Gluten sensitivity

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Gluten-related disorders

Gluten sensitivity (also gluten intolerance) is a spectrum of disorders including celiac disease in which gluten has an adverse effect on the body. Symptoms include bloating, abdominal discomfort or pain, diarrhea, constipation, muscular disturbances, headaches, migraines, severe acne, fatigue, and bone or joint pain.[1][2]

However, self-reported non-celiac gluten sensitivity may not be a discrete entity or part of this spectrum disorder bringing its role in functional bowel disorders like irritable bowel syndrome into question.[3]

Gluten, named from the Latin gluten meaning glue,[4] is a substance that gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet.


More than 250 symptoms of gluten sensitivity have been reported, including bloating, abdominal discomfort or pain, constipation and diarrhea. [5] Sensitivity may also present with extraintestinal symptoms, including headache, “brain fog,” tingling and/or numbness in hands and feet, fatigue, as well as muscular disturbances and bone or joint pain;[1][2][6] also neuropsychiatric manifestations have been reported on.[7]

Difference between idiopathic gluten sensitivity and celiac disease[edit]

In a 2009 paper, Verdu et al. defined gluten sensitivity as "one or more of a variety of immunological, morphological or symptomatic manifestations that may also be shared by celiac disease and irritable bowel syndrome (IBS)".[8] In cases where there is reactivity to gluten, yet celiac disease and wheat allergy are eliminated as possibilities, non-celiac gluten sensitivity (NCGS) may be considered. While the general clinical picture for NCGS is similar to celiac disease in particular, it is usually less severe and neither anti-tissue transglutaminase antibodies nor autoimmune comorbidities are found.

However, in 2013, Biesiekierski JR et al. concluded that NCGS, as currently defined, might not be a discrete entity (or its effects might be confounded by FODMAP restriction), and that gluten might not cause functional gut symptoms once dietary FODMAPs are reduced.[3] An editorial in Gastroenterology calls into question the existence of NCGS as a discrete entity.[9] The authors[clarification needed] suggest that reduction of FODMAPs, rather than gluten or other wheat proteins, might be mechanism by which low-gluten diets improve gastrointestinal symptoms. These findings suggest that gluten sensitivity may not play a significant role in the etiology of functional gastrointestinal disorders like irritable bowel syndrome.

Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should[clarification needed] eventually fall into gluten-sensitive enteropathy (GSE)[clarification needed] or wheat allergy. Only rarely should[clarification needed][citation needed] gluten sensitivity be idiopathic. Idiopathic gluten sensitivity (IGS)[clarification needed] arises spontaneously or from an obscure or unknown cause and may involve neuropathy, myopathy, dermal, or intestinal abnormalities. Anti-gliadin antibodies are the primary link between gluten and idiopathic sensitivity in instances "in which enteropathy or allergy are not clearly involved".[not in citation given][10]


When enteropathy develops in early childhood, symptomatic disease is more rapidly evident. A survey of geriatrics with celiac disease in Finland revealed that the incidence of disease was much higher than the general population.[11] Allergic disease may rise or fall with age; certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as an increased risk factor for urticaria or anaphylaxis, and the sensitizing dose may include low-dose aspirin therapy used in the treatment of heart disease. Idiopathic disease appears largely late onset[clarification needed][citation needed].

A double-blind placebo-controlled trial found that gluten caused significantly worse pain, tiredness, bloating and stool consistency than a placebo diet in IBS patients. There was no difference in celiac or gliadin antibodies between the gluten and control groups.[12] However a more detailed follow-up trial by the same authors found no difference between gluten or placebo groups.[3]

Causes of gluten sensitivity[edit]

Immunochemistry of glutens[edit]

Triticeae glutens are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), class II mediated presentation (HLA DQ), class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In enteropathy, there are at least 3 types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ and antibody recognition of gliadin and transglutaminase.[13] With idiopathic disease only antibody recognition to gliadin has been resolved[clarification needed]. In wheat allergy, there appears to be an innate component and the response pathways are mediated through IgE against gliadin and other wheat proteins.[14][15][16]

Separating forms of gluten sensitivity[edit]

Persons suspected of having celiac disease may be tested for anti-transglutaminase antibodies followed by duodenal biopsy; this test will confirm or refute active celiac disease.[17] The study that recommends this has some ATA positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology.[18][19]

