Celiac Disease and Gluten Sensitivity

Written by: Gerda Endemann, PhD


Updated on: October 1, 2020

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Understanding Celiac Disease and Gluten Sensitivity

Gluten is made up of two proteins—gliadins and glutenins—and is most commonly found in wheat, barley, and rye. Celiac disease is a serious autoimmune condition in which gluten consumption results in damage to the intestine. For people with celiac disease, gluten triggers the body’s own immune system to attack the cells of the intestinal lining. But even if you don’t have celiac disease, there are a few other reasons you might want to avoid gluten and wheat.

Celiac disease can develop at any age. It is frequently misdiagnosed or overlooked until serious damage is done, and it is found in almost one out of a hundred people in Western populations (Castillo, Theethira, & Leffler, 2015; Hujoel et al., 2018; Parzanese et al., 2017).

Wheat is one of the “big eight” allergens; many people develop an allergy to wheat, with the classic symptoms of anaphylaxis, a swollen throat, or an itchy rash. This response is mediated by IgE antibodies, and it is considered a true allergy, as opposed to an “intolerance” or “sensitivity,” terms used for conditions that are less well understood.

Gluten and other components of wheat have been implicated in nonceliac wheat sensitivity (NCWS) and nonceliac gluten sensitivity (NCGS) (Fasano & Catassi, 2012). These components can trigger the immune system even without an autoimmune disease like celiac (Elli et al., 2016). Mainstream medicine has finally accepted this problem, as evidenced by new research on NCGS and NCWS. For instance, a clinical study in Italy looking for blood and tissue markers for NCWS was just completed.

This article will cover both celiac disease and gluten and wheat sensitivities. For practical purposes, the bottom line is to listen to your body. If it reacts poorly to wheat or other foods, believe it. Keep in mind that many individuals handle wheat just fine, likely due to genetic variation, the gut microbiome, and the health of the digestive tract.

What’s the Difference between Nonceliac Wheat and Gluten Sensitivity?

Nonceliac wheat sensitivity refers to adverse reactions to wheat, which could be due to gluten or other components of wheat. Nonceliac gluten sensitivity refers to adverse reactions to gluten specifically. Although NCGS is not necessarily the same as NCWS, these terms are sometimes used interchangeably. In this article, we use these terms as they are used in the cited sources. “Gluten intolerance” can refer to celiac disease or to NCGS.

Primary Symptoms

In celiac disease, when an immune attack is mounted against the cells lining the intestine, they are no longer able to carry out their function of absorbing nutrients. Without these cells transporting nutrients from the intestine into the body, serious nutritional deficiencies can result (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], 2016). When you don’t absorb nutrients, one immediate consequence can be diarrhea. Unabsorbed foods attract water, and they also attract the attention of bacteria in the colon that thrive on the leftovers, generating gas, bloating, pain, and pale, foul-smelling stool. But some people experience the opposite: constipation.

Over time, not absorbing iron leads to anemia—the most common symptom of celiac disease in adults—and not absorbing calcium leads to osteoporosis. A characteristic horribly itchy skin rash is called dermatitis herpetiformis. Other consequences can include dental enamel spots, infertility, miscarriage, and neurological conditions, including headache (NIDDK, 2016a).

Kids may not have a lot of obvious symptoms, especially if a portion of the intestine is undamaged and can absorb some nutrients. Symptoms may be irritability or failure to thrive.

In NCGS and NCWS, symptoms may include diarrhea, constipation, bloating, nausea, pain, anxiety, tiredness, fibromyalgia, chronic fatigue, foggy mind, headache, migraine, and arthritis (Biesiekierski et al., 2013; Brostoff & Gamlin, 2000; Elli et al., 2016).

Potential Causes of Celiac and Gluten Sensitivity and Related Health Concerns

The causes of gluten intolerance are poorly understood. There is an inherited predisposition, and the chances of developing celiac disease are one in ten in someone with a first-degree relative with diagnosed celiac disease. Celiac is also more prevalent in people with other autoimmune diseases, such as diabetes or an autoimmune thyroid disease.

Having celiac disease is associated with a higher likelihood of developing heart disease, small intestinal cancer, and other autoimmune diseases, such as type 1 diabetes and multiple sclerosis. The sooner celiac is diagnosed the better as far as reducing the risks of developing other autoimmune diseases (Celiac Disease Foundation, 2019; U.S. National Library of Medicine, 2019).

The Basics of Leaky Gut

Gluten proteins are not easy for our digestive enzymes to break down. Ideally, food proteins are completely digested, down to one to three amino acids, which can then enter the cells of the intestinal wall and be used by the body to make new proteins as needed. The problem is that gluten tends to be partially digested, yielding a particularly toxic chain of 33 amino acids called a gliadin peptide. Normally, peptides this long are trapped in the intestine and can’t enter the body. In a healthy intestine, the epithelial cells forming the surface of the intestine are linked together via “tight junctions” to form an impermeable barrier. But gliadin peptides cause tight junctions between cells to fall apart, allowing them and other molecules to pass through.

Once inside the body, gliadin peptides initiate inflammation and the production of chemicals and antibodies that attack the intestine. The inflamed intestine is now even less able to form an impermeable barrier, and the leaky gut lets in more inflammatory peptides, setting up a destructive cycle. Bacterial toxins are thought to play a role, as they can initiate inflammation and the disruption of the barrier (Khaleghi et al., 2016; Schumann et al., 2008).

