or] healthy controls. Those are sensitive markers of microbial translocation, which means [that] bacteria that should stay in the gut [were] leaking into the bloodstream and inducing a low-grade chronic inflammatory response. Analysis of the tissue biopsy showed that the non-celiac wheat sensitivity group also had epithelial cell damage similar to the celiac disease group, which was supported by elevated levels of a marker called [fatty acid-binding protein 2] (FABP2). In the subset of non-celiac wheat-sensitive individuals [who] were analyzed before they started their gluten-free diet, they found that inflammation and cell damage markers improved significantly after six months of gluten avoidance. This was a much more carefully designed study, as you can see, and I think it pretty conclusively proves the existence of non-celiac wheat sensitivity as a condition.

Diagnostic Criteria for Non-Celiac Wheat Sensitivity

As the research has progressed over the past few years, there have been some diagnostic criteria established for non-celiac wheat sensitivity, [including whether] eating gluten provokes a rapid occurrence of intestinal and extraintestinal symptoms. “Extraintestinal” means outside of the gut, so some of the things we talked about before—brain-related issues [like] anxiety, depression, [or] cognitive dysfunction, skin [issues] like eczema or psoriasis, hormone imbalance, changes in blood sugar, [or] anemia. We’ll talk a little more about some of the other conditions that gluten intolerance can provoke in a little bit, but one thing I would add to this is that the reaction is not always rapid, in my experience. Often, [it] is, but it can [also] be delayed by a few hours, or even a day, in some people. And that can make it more difficult to identify [the] problem. [Let’s say] someone eats gluten for lunch one day and they don’t notice a significant response right after, [or] even that evening. But the next day, they feel terrible. They might not trace it back to the gluten they ate at lunchtime the day before.

It’s becoming clear that celiac disease is only one manifestation of gluten intolerance, and that non-celiac gluten sensitivity is a legitimate health condition. Tune into this episode to learn more about gluten intolerance and the shockingly diverse range of conditions it can contribute to. #chriskresser #glutenintolerance #celiac #NCGS

The next [criterion] is that symptoms disappear or are greatly relieved when gluten is removed from the diet, and recur if gluten is reintroduced. Wheat allergy has been ruled out. An allergy is different [from] an intolerance. That’s mediated by a different part of the immune system and can be easily tested for [by] any immunologist or clinician [who] focuses on food allergies. It’s good to rule out an [immunoglobulin E] (IgE)-mediated wheat allergy, and also good to get the basic celiac disease testing, even though it’s not perfect, to rule out celiac disease. Intestinal mucosa is normal, so no atrophy or blunting of the intestinal villi. That’s part of the standard workup for celiac disease. With non-celiac wheat sensitivities, about 50 percent of the time, you’ll see antibodies to gliadin, but 50 percent of the time, you won’t. It’s really just a coin flip. A negative result, and this is really important to understand, with this conventional test does not mean that you don’t have the condition. Likewise, with the genetic markers HLA-DQ2 or HLA-DQ8, only about 40 percent of the time those are positive. The majority of the time, they’re negative, so those are not very useful diagnostic markers, either.

Why Gluten Intolerance Is Likely More Common Than We Think

One of the biggest issues here, as I’ve alluded to, is that the conventional testing is really poor. In order to explain why, I have to give you a quick lesson in [the] biochemistry of wheat and wheat digestion. I’ll try to make it as brief as possible. Wheat contains several different classes of protein. You hear a lot about gluten, but wheat is a complex plant and has many different proteins in it, [including] gliadin, which is the scientific name for gluten, and glutenin. That’s very confusing. That’s spelled g-l-u-t-e-n-i-n. It’s not gluten. It’s a different protein called glutenin. Those are the two main components of the gluten fraction of the wheat seed. You have gliadin and glutenins. Incidentally, these are essential for giving bread the ability to rise properly during baking, and it explains why you’ve probably never had a good gluten-free croissant. Gluten is pretty amazing in that regard, and the components of gluten that are responsible for this are the gliadins and the glutenins. Within the gliadin class, there are four different epitopes of gliadin. There’s alpha-gliadin, beta-gliadin, gamma-[gliadin], and omega-gliadin. Then wheat contains proteins called glutenins that bind to sugar and prodynorphins, which are proteins involved with cellular communication. Once wheat is consumed, enzymes in the digestive tract called transglutaminases help break down that wheat compound, and, in that process, additional proteins are formed, including deamidated gliadin and gliadorphins, which are sometimes called gluteomorphins.

