Is Non-Celiac Gluten Sensitivity Real?

The term Non-Celiac Gluten Sensitivity (NCGS) first arose in 1978 when a patient with persistent gastrointestinal symptoms, in whom celiac disease and wheat allergy had been ruled out, achieved symptom relief after gluten was removed from her diet (1). A small study on eight female patients published two years later found that chronic diarrhea resolved on a gluten-free diet in spite of no evidence of celiac disease (2). The ensuing decades have seen intensive investigations into NCGS that have so far failed to come up with any clear definition of the syndrome or a determination of its underlying mechanisms (3). In short, NCGS is mired in confusion.

Two gastrointestinal syndromes connected to the eating of gluten-containing grains such as wheat, barley, rye, kamut and grain hybrids such as triticale are well-defined and widely recognized by health professionals (29).
1 Celiac disease is an inflammatory auto-immune condition that arises from an increased immunological response to gluten. Ingestion of even a very tiny amount of gluten can trigger the immune reaction and cause damage to the lining of the small intestine. Epidemiological studies estimate the worldwide prevalence of celiac disease to be approximately 1 in 100 individuals. Regrettably many sufferers are undiagnosed and untreated (4,5).
2 Wheat allergy is a classic food allergy that results from an IgE antibody interaction with one of the many proteins contained in wheat. Wheat Allergy can affect the skin (itchiness and rash), the gastrointestinal tract (abdominal pain, bloating, diarrhea, constipation) and the respiratory tract (cough, wheezing, trouble breathing) and can even lead to anaphylaxis, a life-threatening condition. The only treatment for wheat allergy is a wheat-free diet. Bakers who lived and worked as far back as the Roman Empire were familiar with wheat allergy; it was known as Baker’s Asthma at that time. Over past centuries wheat allergy has affected up to 10 to 15% of those in the baking industry. Wheat allergy can also affect adults and children in the general population at a rate of about 1 in 1000. Young children who develop wheat allergy often outgrow it. (6).

Besides these two accepted manifestations of intolerance to components of some grains, there appear to be cases of reactions to gluten which are not caused by allergic or autoimmune processes. The hallmark of this third syndrome is an adverse reaction that arises from eating gluten-containing products and improves when following a gluten-free diet (7). It is these reactions that are known as non-celiac gluten sensitivity. By early 2013 the medical community somewhat reluctantly agreed that there was enough credible evidence for the existence of three gluten-related conditions; celiac disease, wheat allergy and non-celiac gluten sensitivity (7,8).



At this point in our knowledge about NCGS the condition can only be defined by looking at clinical symptoms and ruling out other conditions. There are no biological markers that can be measured to pinpoint the disorder. In other words, people with adverse reactions to gluten which resolve when following a gluten-free diet and in whom celiac disease and wheat allergy have been ruled out fall into the NCGS category (9,10). The prevalence of NCGS is not clearly known and has ranged wildly in research studies, from 0.6% to 6% of the population of Western countries (7).

NCGS reactions are difficult to differentiate from those caused by celiac disease. The intestinal symptoms (diarrhea, bloating, abdominal pain and constipation) are very similar and the effects in other parts of the body (eczema or rash, “foggy mind”, depression, behavioral changes, bone or joint pain, muscle cramps, leg numbness, weight loss and chronic fatigue) can also occur in both cases. Although NCGS symptoms are similar to those of celiac disease, NCGS does not cause intestinal damage.

Even though NCGS is now recognized, it is poorly understood and the controversy surrounding it has not abated. A look at the available evidence makes it obvious why this is so. Several double-blind, randomized, placebo-controlled investigations, the “gold standard” of scientific study, have been completed on NCGS patients but the results are largely inconclusive.

For example in 2011 researchers performed just such a study. Participants started out gluten-free and symptom-free for two weeks then were challenged with either gluten-containing bread and muffins or gluten-free bread and muffins. All the participants got worse, even those continuing on a gluten-free diet, however those actually eating gluten-containing foods experienced the worst symptoms. 68% of the participants eating gluten perceived that their symptoms were not adequately controlled while 40% of the participants eating the placebo foods claimed the same thing (11). Researchers concluded that these results point to the possible existence of a syndrome such as NCGS. Unfortunately this study had some problematic areas. The number of participants was small, only eleven people. The proportion of apparent adverse effects from the placebo food was very high. All the subjects suffered from irritable bowel syndrome. The presence of this condition, one with similar symptoms to those of NCGS, makes it difficult to come to a clear conclusion about what results are actually caused by NCGS (11).