We don’t know why some people (and Irish setter puppies) respond to gluten with increased permeability of the gut. We do know that permeability is high in other inflammatory and autoimmune diseases and in close relatives of those with celiac disease.

Why Do We Seem to Be Having a Gluten-Sensitivity Epidemic?

Celiac disease has been underdiagnosed for many years, and even now it is estimated that most cases still go undiagnosed (Hujoel et al., 2018). Gluten in large amounts is a relatively recent addition to the human diet in evolutionary terms (Caio et al., 2019; Charmet, 2011). Efficient production of wheat flour didn’t take off until the 1800s, with mechanization of agriculture, transportation, and milling (Encyclopedia.com, 2019). Breeding wheat for a higher gluten content was popularized in the late twentieth century, with particular fervor in the 1990s (Clarke et al., 2010). It is not a given that our digestive tracts should be able to handle increasingly large amounts of this digestion-resistant protein. Increasing use of antibiotics that disrupt our gut microbiota could also play a role (see more in the research section).

How Celiac Disease Is Diagnosed

It isn’t always easy diagnosing celiac disease. In the past, people lived with symptoms for many years before being diagnosed, and even now it can take years before a diagnosis is made. Clues may include a family history of the disease, diarrhea, nutrient deficiencies, anemia, osteoporosis, an itchy skin rash, and especially in children, spots on the teeth. There may not be intestinal symptoms at all (NIDDK, 2016a). Diagnostic tests include measuring antibodies in blood samples or skin, a blood test for gene variants, and an intestinal biopsy. Tests may turn up negative if gluten hasn’t been consumed for a while, so it’s best to carry out as many tests as needed to confirm the diagnosis before excluding gluten from the diet (NIDDK, 2016b).

Who Should Be Tested for Celiac Disease?

The University of Chicago Celiac Disease Center says that anyone with any autoimmune disease or with a close relative with celiac should be tested even if they don’t have obvious symptoms. Children who are not thriving or have persistent diarrhea should be tested. The standard antibody test might not work in young children who haven’t been eating gluten long enough to generate antibodies, and they should see a pediatric gastroenterologist (University of Chicago Celiac Disease Center, 2019).

A Blood Test for Genetic Predisposition to Celiac Disease

The HLA-DQ2 and HLA-DQ8 genes are associated with celiac, and risk of the disease is high in people with HLA-DQ2 plus HLA-GI. Many people without celiac disease have these same gene variants, so this test is not the last word—it just provides a piece of the puzzle (NIDDK, 2013).

Antibody Tests for Diagnosing Celiac Disease

Three antibody tests can be done on blood samples to help diagnose celiac disease. Antibodies are produced by white blood cells to neutralize molecules that are perceived as foreign, such as molecules on the surface of bacteria—or in this case, the wheat protein gliadin. For poorly understood reasons, in autoimmune diseases like celiac, antibodies are also made to attack your own body—in this case, your intestinal cells. Celiac disease is diagnosed by the presence of gliadin antibodies and autoimmune antibodies to intestinal molecules. The major test measures antitissue transglutaminase IgA antibodies, and it is quite sensitive, except in people with mild celiac disease. Testing for endomysial IgA antibodies can confirm the diagnosis. Testing for deamidated gliadin peptide IgG antibodies can be useful in people who don’t have IgA (NIDDK, 2013; NIDDK, 2016b).

Antibodies can also be tested in a skin biopsy if the dermatitis herpetiformis rash is present. This rash looks like herpes, with small blisters in clusters that itch intensely and generally appear on the elbows, knees, scalp, buttocks, and back. The rash clears up when the antibiotic dapsone is applied, a result indicative of celiac disease (NIDDK, 2014).

Definitive Diagnosis of Celiac Disease with Intestinal Biopsy

Absolute confirmation requires a biopsy of the small intestine to look for the characteristic flattened appearance of the intestinal surface. The intestine is normally covered with thousands of tiny projections (villi), and these in turn are covered with absorptive cells, providing an enormous surface area for nutrients to enter the body. The autoimmune antibodies destroy the cells and the villi, preventing nutrient absorption (Celiac Disease Foundation, 2019; NIDDK, 2016b).

Diagnosing Nonceliac Gluten or Wheat Sensitivity

There aren’t any blood tests to identify NCGS or NCWS, although a possible biomarker (a biological indicator of a disease) is discussed in the research section of this article. NCGS and NCWS are identified by symptoms including constipation, diarrhea, pain, bloating, early satiety, fatigue, and headache, and by lab tests to rule out celiac disease and a wheat allergy. The other major indicator is when your symptoms improve on a gluten-free diet. These are subjective measures that many physicians may think are not conclusive. To address this uncertainty, double-blind, placebo-controlled wheat challenges have been carried out, in which the subjects do not know whether they are given wheat or not. In many cases, subjects react poorly to wheat and not to control foods, confirming a diagnosis of wheat sensitivity (Järbrink-Sehgal & Talley, 2019).

If you are going to try an elimination diet for self-diagnosis, it’s a good idea to work with a dietitian or functional medicine practitioner who can help make sure you don’t waste your time doing it incorrectly or harmfully. Eliminating gluten is not always straightforward, as it can be present in many processed foods, medicines, and supplements.