Here’s the crucial thing to understand. Celiac disease is characterized by an immune response to one specific epitope of gliadin, alpha-gliadin, and one specific type of transglutaminase enzyme, which is tTG2. But we now know that people can and do react to the other components of wheat and gluten, including the other three epitopes of gliadin (beta, gamma, and omega), the gluten in part of the wheat protein (wheat germ agglutinin), deamidated gliadin, as well as the other types of transglutaminase enzymes, including type 3, which is primarily found in the skin, and type 6, which is primarily found in the brain. An example of how this might play out is that, in the more comprehensive testing that I do with patients, I might screen somebody for wheat and gluten intolerance, and they might test positive for beta- and gamma-gliadin antibodies, and then maybe wheat germ agglutinin, and maybe transglutaminase-3. I could predict, based on the particular enzyme they’re reacting to, transglutaminase-3 in this case, that their response to gluten is going to manifest primarily in the skin because that’s where that enzyme is found. But [if] this person were to go get a conventional test for gluten intolerance, [they] would be completely missed and misdiagnosed as having no response because that conventional test only looks at antibodies to alpha-gliadin and transglutaminase-2. If you’re reacting to any of the other fractions of the wheat protein or any other type of transglutaminase, you’re going to test negative, and you’ll be told that you don’t have an issue with gluten. I can’t tell you how many times I’ve seen that in my practice over 15 years. Probably over 100 times because I test almost all patients for non-celiac wheat sensitivity, and many of them had already had previous tests that were mislabeled as being normal.

Another reason non-celiac wheat sensitivity continues to be underdiagnosed is because of the shockingly diverse range of problems it can cause. Gluten intolerance can affect nearly every tissue in the body, including the brain, skin, endocrine system, stomach, liver, blood vessels, smooth muscles, and even the nucleus of cells. As I said earlier, it’s associated with an astonishing variety of diseases from schizophrenia to epilepsy, type 1 diabetes, osteoporosis, skin conditions, Hashimoto’s [disease], hypothyroidism, [and] peripheral neuropathy. Because the range of symptoms associated with gluten intolerance is so broad and nonspecific, which means it could potentially be attributed to any number of conditions, many patients and doctors don’t even suspect that gluten may be the cause of a particular problem, especially if the patient doesn’t present with the classic GI symptoms that many people assume must be present if someone has gluten intolerance. Let me give you a few specific examples. You get an annual physical from your doctor, and [they discover] you have anemia. [They’ll] likely prescribe an iron supplement or, if you’re a female, ask you questions about your menstrual cycle. However, iron deficiency anemia is well-documented as a symptom of gluten intolerance in scientific studies. In fact, research suggests that it may often be the first noticeable symptom of celiac disease and that up to 75 percent of those with an anemia diagnosis may be gluten intolerant. Gluten intolerance can interfere with the uptake of iron from food, which causes malabsorption of iron and can lead to anemia.

Or let’s say you visit your doctor complaining of a headache. It’s highly unlikely [they’ll] test you for gluten intolerance, which is unfortunate because headache is a frequent finding in non-celiac wheat-sensitive patients, with one study reporting that symptom in more than half of the participants. That was especially true for people with migraines. Or maybe you visit your dermatologist complaining of eczema or psoriasis or another skin condition. There’s virtually no chance you’ll be tested for gluten intolerance. But, again, this is a mistake, because people with non-celiac wheat sensitivity can notice a worsening of skin symptoms like eczema, rash, and dermatitis after consuming gluten. The most commonly reported skin lesions include those similar to subacute eczema, as well as the bumps and blisters indicative of dermatitis herpetiformis, or Duhring’s disease, which celiac disease is closely linked to. Those who are gluten intolerant may also experience scaly patches resembling psoriasis, and the lesions are typically found on the muscles of the upper limbs, although not always.