Another larger study from 2014 looked at the symptoms of 486 patients with suspected NCGS. Based on study data, NCGS was confirmed in only 3.19% of this group, all of whom believed when they began the study that they had the condition (12).

In 2012 Italian researchers gathered together 920 patients suspected of having NCGS and, in a double-blinded challenge where neither the participants nor the researchers knew what the participants were ingesting, gave them capsules of either wheat flour or placebo powder. More than 60% of the participants unaccountably suffered worse symptoms on the placebo or became better on the wheat. However, the approximately 30% who actually worsened on the wheat and improved on the placebo showed continuing benefit by continuing to eat wheat-free. Investigators postulated that these patients might be sensitive to a different component of wheat, not specifically gluten. The avoidance of gluten may simply be helping them to steer clear of other grain proteins that are perhaps the real cause of their problems. This study concluded that a condition indeed does exist but its probable cause should not be limited to gluten. The investigators suggested changing its name to non-celiac wheat sensitivity (13). Unfortuantely this move would not help to clear up the picture; NCGS symptoms also occur after ingestion of barley and rye (14).

Two more recent studies include a randomized double-blind placebo control study from 2015 that found that a scant 5% of participants thought to have NCGS at the start of the study responded with worsening symptoms after a gluten challenge (15) while a similar 2016 double-blind placebo-controlled study found a response to gluten in only 14% of participants (16).

Boiling all this down, researchers conclude that a small percentage of people actually do react negatively to gluten. But what about all the others who are experiencing gastrointestinal and other symptoms caused by something that does not appear to be gluten?



And so the search is on to elucidate exactly what is happening in people suffering from NCGS and this quest has followed a varied path. In 2011 the state-of-mind of NCGS sufferers was studied to see if somehow their personality traits or outlook on life might be a factor in the development of NCGS. It appears not though. No difference was found in anxiety, depression, neuroticism, hostility, aggression, physical complaints or health-related quality of life between NCGS patients and patients with clear celiac disease. Curiously though the patients with NCGS actually reported more symptoms after a gluten challenge than did the patients with celiac disease (17).

Investigations then turned to digging into other factors in food besides gluten that might be causing the symptoms of NCGS (1). In an interesting twist, a placebo-controlled cross-over challenge observed the effects of gluten in participants with self-reported NCGS after they had been stabilized on a low FODMAP diet. Gluten-type adverse effects occurred in only a very small percentage of participants (18).

Excuse me while I interrupt this blog for a short tutorial on FODMAPs. FODMAP stands for Fermentable, Oligo-, Di- and Mono-saccharides (sugars) and Polyols (sugar alcohols). This group of food components includes fructose, lactose, fructans and galactans and can be found in foods such as apples, watermelon, pears, mangoes, broccoli, cauliflower, garlic, onions, chickpeas, beans, soy and grains such as wheat, barley and rye. FODMAPs are foods that resist digestion in the small intestine. Some FODMAPs cause trouble when a person does not have enough of the enzymes needed to break them down (for example, lack of lactase to break down lactose); other FODMAPs require enzymes that human beings and other mammals just cannot produce (for example, fructans). Inevitably these undigested FODMAPs reach the large intestine where they are rapidly fermented by the bacteria that live there. FODMAP fermentation in large amounts can cause stretching of the intestinal tube due to the release of gas and an increase in fluids in the large intestine leading to GI discomfort, gas, bloating and diarrhea, especially for those with a sensitive gut. On the other hand, FODMAPS have quite substantial health benefits. One of the most important is that the beneficial microbes living in our guts thrive on FODMAPs. This is especially true of fructans because they are rich in the soluble fiber that is the preferred food for these valuable microbes. Restricting FODMAPs means restricting healthy fruits, vegetables, legumes and grains, thus diminishing important nutrients, fiber and antioxidants and threatening the fragile balance of “good” and “bad” microbes in our guts (19).

So back to the study…. researchers performed a double-blind cross-over trial on 37 subjects. First they were all stabilized on a reduced FODMAP diet and then were randomly placed on one of four diets for one week– high-gluten, low-gluten, whey protein or control. After a two week break, twenty two of the participants were then “crossed over” into groups given one of three diets for three days – high-gluten, whey protein or a control diet. In all participants symptoms improved on the reduced FODMAP diet and worsened to a similar extent when they received either gluten or whey protein. Results showed gluten-specific effects in only 8% of participants with a large proportion of the subjects experiencing no worsening of symptoms after a gluten challenge while on the reduced FODMAP diet (18).