Simply eliminating gluten from your diet may not be sufficient to resolve your symptoms if sensitivities to other foods are also present. An experienced practitioner can help efficiently guide you through an elimination diet that will cut out common problematic foods but also be nutritionally complete. Symptoms of gluten sensitivity can overlap with symptoms of intolerances to dairy products, sugar, fruit juices, corn, wine, fermented foods, many vegetables, and more (Brostoff & Gamlin, 2000).

Dietary Changes for Celiac Disease and Gluten Sensitivity

A diagnosis of celiac disease requires strict avoidance of all gluten forever, as described in the conventional treatments section below. Other sorts of wheat or gluten intolerance may not require such strict avoidance, and intolerance may lessen over time. If you are going to be tested for celiac disease, don’t avoid gluten yet, as that could mask the disease.

In addition to intestinal discomfort and other symptoms, celiac disease results in nutrients not being absorbed properly. People with any problem absorbing nutrients need to be careful to eat nutritious foods. Everyone can benefit from whole foods that are naturally high in vitamins and minerals. But it’s particularly important that those of us with celiac disease do not fill up on white sugar and refined oils that have been depleted of nutrients during processing.

Ancient Grains, Heirloom Wheat, Sourdough, and Nonceliac Gluten Sensitivity

Ancient grains are grains and seeds that have not changed much genetically over the past 200 years, or even thousands of years (Taylor & Awika, 2017). The term excludes modern varieties of wheat bred for high gluten content but doesn’t necessarily exclude all gluten-containing grains. It’s also sometimes used to refer to a group of grains and seeds that do not contain gluten, including sorghum, millet, wild rice, quinoa, amaranth, and buckwheat.

Modern wheat varieties used for bread and pasta—but not for cake flour or pastry flour—have been bred to contain more gluten than older varieties, so the question has been raised: Can people with NCWS better tolerate heirloom varieties of wheat, such as einkorn and emmer? There is some evidence that einkorn wheat may provoke less of an immune response than common wheat, but there is significant variation even within einkorn varieties, and none of them are safe for people with celiac disease (Kucek, Veenstra, Amnuaycheewa, & Sorrells, 2015; Kumar et al., 2011). For people with NCWS, if you just can’t do without bread, it seems worth trying einkorn wheat flour, which is available commercially these days.

There are occasional reports of specific products being tolerated better than others. Pasta made from a traditional variety of durum wheat, Senatore Capelli, was compared to a commercial pasta for tolerability by subjects with NCWS in a controlled study. Subjects reported significantly less bloating, fewer feelings of incomplete bowel movements, and less gas and dermatitis after consuming the Senatore Capelli pasta versus the control pasta (Ianiro et al., 2019).

Is Sourdough the Answer to Gluten Sensitivity?

It’s likely that the gluten content in our bread is higher now than it was a hundred years ago, due to the high gluten content in modern grain varieties, but it has been proposed that faster leavening times also contribute to the problem. The theory is that during the long, slow bread-leavening processes using sourdough starter (instead of commercial quick-acting yeast), enzymes help predigest gluten. Enzymes may come from the grains themselves or from microorganisms, such as lactobacilli in sourdough starter. The ability to break down gluten has been demonstrated with enzymes from sprouted grains and with sourdough lactobacilli. But this phenomenon does not translate to the real world of bread-making: There is not yet a way to predigest gluten enough to make bread safe for people who are intolerant (Gobbetti et al., 2014). Even reducing the gluten content of pasta and bread by 50 percent, with added protease enzymes in addition to sourdough lactobacilli, was not very helpful for subjects with gluten-sensitive irritable bowel syndrome (Calasso et al., 2018). One could speculate that sourdough bread made from sprouted einkorn wheat may be worth further investigation.

Nutrients and Supplements for Celiac Disease

Celiac disease destroys the normal architecture of the intestinal surface, reducing the number of cells that can absorb nutrients. Envision all of the windows in a skyscraper and compare this to the number of windows in a single-story building. This will give you some idea of the magnitude of the loss of cells through which vitamins and other nutrients can enter the body. A recent study found that individuals with celiac disease had deficiencies of zinc, copper, iron, and folate. The most astounding number: Almost 60 percent of celiac patients had low levels of zinc compared to 33 percent of control subjects (Bledsoe et al., 2019).

Which Supplements Are Recommended for Celiac Disease?

Since vitamin and mineral deficiencies are common in celiac disease, doctors will likely request blood tests for nutrient status and recommend a good multivitamin and mineral supplement. In particular zinc, iron, copper, folate, vitamin D, and vitamin B12 are likely to be low (Bledsoe et al., 2019). Supplements may contain processing aids, excipients, fillers, and other additives that may contain gluten, so they need to be carefully evaluated. For example, starch, maltodextrin, dusting powder, dextrin, cyclodextrin, carboxymethyl starch, and caramel color may come from wheat or safe sources, so double-check food labels (Kupper, 2005).

Lifestyle Support for Celiac Disease

Most people with celiac disease report difficulties eating out and traveling, and some report a negative impact on work and career. Celiac disease can be particularly hard on children and may contribute to social alienation and stress on families (Lee & Newman, 2003).