One study recommended biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of celiac disease can generally be done by adding HLA-DQ typing, (in which DQ2 and DQ8 are found in coeliac disease 98% of the time in Caucasians, DQ7.5 the remaining 1.6% and 0.4% not found with either of these 3). Without ATA or HLA-DQ2/8 positivity, celiac disease is not likely the cause of the sensitivity. In either case, other avenues of diagnostics, such as allergy testing are available.[20]

A literature review of 2014 found that patients suffering from non-coeliac gluten sensitivity "are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis and clinical history, and, probably, clinical course" and that non-coeliac gluten sensitivity diagnosis can be reached only by excluding celiac disease and wheat allergy.[21] Another review article emphasizes that a final confirmation of NCGS diagnosis requires, additionally, a positive oral gluten challenge after at least three weeks of gluten-free diet.[22]

Rarely gluten sensitivity may be idiopathic[clarification needed], a potential that[clarification needed] wheat proteins play a role in other disease, in these instances DQ1 may be associated with sensitivity. There is research showing that in certain patients with gluten ataxia early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression.[23]

Idiopathic gluten sensitivity[edit]

Studies using anti-gliadin antibodies (AGA) reveal that diagnosed or untreated[clarification needed] individuals with AGA have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.[24]


Other conditions[edit]

Antibodies to α-gliadin have been significantly increased in non-celiacs individuals with oral ulceration.[25] Anti-α-gliadin antibodies are frequently found in celiac disease (CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA.[26] One fourth of people with Sjögren's syndrome had responses to gluten, of 5 that had positive response to gluten, only one could be confirmed as CD and another was potentially GSE[clarification needed], the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.[27]


Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates.[28] Recent studies show that gluten-sensitive individuals on a gluten-free diet often get too much simple carbohydrate, too little fiber and vitamin B. Currently most guidelines do not include oats in a gluten-free diet. While this is likely to change, oats are not recommended within a year of diagnosis because of the oat-sensitive enteropathy (ASE) risk, the desire to establish a clinical baseline and complexity of the contamination issue.[29]

Consuming oats when anti-gliadin antibodies or gliadin are present increases anti-avenin antibodies, and may promote ASE. Duodenal biopsy may be recommended after oat consumption is initiated. The DQ phenotype of all 3 ASE individuals studied so far indicated DQ2 homozygotes are at risk for ASE.

Preferably, newly diagnosed celiacs seek the help of a dietician. Guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet.[30]

Sensitivity to other proteins in wheat[edit]

Some patients' may have a reaction not (or not only) to gluten as such, but to other substances present in wheat.

Specifically, in a publication of 2012, a particular fraction of wheat albumin that is able to inhibit amylase and trypsin (α-amylase/trypsin inhibitors (ATIs) from wheat, which are part of the plant's natural defense against insects) was shown to cause Toll-like receptor 4 (TLR4)-mediated intestinal inflammation in humans.[31][32] This can be the case for both celiac and non-celiac patients. Detlef Schuppan, whose research team discovered this role of the ATIs, emphasizes that modern wheat cultivations are bred to have a high ATI content and that this may play a role in the onset and course of disorders such as celiac disease and gluten sensitivity.[33]


Recent studies indicate that AGA IgG is high in slightly more than half of NCGS patients[22] and that for these patients, unlike for coeliac disease patients, the IgG AGA decreases strongly over 6 months of gluten-free diet; AGA IgA is usually very low in NGCS patients.[22][34][35]

There are many open question on gluten sensitivity and, as stated in a review article, "there is general agreement in the scientific community that additional studies are needed to shed light on NCGS".[35] In another review, it is emphasized that "it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity".[36] The need for developing biomarkers for NCGS is frequently emphasized;[22][37] for example, the authors of a recent review article indicate: "There is a desperate need for reliable biomarkers and/or an algorithm that include clinical, biochemical and histopathological findings which support the diagnosis of NCGS."[6]

See also[edit]