Other research also points to fructans present in wheat, barley and rye as a probable culprit for at least some of the symptoms of people with NCGS (20). A 2018 randomized, placebo-controlled, cross-over study stabilized participants on a gluten-free diet then had them consume a daily muesli bar containing either 5.6 gm of gluten (but no fructans), 2.1 gm of fructans (but no gluten) or a placebo containing neither gluten nor fructans. NCGS symptoms were significantly higher after ingestion of the fructan-containing bar compared to the effects from the gluten-containing bar or the placebo (20). Although intolerance to fructans and other FODMAPs may contribute to NCGS symptoms they only explain the gastrointestinal symptoms and not the effects on other body processes such as skin rash, “brain fog”, depression and chronic fatigue (21). It is likely that fructans are not the sole cause of NCGS.

There is yet another group of plant proteins present in wheat, barley and rye that are a potential cause of NCDS symptoms. These are α-amylase-trypsin inhibitors (ATI) (22,23). ATIs protect plants against pests through their inhibition of the digestive enzymes of the bugs. ATIs resist digestion in the human intestine and can activate immune cells such as monocytes and macrophages causing inflammation (24). Levels of ATIs in wheat have increased over time due to selective breeding for wheat varieties that are more pest resistant (23). The study of ATIs and gastrointestinal problems is still in its infancy. More studies are needed to examine the effects of ATI-free diets in human beings and to compare diets including modern wheat with those using ancient cultivars of wheat such as Einkorn and Emmer.



Complicating the story further are other conditions that can be confused with NCGS. Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis show very similar symptoms to those of NCGS and their presence should be ruled out before a diagnosis of NCGS. It is not unusual for inflammatory bowel diseases and NCGS to be present in the same patient. Celiac disease has been found to be four times more common in those with inflammatory bowel disease (9,25). In addition, people who suffer reactions from wheat or gluten often have a variety of other food sensitivities. About two-thirds of NCGS sufferers are sensitive to cow’s milk and a somewhat lower proportion show problems after egg consumption (13). Additional alternative diagnoses to NCGS include fructose or lactose intolerance, small intestinal bacterial overgrowth (SIBO) and reactions to other components of grains such as alpha amylase trypsin inhibitors (ATIs), wheat-germ agglutinin or fermentable carbohydrates (FODMAPs) (21,26,27). A cross-sectional study was performed on 84 patients with NCGS symptoms who avoided gluten and were being reassessed by gastroenterologists at one celiac disease centre. 30% of these patients were in fact rediagnosed as having small intestinal bacterial overgrowth, fructose or lactose intolerance, colitis, gastroparesis or pelvic floor dysfunction. (28)

The story of NCGS is far from over. Scientific investigations continue to pursue an answer to the puzzle of defining this condition and its cause. A diagnosis of celiac disease means avoiding gluten-containing foods for life. However, if you have symptoms of NCGS, simply avoiding gluten is obviously not the answer to this problem. In fact, restricting gluten intake unnecessarily can be a very unhealthy lifestyle choice. Watch for the next blog for a review of some important considerations to take into account when confronting possible NCGS and the adoption of a gluten-free diet.



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3 – Di Sabatino, A., Coraza, G.R. Nonceliac gluten sensitivity: sense or sensibility? Ann Intern Med. 2012 Feb 21; 156(4):309-311.

4 – Fasano, A., Berti, I., Gerarduzzi, T., Not, T., Colletti, R.B., Drago, S., Elitsur, Y., Green, P.H., Guandalini, S., Hill, I.D., et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286–292.

5 – Volta, U., Bellentani, S., Bianchi, F.B., Brandi, G. De Franceschi, L., Miglioli, L., Granito, A., Balli, F., Tiribelli, C. High prevalence of celiac disease in Italian general population. Dig Dis Sci. 2001; 46:1500–1505.

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7 – Sapone, A., Bai, J.C., Ciacci, C., Dolinsek, J., Green, P.H.R., Hadjivassiliou, M., Kaukinen, K., Rostami, K., Sanders, D.S., Schumann, M., Ullrich, R., Villalta, D., Volta, U., Catassi, C., Fasano, A. Spectrum of gluten-related disorders: Consensus on new nomenclature and classification. BMC Med 2012 10:1.