Social and Emotional Well-Being and Celiac Disease

Being hypervigilant around gluten avoidance may be associated with a lower quality of life, and health professionals need to focus not only on strict dietary adherence but also on social and emotional well-being. Eating out can be become stressful if you’re worried about inadvertently consuming gluten or you feel embarrassed about asking questions about the menu (Wolf et al., 2018). Working with a registered dietitian is considered the best way to achieve adherence while minimizing stress and confusion. The Celiac Disease Foundation provides educational resources for health professionals about the psychological impacts of chronic diseases and how to facilitate coping strategies.

Support Groups for Celiac Disease

A support group can be a place for children to meet other children with celiac disease. Your local hospital or clinic may operate a support group; for example, St. Christopher’s Hospital for Children in Philadelphia offers one through its department of clinical nutrition. The Celiac Community Foundation of Northern California offers a variety of resources, including information about local expos, health days, and restaurants. A number of associations and support groups in other locations can be found on the Beyond Celiac website. You might also ask your physician or dietitian about local resources.

Smart Patients is an online forum founded by Gilles Frydman and Roni Zeiger, the former chief health strategist at Google, to tap into the wisdom of patients and caregivers who share questions and experiences.

Conventional Treatment Options for Celiac Disease and Gluten Sensitivity

Treatment for celiac disease relies on complete avoidance of dietary gluten. This is not always easy and requires working with a dietitian to avoid both gluten and nutrient deficiencies. NCGS is poorly understood and may or may not require such strict avoidance.

Complete Avoidance of Gluten for Celiac Disease

In celiac disease, it’s very important not to consume any gluten, even occasionally. Gluten is found in wheat, barley, rye, and triticale (a cross between wheat and rye). Other names for wheat are wheatberries, durum, emmer, semolina, spelt, farina, farro, graham, kamut, khorasan wheat, and einkorn. Even a tiny amount of pasta, bread, cake or other baked goods, or fried foods coated with flour or bread crumbs can trigger damage to the intestine.

What Are the Best Gluten-Free Alternatives?

Starchy alternatives that do not contain gluten include rice, soy, corn, amaranth, millet, quinoa, sorghum, buckwheat, potato, and beans (NIDDK, 2016c). For more ideas, see the guide to gluten-free pastas that our food editors put together.

Although it’s been thought in the past that oats are problematic, this is likely due to contamination with wheat, and the latest evidence has cleared oats themselves (Pinto-Sanchez et al., 2015). It’s recommended to stick with gluten-free oats that have not come in contact with any wheat, although the safety of this approach depends on the quality control of the manufacturer (Celiac Disease Foundation, 2016).

Gluten from wheat has made its way into a huge number of foods, supplements, medications, and products, from Play-Doh and cosmetics to communion wafers. It can be difficult to avoid gluten in prepared foods with long ingredient lists—ingredients made from wheat and barley include modified food starch, malt, beer, and many more.

To completely avoid gluten, celiac patients will need to work with a registered dietitian for help implementing a safe diet that is still nutritionally complete. Because damaged intestinal cells can’t absorb nutrients, it’s common to be deficient in many vitamins and minerals as well as in fiber, calories, and protein. A dietitian can recommend a gluten-free complete multivitamin and multimineral with 100 percent of the recommended dietary allowances.

Symptoms may improve within days of not consuming gluten, but healing can take months in children and years in adults. It is not uncommon for patients to continue to experience abdominal symptoms as well as fatigue even when following a gluten-free diet to the best of their ability. In refractory celiac disease, patients are not able to heal the gut or improve absorption on a documented gluten-free diet (Rubio-Tapia et al., 2010). However, in many cases, the problem is not being able to completely remove gluten from the diet (Castillo et al., 2015).

Gluten-Free Labels and Gluten Tolerance Levels

If a product is tested for gluten and it contains less than 20 parts per million (20 micrograms per gram), it can be labeled as gluten-free. Products that contain absolutely no wheat, rye, or barley can be labeled gluten-free but should be manufactured with quality-control processes that ensure no contamination with gluten, or they should be tested for gluten contamination. A food labeled gluten-free, containing at most 20 parts per million gluten, would contain less than 2 milligrams of gluten in a 3-ounce serving (100 grams). In theory, consuming more than 15 ounces of a gluten-free food could result in eating more than 10 milligrams of gluten.

The consensus for now is to aim for less than 10 milligrams of gluten per day if you have celiac disease (Akobeng & Thomas, 2008; Catassi et al., 2007). The best course would be to avoid all foods with ingredients that could possibly contain hidden gluten. Grilled steak and baked potatoes made at home are likely to be absolutely free of gluten, whereas gluten-free pasta with multiple ingredients served in a restaurant could contain a small amount of gluten depending on the ingredients, the sauce, and contamination during manufacturing and preparation.

How Do You Know If You Are Inadvertently Eating a Little Gluten?

It’s not always obvious when you’re experiencing symptoms due to gluten that has inadvertently made its way into your body. Testing urine and stool samples for leftover gluten can help resolve whether gluten was eaten or not. Gluten Detective kits detect gluten in stool or urine samples. Maybe there are times when you wonder if you accidentally ate gluten in the past twenty-four hours, in which case you could detect as little as two bites of bread in your urine. Or you want to know the overall exposure to gluten in the past week, in which case you could detect as little as a crumb of bread in your stool.

Medications Used in Celiac Disease

There aren’t any drugs that can treat celiac disease, but dapsone or another medication may be prescribed to help with dermatitis herpetiformis. Even in children, bone density may be low due to poor nutrient absorption, and tests for bone density and medical treatment may be appropriate. Over-the-counter or prescription drugs may be used to treat diarrhea.