Finally, brain-related issues like depression, anxiety, dementia, Alzheimer’s [disease], and Parkinson’s [disease] are frequently associated with gluten intolerance. Recent statistics suggest that up to 22 percent of patients with celiac disease develop such dysfunctions, with anxiety and depression occurring most commonly. One study found that [patients with] celiac disease were more likely than others to feel anxious in the face of threatening situations, while additional research has linked conditions like panic disorder and social phobia to gluten response. Depression and other related mood disorders also appear to occur with both non-celiac wheat sensitivity and celiac disease. And studies now suggest that gut dysfunction, which can be driven by undiagnosed gluten intolerance, leads to inflammation in the brain and the hallmark signs and symptoms of cognitive and neurodegenerative conditions. I cover this in more detail in a recent Tuesday Tip video on my YouTube channel called “Is Gluten Actually Harming Your Brain?” I’ll put a link to [it] in the show notes, or you can visit YouTube.com/ChrisKresser to find it.

How to Test Whether You’re Sensitive to Wheat, Gluten, or Both

Okay, with all this in mind, how do you know if you or your children may be affected by non-celiac wheat sensitivity? Unfortunately, you can’t rely on the conventional testing that your primary care physician or GI [doctor] might offer, for the reasons we’ve just discussed. I can’t tell you how many times patients have come to me and said their doctor tested them for celiac or non-celiac wheat sensitivity and they were negative, only to find out that they were hugely positive when we use more accurate testing. The two tests I’ve used in the clinic with patients are Array 3X from Cyrex Labs, and the Wheat Zoomer panel from Vibrant Wellness. These tests aren’t perfect, and they do require some expertise to interpret, but they are far more comprehensive than conventional tests because they look at all the other components of the wheat protein rather than just looking at alpha-gliadin and transglutaminase 2, like the conventional tests do.

You do need a doctor to order these tests, and, in my experience, most conventional primary care or GI [doctors] are not familiar with them and generally won’t order them. Your mileage may vary. I have heard of some cases of patients being able to convince their doctors to order those tests, so it’s certainly worth a try. But you’re more likely to find success with an Integrative or Functional Medicine doctor or clinician, or a nutritionist who has this kind of training. They’re more likely to work with these labs and be able to interpret them properly. If you don’t have access to a practitioner who uses these labs, you can still do a gluten-elimination provocation challenge. The reality is [that] this is still the gold standard when it comes to identifying gluten intolerance. I will often ask patients to do it, even if they’ve tested positive with the Cyrex Array 3X or Vibrant Wheat Zoomer, in order to confirm the diagnosis.

Here’s how you do it. You remove all gluten-containing foods and products from your diet for 60 days. There’s a lot of information online available about how to do this, and the good news is that it’s so much easier to do it now than it was when I first started practicing 15 years ago. In virtually all places in the world, well, I won’t say all places in the world, but [in] many places in the world, it’s quite easy to avoid gluten if you’re diligent. There are lots of gluten-free alternatives at this point. But it’s really important to be strict during [those] 60 days because you’re trying to get your body to a baseline reset without any gluten at all. Cheating during this time can really be counterproductive because you’ll never get to that baseline. So during this elimination provocation challenge, it’s vital to be strict for that first 60-day period. At the end of the 60-day period, cook up a bowl of barley and eat it, and see what happens. You can get barley at a lot of health food stores. You can buy it, generally in the bag, where other grains are sold. And you don’t need to get fancy here. This is just part of a test. I’m sure many people have not ever eaten barley as a whole grain, but you just cook it like you do rice. The instructions will be on the bag. Just eat a bowl and see what happens. The reason for doing this is that barley is a gluten-containing grain that is low in FODMAPs. Remember, we talked about the studies that showed that some people who thought they were gluten intolerant were actually FODMAP intolerant. If you eat the barley and react to it, that suggests you’re intolerant of gluten or other gluten-like compounds, because there are very few FODMAPs in barley. If it was FODMAP intolerance that was a problem for you, then consuming barley would not provoke a response because there aren’t many FODMAPs in barley. Then, a few days later, eat a piece of wheat bread. The wheat bread has both gluten and FODMAPs. If you didn’t react to the barley but you do react to the wheat bread, it suggests that you may be FODMAP intolerant, rather than gluten intolerant. If you react to both the barley and the wheat, then that suggests you are gluten or wheat intolerant.