  1. ^ a b Sapone A, Lammers KM, Mazzarella G, et al. (2010). "Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease". Int. Arch. Allergy Immunol. (Research Support, N.I.H., Extramural) 152 (1): 75–80. doi:10.1159/000260087. PMC 2956008. PMID 19940509. 
  2. ^ a b Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, et al. (April 2007). "Myopathy associated with gluten sensitivity". Muscle Nerve (Research Support, Non-U.S. Gov't) 35 (4): 443–50. doi:10.1002/mus.20709. PMID 17143894. 
  3. ^ a b c Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR (August 2013). "No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates". Gastroenterology (Randomized Controlled Trial) 145 (2): 320–8.e1–3. doi:10.1053/j.gastro.2013.04.051. PMID 23648697. 
  4. ^ "Gluten" def. 3. Oxford English Dictionary Second Edition on CD-ROM (v. 4.0) © Oxford University Press 2009
  5. ^ Korn, Danna. Living gluten-free for dummies. Hoboken, NJ: Wiley Pub., 2006. 14, 27-31. Print.
  6. ^ a b Nijeboer P, Bontkes HJ, Mulder CJ, Bouma G (December 2013). "Non-celiac gluten sensitivity. Is it in the gluten or the grain?". Journal of Gastrointestinal and Liver Diseases : JGLD (Review) 22 (4): 435–40. PMID 24369326. 
  7. ^ Genuis, Stephen J.; Lobo, Rebecca A. (2014). "Gluten Sensitivity Presenting as a Neuropsychiatric Disorder". Gastroenterology Research and Practice (Review) 2014: 1–6. doi:10.1155/2014/293206. ISSN 1687-6121. PMID 24693281. 
  8. ^ Verdu EF, Armstrong D, Murray JA (June 2009). "Between celiac disease and irritable bowel syndrome: the "no man's land" of gluten sensitivity". Am. J. Gastroenterol. (Review) 104 (6): 1587–94. doi:10.1038/ajg.2009.188. PMC 3480312. PMID 19455131. 
  9. ^ Vanga R, Leffler DA (August 2013). "Gluten sensitivity: not celiac and not certain". Gastroenterology (Comment) 145 (2): 276–9. doi:10.1053/j.gastro.2013.06.027. PMID 23806541. 
  10. ^ Hadjivassiliou M, Grünewald R, Sharrack B, et al. (March 2003). "Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics". Brain 126 (Pt 3): 685–91. doi:10.1093/brain/awg050. PMID 12566288. 
  11. ^ Vilppula A, Collin P, Mäki M, et al. (October 2008). "Undetected coeliac disease in the elderly: a biopsy-proven population-based study". Dig Liver Dis (Research Support, Non-U.S. Gov't) 40 (10): 809–13. doi:10.1016/j.dld.2008.03.013. PMID 18467196. 
  12. ^ Biesiekierski, Jessica R et al (March 2011). "Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial". Am J Gastroenterol (Controlled Clinical Trial) 106 (3): 508–514. doi:10.1038/ajg.2010.487. PMID 21224837. 
  13. ^ van Heel DA, West J (July 2006). "Recent advances in coeliac disease". Gut (Review) 55 (7): 1037–46. doi:10.1136/gut.2005.075119. PMC 1856316. PMID 16766754. 
  14. ^ Bittner C, Grassau B, Frenzel K, Baur X (March 2008). "Identification of wheat gliadins as an allergen family related to baker's asthma" (Research Support, Non-U.S. Gov't) (3). pp. 744–9. doi:10.1016/j.jaci.2007.09.051. PMID 18036646. 
  15. ^ Matsuo H, Dahlström J, Tanaka A, et al. (February 2008). "Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis". Allergy (Evaluation Studies) 63 (2): 233–6. doi:10.1111/j.1398-9995.2007.01504.x. PMID 18186814. 
  16. ^ Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K (August 2007). "Proteomic analysis of wheat flour allergens". Journal of Agricultural and Food Chemistry (Research Support, Non-U.S. Gov't) 55 (17): 6863–70. doi:10.1021/jf070843a. PMID 17655322. 
  17. ^ Hopper AD, Cross SS, Hurlstone DP, et al. (April 2007). "Pre-endoscopy serological testing for celiac disease: evaluation of a clinical decision tool". BMJ (Evaluation Studies) 334 (7596): 729. doi:10.1136/bmj.39133.668681.BE. PMC 1847864. PMID 17383983. 
  18. ^ Hopper AD, Cross SS, Sanders DS (March 2008). "Patchy villous atrophy in adult patients with suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy appropriate?". Endoscopy (Clinical Trial) 40 (3): 219–24. doi:10.1055/s-2007-995361. PMID 18058655. 