Note: The FDA issued a warning that taking more than the prescribed dose of the antidiarrheal drug loperamide (Imodium) can “cause serious heart problems that can lead to death.” This was mostly in people using high doses to “self-treat opioid withdrawal symptoms or to achieve a feeling of euphoria” (Food and Drug Administration, 2019).

Alternate Treatment Options for Celiac Disease and Gluten Sensitivity

There is very little published in the way of novel treatments for gluten intolerances. Support for gut health may be provided with probiotics, digestive enzyme supplements, and a holistic approach to whole-body health.

Working with Traditional Medicine, Herbalists, and Holistic Healers to Support Gut Health

Holistic approaches often require dedication, guidance, and working closely with an experienced practitioner. Functional, holistic-minded practitioners (MDs, DOs, and NDs) may use herbs, nutrition, meditation, and exercise to support the entire body and its ability to heal itself.

Traditional Chinese medicine degrees may include LAc (licensed acupuncturist), OMD (doctor of Oriental medicine), or DipCH (NCCA) (diplomate of Chinese herbology from the National Commission for the Certification of Acupuncturists). Traditional Ayurvedic medicine from India is accredited in the United States by the American Association of Ayurvedic Professionals of North America and the National Ayurvedic Medical Association. There are several certifications that designate an herbalist. The American Herbalists Guild provides a listing of registered herbalists, whose certification is designated RH (AHG).

Probiotics for Celiac Disease

There is some indication that probiotics, especially bifidobacteria and lactobacilli, may be helpful in celiac disease. People with celiac disease should discuss any supplement with their doctor—it could contain gluten. Probiotics escaping the gut and causing infection throughout the body is extremely rare (Borriello et al., 2003) but may be a concern if you have a damaged, permeable intestine.

Differences have been reported in the gut microbiota of people with celiac disease, including lower numbers of beneficial bifidobacteria (Golfetto et al., 2014). In a small clinical study, Bifidobacterium infantis, Natren Life Start Super Strain was reported to help alleviate symptoms of indigestion and constipation in subjects with celiac disease who were consuming gluten (Smecuol et al., 2013). In another small clinical study, two Bifidobacterium breve strains (B632 and BR03) given to children on a gluten-free diet were shown to partially normalize the microbial balance (Quagliariello et al., 2016). A clinical trial in Italy is testing a probiotic mixture called Pentabiocel, which contains five specific strains of Lactobacillus and Bifidobacterium, in children already on a gluten-free diet.

There is a possible explanation for the benefits of bifidobacteria in celiac disease. B. longum may be able to help digest gluten into smaller, less inflammatory peptides, although this has been demonstrated only in experiments with cells and not yet in people (de Almeida et al., 2020).

Gluten-Digesting Enzymes for Nonceliac Gluten Sensitivity

There are quite a few dietary supplements on the market that claim to be gluten-digesting. People with celiac disease cannot rely on these products, as no product has been shown to effectively digest gluten under real-life conditions, and dietary supplements cannot be used to treat a disease. However, people may wish to consider trying an enzyme supplement if celiac disease has been ruled out and a wheat sensitivity is suspected. Pharmaceutical companies are interested in developing effective gluten-digesting enzymes as drug products—the clinical trials section of this article discusses the promising ones.

Scientists from the Celiac Disease Center at Columbia University reviewed fourteen commercially available “glutenase” products intended to help digest gluten. They were quite negative about the lack of evidence that the products work and were concerned about the possible harm that could result if people with celiac disease think that one of these products will allow them to eat gluten. However, they did call out that one enzyme, Tolerase G, has potential (Krishnareddy et al., 2017).

Tolerase G is the brand name for a gluten-digesting enzyme produced by the company DSM that is available in several dietary supplement products. Its ability to help digest gluten has been demonstrated in research at Maastricht University Medical Center in the Netherlands. The actual name of the enzyme is AN-PEP, for Aspergillus niger prolyl endopeptidase. In a clinical study, healthy humans were given a hefty dose of AN-PEP along with a meal containing 4 grams of gluten. Samples were taken through tubes inserted into the stomach and intestine, and they demonstrated that the gluten was indeed digested (Salden et al., 2015). Compare this clinically validated dose of 1,600,000 protease picomole international units with the lower doses available in supplements and you can see that it could be very expensive to use these products routinely. It’s also important to remember that we have no idea how many units it would take to deal with more than 4 grams of gluten, which is roughly what you’d consume in one slice of bread. And this study was conducted with only healthy individuals, so we don’t know if it would work for patients with NCGS. But it may be worth trying. Again, though, it is not intended to allow anyone with celiac disease to consume gluten.

Another gluten-digesting enzyme present in quite a few dietary supplements is DPP-IV. Preliminary evidence has suggested that DPP-IV may be useful in combination with other enzymes for digesting gluten (Ehren et al., 2009). However, when five commercially available gluten-digesting enzyme supplements containing DPP-IV were tested (together with a variety of other enzymes) for their ability to break down gluten, they were all shown to be ineffective at breaking down the toxic, inflammatory portions of gluten (Janssen et al., 2015). The makers of Tolerase G were involved in this study, so there is a conflict of interest that may warrant further unbiased studies of DPP-IV. Those with NCGS or poorly understood intolerances, but not those with diagnosed celiac disease, may wish to try these digestive enzyme supplements.