Now, some patients have asked me about this test over the years. They say, “If I do that, I’m going to be in pain for a week afterward. If I eat a piece of wheat bread, it’s going to be ugly.” My response to that is, “Then you’re almost certainly gluten or wheat intolerant, and that’s really the end of the story.” You don’t need to go further than that. If you notice a violent reaction anytime you eat anything with gluten or wheat in it, and you don’t have access to the testing to confirm, that should be enough. You don’t really need your doctor or friends or family to buy into your diagnosis, although I know how frustrating it can be when they don’t, and it’s irritating when that happens. But at the end of the day, it’s your body, and you are going to be the one that suffers if you continue eating gluten and wheat when you’re reactive to it. If the people in your life are not supportive of that, then that’s on them, not you. I personally don’t feel like it’s worth it to put yourself through a week or more of intense pain and diarrhea, gas, bloating, pain, [and] whatever other symptoms that you experience, just to prove a point. If you already know that you’re that sensitive, then I wouldn’t recommend doing this. This is more for people who are not sure and don’t have access to the testing that I just talked about, and they want to get more clarity about whether they’re reacting. They also want to get clarity about whether they might be responding to FODMAPs, or to wheat and gluten specifically.

Going back to this test, if you react to the wheat bread, that tells you that you are sensitive to wheat. As I mentioned, there are many compounds in wheat, only some of which are gluten. So it is possible that if you react to wheat bread, you may be able to safely consume gluten-containing products other than wheat. For example, I have patients who are able to consume small amounts of soy sauce if they go out for sushi or Japanese food. But if they have a piece of bread, that’s problematic. That’s not uncommon. It’s better for us to think about wheat and gluten sensitivity on a spectrum instead of just a binary black or white condition, which is [how] it’s been looked at historically. You may be someone who can have a small amount of gluten in a packaged food, or have soy sauce, like I said, but you can’t have any flour. That’s a fairly common scenario that I see in my patients. I would argue [that], even then, because there’s some already demonstrated sensitivity to wheat or gluten, you should probably take it easy on the soy sauce or other gluten-containing foods. But eating them occasionally, if you go out to dinner or something like that and you don’t have a noticeable reaction, could be fine. So, after you’ve done that three-step test of removing gluten for 60 days, cooking barley, eating it [and] seeing what happens, and then eating wheat bread, the next steps beyond that, if you want, would be to try things like soy sauce or other foods that have gluten that aren’t wheat, and see how you do with those. From there, you should have a pretty good idea of where you fall on that spectrum.

Okay, that’s it for now. I hope this podcast has been helpful. There’s still so many misconceptions about gluten intolerance and wheat sensitivity, and I’ve tried to cover the highlights in this episode. If you want to do a deeper dive, check out my free eBook called Should You Go Gluten Free? It goes into everything I’ve covered in this podcast in more detail and contains all the scientific references, studies, links, and other useful resources. You can find that at ChrisKresser.com/gluten-free. Thanks for listening, everybody. Keep sending your questions to ChrisKresser.com/podcastquestion. Even though I’m not doing Q&A episodes at this point, I still source topics from that list of questions, and in fact, that’s where this topic came from. So please keep sending your questions in. I love hearing from you. I will see you next time.

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