8 – Mooney, P.D., Aziz, I., Sanders, D.S. Non-celiac gluten sensitivity: Clinical relevance and recommendations for future research. Neurogastroenterol. Motil. 2013; 25(11):864 – 871.

9 – Ontiveros, N., Hardy, M.Y., Cabrera-Chavez, F. Assessing of Celiac Disease and Nonceliac Gluten Sensitivity. Gastroenterol Res Pract. 2015; 2015: 723954.

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11 – Biesiekierski, J.R., Newnham, E.D., Irving, P.M., Barrett, J.S., Haines, M., Doecke, J.D., Shepherd, S.J., Muir, J.G., Gibson, P.R. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 2011; 106(3):508 – 514.

12 – Volta, U., Bardella, M.T., Calabrò, A., Troncone, R., Corazza, G.R. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014 May 23;12:85.

13 – Carroccio, A., Mansueto, P., Iacono, G., Soresi, M., D’Alcamo, A., Cavataio, F., Brusca, I., Florena, A.M., Ambrosiano, G., Seidita, A., Pirrone, G., Rini, G.B. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: Exploring a new clinical entity. Am. J. Gastroenterol. 2012 107(12):1898 – 1906.

14 – Carroccio, A., Rini, G., and Mansueto, P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014; 146: 320–321.

15 – Di Sabatino, A., Volta, U., Salvatore, C. et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clin Gastroenterol Hepatol. 2015; 13: 1604–1612.

16 – Elli, L., Tomba, C., Branchi, F. et al. Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: results from a multicenter randomized double-blind placebo-controlled gluten challenge. Nutrients. 2016; 8: 84.

17 – Brottveit, M., Vandvik, P.O., Wojniusz, S., Lovik, A, Lundin, K.E., Boye, B. Absence of somatization in non-coeliac gluten sensitivity. Scand. J. Gastroenterol. 2012 47(7):770 – 777.

18 – Biesiekierski, J.R., Peters, S.L., Newnham, E.D. et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013; 145: 320–328.

19 – Hill, P., Muir, J.G., Gibson, P.R. Controversies and Recent Developments of the Low-FODMAP Diet. Gastroenterol Hepatol (N Y). 2017 Jan; 13(1): 36–45.

20 – Skodje, G.I., Sarna, V.K., Minelle, I.H. et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018; 154: 529–539.

21 – Aziz, I., Hadjivassiliou, M., Sanders, D.S. The spectrum of noncoeliac gluten sensitivity. Nat Rev Gastroenterol Hepatol Sep 2015 (Review); 12 (9): 516–526.

22 – Schuppan, D., Pickert, G., Ashfaq-Khan, M., Zevallos, V. Non-celiac wheat sensitivity: Differential Diagnose, Triggers and implications. Best Practice and Research Clinical Gastroenterology 2015; 29: 469-476.

23 – Zevallos, V.F., Raker, V., Tenzer, S. et al. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology. 2017; 152: 1100–1113.e12.

24 – Junker, Y., Zeissig, S., Kim, S.J. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of Toll-like receptor 4. J Exp Med. 2012; 209: 2395–2408.

25 – Cristofori, F., Fontana, C., Magistà, A., Capriati, T., Indrio, F., Castellaneta, S., Cavallo, L., Francavilla, R. Increased prevalence of celiac disease among pediatric patients with irritable bowel syndrome: a 6-year prospective cohort study.
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26 – Volta, U., Caio, G., De Giorgio, R., Henriksen, C., Skodje, G., Lundin, K.E. Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders. Best Pract Res Clin Gastroenterol June 2015 (Review); 29 (3): 477–491.

27 – Lebwohl, B., Ludvigsson, J.F., Green, P.H. (Oct 2015). Celiac disease and non-celiac gluten sensitivity. BMJ Oct 2015 (Review); 5: 351:h4347.

28 – Tavakkoli, A., Lewis, S.K., Tennyson, C.A., Lebwohl, B., Green, P.H. Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease. Dig Dis Sci. 2014 Jun; 59(6):1255-1261.

29 – Bascu~nan, K.A., Roncoroni, L., Branchi, F., Doneda, L., Scricciolo, A., Ferretti, F., Araya, M., Elli, L. The 5 Ws of a gluten challenge for gluten-related disorders. Nutrition Reviews; 76(2): 79–87.

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My name is Debra Harley (BScPhm) and I welcome you to my retirement project, this website. Over the course of a life many lessons are learned, altering deeply-rooted ideas and creating new passions.

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