New and Promising Research on Celiac Disease and Gluten Sensitivity

Current research is aimed at trying to understand the causes of celiac disease and identify therapies (in addition to gluten avoidance) that can help people. And the newest research is looking at gluten intolerance, why it occurs, and what can alleviate symptoms or resolve the root causes.

How Do You Evaluate Clinical Studies and Identify Promising Results?

The results of clinical studies are described throughout this article, and you may wonder which treatments are worth discussing with your doctor. When a particular treatment is described as beneficial in only one or two studies, consider it of possible interest or perhaps worth discussing, but its efficacy has definitely not been shown conclusively. Repetition is how the scientific community polices itself and verifies that a particular treatment is of value. When benefits can be reproduced by multiple investigators, they are more likely to be real and meaningful. We’ve tried to focus on review articles and meta-analyses that take all the available results into account; these are more likely to give us a comprehensive evaluation of a particular subject. Of course, there can be flaws in research, and if by chance all of the clinical studies on a particular therapy are flawed—for example with insufficient randomization or lacking a control group—then reviews and meta-analyses based on these studies will be flawed. But in general, it’s a compelling sign when research results can be repeated.

A Drug to Break the Leaky Gut Cycle

Larazotide is a new drug designed to improve the gut barrier by strengthening the junctions between the epithelial cells lining the intestine. The hope is this will prevent gluten peptides and bacterial toxins from bypassing the barrier and entering the body. Even when people with celiac disease are on a gluten-free diet, they frequently have recurrent, ongoing symptoms, perhaps from unknowingly eating gluten, or possibly unrelated to gluten. In a clinical trial, a tiny dose of larazotide showed promising results for symptom relief in celiac disease. Subjects had been on a gluten-free diet, but 90 percent were still living with GI symptoms, and over two thirds reported having headaches and feeling tired. All of these symptoms lessened after treatment with larazotide (Leffler et al., 2015). Another clinical trial asked whether larazotide could prevent symptoms caused by purposely feeding gluten to subjects with celiac. Larazotide was able to significantly reduce symptoms and the activation of the immune system (Kelly et al., 2013). Clinical assessment of this promising drug is progressing with a phase 3 trial (as described in the clinical trials section of this article).

Avoiding Antibiotics to Prevent Celiac Disease

Our gut bacteria seem to play a role in everything. Could taking antibiotics that disrupt the normal gut microbiome have anything to do with celiac disease or NCWS? A recent study in Denmark and Norway found that each prescription of antibiotics for infants up to the age of one was associated with an 8 percent increased chance that they would develop celiac disease. It’s tempting to assume a cause-and-effect relationship between antibiotic use and celiac, but it could just be a coincidence, or it could be that some infants’ immune systems predisposed them to both celiac disease and infections requiring antibiotics (Dydensborg Sander et al., 2019).

Feeding Infants Gluten to Prevent Celiac Disease

There’s a theory that if children regularly consume a particular food from an early age, they might develop tolerance—that is, they may be less likely to develop an allergy to the food. Limited research suggests that the best bet is to start feeding babies gluten sometime later than four months but before seven months of age and to continue to breastfeed at that time (Szajewska et al., 2012).

Recent research has lent further support to that recommendation. In the EAT study, over 1,000 babies that were exclusively breastfed were divided into two groups. The control group was not given allergenic foods—foods that children tend to develop allergies to—until at least six months of age. The other group was fed six common allergenic foods by five months of age. Peanut, sesame, eggs, cow’s milk, codfish, and wheat were added to the infants’ diets one at a time. At three years of age, celiac disease was diagnosed in seven of the control children and in none of the children who were fed wheat and other allergenic foods early on. This suggests that early exposure to allergenic foods could be an effective way to prevent celiac disease. However, this study was carried out in a very specific way in a particular population, and it isn’t yet known whether the findings will be generally relevant or not—or how the protocol could be widely implemented (Logan et al., 2020).

FODMAPS and GI Symptoms

A gluten-free diet cuts out a lot more than just gluten. Wheat contains other potential irritants, including fibers called FODMAPs. We don’t digest these, but our intestinal bacteria do, sometimes with adverse consequences. FODMAPS include fructans in wheat, inulin, and some vegetables; fructose in fruit; lactose in dairy products; oligosaccharides in beans and some vegetables; and sweeteners such as sorbitol and xylitol, which are used in sugar-free foods. It has been proposed that in some cases cutting out FODMAPs may be more important than cutting out gluten, but clinical results are not yet convincing (Biesiekierski et al., 2013; Skodje et al., 2018). The bottom line (as mentioned earlier) is to listen to your body, and if it reacts poorly to wheat, believe it.

ATIs, WGA, Lectins, and Other Inflammatory Proteins in Wheat

Grains make proteins called amylase trypsin inhibitors (ATIs) to deter pests. These proteins act like gluten and activate inflammatory immune cells in the gut (Junker et al., 2012). Like gluten, ATIs are difficult to digest. Researchers at McMaster University in Ontario recently reported that ATIs induce gut permeability and inflammation in mice, and exacerbate the effects of gluten. The researchers looked at how we might protect the gut from gluten and ATIs. They identified strains of lactobacilli that were able to break down both gluten and ATIs, and showed that these probiotics could reduce inflammation in mice. Their conclusion: ATIs can induce leaky gut and inflammation without celiac disease. Probiotic strains that can degrade ATIs can reduce these effects and should be tested in people with wheat sensitivities (Caminero et al., 2019). The only variety of wheat that does not appear to have significant amounts of ATIs is einkorn (Kucek, Veenstra, Amnuaycheewa, & Sorrells, 2015).

Wheat also contains proteins called lectins, which bind carbohydrates, in particular carbohydrates on the surface of cells. A lectin found in wheat germ called wheat germ agglutinin (WGA) may contribute to wheat sensitivities (Molina‐Infante et al., 2015). WGA can bind to and damage intestinal cells and increase gut permeability, in addition to activating white blood cells and being proinflammatory (Lansman & Cochrane, 1980; Pellegrina et al., 2009; Sjolanderl et al., 1986; Vojdani, 2015).

WGA is found more specifically in the nutrient-rich portion of wheat. This part is removed during the production of white flour. So even though whole-wheat flour contains valuable fiber, vitamins, and minerals, white flour could be easier for some to digest because it has a lower WGA content. We’ll eagerly await data on the tolerability of white einkorn flour, which contains gluten but fewer ATIs and less WGA.

Commercial Development of Gluten-Digesting Protease Enzymes

If our digestive enzymes that break down proteins, called proteases, could break down gluten more effectively, we could eat it with fewer problems. That is why proteases that can digest even the trickiest parts of gluten are being developed for commercial use. A product from ImmunogenX, called Latiglutenase (ALV003), contains two enzymes that are genetically engineered versions of proteases from barley and bacteria. This product appears to be promising, as it prevented damage to the intestine when people with celiac disease were fed 2 grams of gluten daily for six weeks (Lähdeaho et al., 2014). This is about a hundred times as much gluten as a gluten-free diet should contain, and about one tenth as much as might be eaten in a typical diet. Latiglutenase also appears to be useful for people with celiac disease who are on a gluten-free diet but still not well. People with celiac who were trying not to eat gluten but who did not have their disease under control (blood antibody tests were positive) reported significantly less abdominal pain and bloating after twelve weeks of taking the enzyme with every meal (Murray et al., 2017; Syage et al., 2017). See the clinical trials section of this article for an additional clinical trial that is currently recruiting.

Developing Biomarker Tests for Nonceliac Wheat Sensitivity

Scientists are beginning to find biomarkers for NCWS that may be used to develop diagnostic tests and demonstrate the physiological basis of symptoms. It was reported that people with NCWS have elevated numbers of eosinophils—a specific kind of white blood cell—in intestinal tissues. In order to identify subjects with NCWS for this study, people were tested for their response to wheat in a double-blinded controlled study. Those who had symptoms after eating wheat unknowingly in the blinded study were considered to have documented NCWS. Higher levels of eosinophils were found in intestinal biopsies from the people with documented NCWS than in those from control subjects.

A second biomarker may be a particular type of antibody that bind to gluten. People with celiac disease have higher levels of antibodies that bind gluten than people without this disease. It has recently been reported that people with NCWS have higher levels of a particular subtype of antibody to gluten, IgG4, than people with celiac disease or without gluten sensitivity. These tests aren’t ready to be routinely implemented as a diagnostic tool, but at least the problem is recognized and being researched (Carroccio et al., 2019, Uhde et al., 2020).

HLA-DQ8 and IL-15 Alone Can Damage the Intestine

The cause of celiac disease may be as simple as one gene, HLA-DQ8, and one inflammatory molecule, interleukin-15 (IL-15). It’s been known that the HLA-DQ8 gene is associated with celiac disease. And the proinflammatory IL-15 is found at high levels in intestinal cells in celiac disease. In one study, researchers created mice with both HLA-DQ8 and high IL-15 in the intestine. When these mice were given gluten, their intestines showed the damage characteristic of celiac disease: the disappearance of the absorptive villi that line the intestine (Abadie et al., 2020).

Clinical Trials for Celiac Disease and Gluten Sensitivity

Clinical trials are research studies intended to evaluate a medical, surgical, or behavioral intervention. They are done so that researchers can study a particular treatment that may not have a lot of data on its safety or effectiveness yet. If you’re considering signing up for a clinical trial, it’s important to note that if you’re placed in the placebo group, you won’t have access to the treatment being studied. It’s also good to understand the phase of the clinical trial: Phase 1 is the first time most drugs will be used in humans, so it’s about finding a safe dose. If the drug makes it through the initial trial, it can be used in a larger phase 2 trial to see whether it works well. Then it may be compared to a known effective treatment in a phase 3 trial. If the drug is approved by the FDA, it will go on to a phase 4 trial. Phase 3 and phase 4 trials are the most likely to involve the most effective and safest up-and-coming treatments.

In general, clinical trials may yield valuable information; they may provide benefits for some subjects but have undesirable outcomes for others. Speak with your doctor about any clinical trial you are considering. To find studies that are currently recruiting for celiac disease or gluten sensitivity, go to clinicaltrials.gov. We’ve also outlined some below.

Studying Infants to Identify Factors That Cause Celiac Disease

Why do some infants at risk develop celiac disease and others do not? Alessio Fasano, MD, of Massachusetts General Hospital, and Francesco Valitutti, MD, of the University of Roma La Sapienza, will be enrolling infants who have a close relative with celiac disease and following them from less than six months old up to five years. Over this period, they’ll record when the infants start consuming gluten and other dietary and environmental factors. They’ll also characterize the infants’ gut microbiota, metabolic profile, gut permeability, tissue transglutaminase antibodies, and other markers. Hopefully some factors can be identified that contribute to disease development or protection. To enroll or learn more, click here.

Gluten-Free Diets to Prevent Celiac in Children with Diabetes

Directed by Annalie Carlsson, MD, PhD, in Lund, Sweden, this clinical trial brings up an interesting theory about the possible prevention of celiac disease. Children and adolescents who develop type 1 diabetes have a much higher than average chance of developing celiac disease. In this trial, subjects ages three to eighteen with recently diagnosed type 1 diabetes will be put on a gluten-free diet for a year, and the number going on to develop celiac will be compared with subjects on their usual diet. The gluten-free diet could help prevent celiac disease, and researchers also hope that this diet will slow the progression of diabetes. To find out more, click here.

Gluten Home Testing and Children’s Food Choices

Now that there are kits to measure gluten in urine and stool, it’s possible to get feedback on whether you are letting a little gluten slip in that supposedly gluten-free diet. At Boston Children’s Hospital, six- to eighteen-year-olds with celiac disease will use these test kits, be asked about their symptoms and diet, and be tested for celiac-related antibody levels. Jocelyn A. Silvester, MD, PhD, will evaluate whether these kits help children and adolescents make connections between what they eat and their symptoms, improving their food choices and control of the disease. For more info, click here.

A Gluten-Digesting Enzyme Supplement for People with Celiac Disease

Jack Syage, PhD, of ImmunogenX, and Joseph Murray, MD, of the Mayo Clinic, are recruiting subjects for a phase 2 trial of a gluten-digesting enzyme product called Latiglutenase. Subjects must have confirmed celiac disease that is well controlled, and they must be willing to eat gluten. Previous clinical trials with this product have been promising. For information and enrollment, click here.

A Gluten-Digesting Enzyme Supplement for Healthy Volunteers

PvP Biologics is carrying out a phase 1 trial looking at the ability of its enzyme, KumaMax (PvP001), to degrade gluten in the stomach. The enzyme was engineered to be active in stomach acid and to break down the most inflammatory parts of gluten. The University of Washington undergraduate team that developed this enzyme won the international grand championship for their achievement in genetic engineering. Peter Winkle, MD, at Anaheim Clinical Trials, is first recruiting healthy volunteers and will then move on to subjects with celiac. More information is here.

A Phase 3 Trial for Leaky Gut

Lorazatide (INN-202) is a drug in phase 3 clinical trials for celiac patients; it strengthens tight junctions between intestinal cells to maintain a healthy gut barrier. A dysfunctional barrier is integral to the initiation and progression of celiac disease. Innovate Biopharmaceuticals is currently enrolling subjects who are on a gluten-free diet but are experiencing GI symptoms, such as abdominal pain, abdominal cramping, bloating, gas, diarrhea, loose stool, or nausea. Previous clinical research has already demonstrated promising benefits, as described in the research section of this article. Go here for more information.

Ancient Grains and Nonceliac Wheat Sensitivity

The wheat we eat now has been bred to have a higher gluten content than ancient varieties. There is a theory that foods with a high gluten content may contribute to NCWS, and that people with NCWS may be able to handle ancient wheat strains with fewer problems. Italian researchers Antonio Carroccio, MD, PhD, in Sciacca, and Pasquale Mansueto, MD, in Palermo, are examining various properties of wheat that could contribute to NCWS, including gluten and ATI content. They’ll compare old wheat cultivars used in southern Italy for pasta and bread to cultivars developed in Italian breeding programs in the 1900s and a line genetically engineered to contain fewer ATIs. The hope is that wheat that is not inflammatory for white blood cells will be identified and then tested in subjects with NCWS. Click here for more information.

An Interleukin-Blocker Drug for Refractory Celiac Disease

Thomas Waldman, MD, at the Mayo Clinic, is heading up a phase 1 trial of a drug for those with celiac who have not been helped by a gluten-free diet and continue to have diarrhea or other GI symptoms, as well as intestinal inflammation. This drug blocks an immune mediator called interleukin 15 that’s implicated in autoimmunity (Waldmann, 2013). This is an antibody drug, so it will have to be given by injection. Information can be found here.

Gluten-Free Diets and Back Pain

Pasquale Mansueto, MD, and Antonio Carroccio, MD, PhD, at the University of Palermo, will study whether a gluten-free diet for one year is helpful for inflammatory back pain. This is defined as back pain that improves with exercise but not with rest, and is associated with morning stiffness. They report that some people with celiac or NCGS who go on a gluten-free diet have experienced improvements in this type of pain. For further information, click here.

Resources for Celiac Disease and Gluten Sensitivity

A Guide to the Best Gluten-Free Pastas

The Autoimmune Spectrum: Does It Exist, and Are You on It?

How an Elimination Diet Can Help You Eat by Your Own Rules

National Institute of Diabetes and Digestive and Kidney Diseases

Celiac Disease Foundation

Society for the Study of Celiac Disease (North American Society for the Study of Celiac Disease)

University of Chicago Celiac Disease Center

US National Library of Medicine Medline Plus


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