  19. ^ Kaukinen K, Peräaho M, Collin P, et al. (May 2005). "Small-bowel mucosal transglutaminase 2-specific IgA deposits in celiac disease without villous atrophy: a prospective and randomized clinical study". Scand. J. Gastroenterol. (Clinical Trial) 40 (5): 564–72. doi:10.1080/00365520510023422. PMID 16036509. 
  20. ^ Kaukinen K, Turjanmaa K, Mäki M, et al. (September 2000). "Intolerance to cereals is not specific for coeliac disease". Scand. J. Gastroenterol. (Research Support, Non-U.S. Gov't) 35 (9): 942–6. doi:10.1080/003655200750022995. PMID 11063153. 
  21. ^ Mansueto, Pasquale; Seidita, Aurelio; D’Alcamo, Alberto; Carroccio, Antonio (2014). "Non-Celiac Gluten Sensitivity: Literature Review". Journal of the American College of Nutrition (Review) 33 (1): 39–54. doi:10.1080/07315724.2014.869996. ISSN 0731-5724. PMID 24533607. 
  22. ^ a b c d Catassi, Carlo; Bai, Julio; Bonaz, Bruno; Bouma, Gerd; Calabrò, Antonio; Carroccio, Antonio; Castillejo, Gemma; Ciacci, Carolina; Cristofori, Fernanda; Dolinsek, Jernej; Francavilla, Ruggiero; Elli, Luca; Green, Peter; Holtmeier, Wolfgang; Koehler, Peter; Koletzko, Sibylle; Meinhold, Christof; Sanders, David; Schumann, Michael; Schuppan, Detlef; Ullrich, Reiner; Vécsei, Andreas; Volta, Umberto; Zevallos, Victor; Sapone, Anna; Fasano, Alessio (2013). "Non-celiac gluten sensitivity: the new frontier of gluten related disorders". Nutrients (Review) 5 (10): 3839–3853. doi:10.3390/nu5103839. ISSN 2072-6643. PMID 24077239. 
  23. ^ Hadjivassiliou M, Sanders DS, Woodroofe N, Williamson C, Grünewald RA (2008). "Gluten ataxia". Cerebellum (Review) 7 (3): 494–8. doi:10.1007/s12311-008-0052-x. PMID 18787912. 
  24. ^ Anderson LA, McMillan SA, Watson RG, et al. (2007). "Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity"". World J. Gastroenterol. (Retrospective Studies) 13 (1): 146–51. doi:10.3748/wjg.v13.i1.146. PMID 17206762. 
  25. ^ O'Farrelly C, O'Mahony C, Graeme-Cook F, Feighery C, McCartan BE, Weir DG (1991). "Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy". J. Oral Pathol. Med. 20 (10): 476–8. doi:10.1111/j.1600-0714.1991.tb00407.x. PMID 1753350. 
  26. ^ Ringvold A, Overgaard RG (1995). "Increased IgA antibodies to gluten and gliadin in serum of persons with ocular pseudo-exfoliation". Acta ophthalmologica Scandinavica (Comparative Study) 73 (2): 171–2. doi:10.1111/j.1600-0420.1995.tb00662.x. PMID 7656149. 
  27. ^ Lidén M, Kristjánsson G, Valtýsdóttir S, Hällgren R (2007). "Gluten sensitivity in patients with primary Sjögren's syndrome". Scand. J. Gastroenterol. (Research Support, Non-U.S. Gov't) 42 (8): 962–7. doi:10.1080/00365520701195345. PMID 17613926. 
  28. ^ Størsrud S, Hulthén LR, Lenner RA (July 2003). "Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences". Br. J. Nutr. (Research Support, Non-U.S. Gov't) 90 (1): 101–7. doi:10.1079/BJN2003872. PMID 12844381. 
  29. ^ Rashid, Mohsin (2007-06-08). "Guidelines for Consumption of Pure and Uncontaminated Oats by Individuals with Celiac Disease". Professional Advisory Board of Canadian Celiac Association. Retrieved 2008-08-14. 
  30. ^ Rashid M, Butzner D, Burrows V, et al. (October 2007). "Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association". Can. J. Gastroenterol. (Guideline) 21 (10): 649–51. PMC 2658132. PMID 17948135. 
  31. ^ Barone, Maria; Troncone, Riccardo; Auricchio, Salvatore (2014). "Gliadin Peptides as Triggers of the Proliferative and Stress/Innate Immune Response of the Celiac Small Intestinal Mucosa". International Journal of Molecular Sciences (Review) 15 (11): 20518–20537. doi:10.3390/ijms151120518. ISSN 1422-0067. PMID 25387079. 
  32. ^ Junker, Y.; Zeissig, S.; Kim, S.-J.; Barisani, D.; Wieser, H.; Leffler, D. A.; Zevallos, V.; Libermann, T. A.; Dillon, S.; Freitag, T. L.; Kelly, C. P.; Schuppan, D. (2012). "Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4". Journal of Experimental Medicine 209 (13): 2395–2408. doi:10.1084/jem.20102660. ISSN 0022-1007. PMID 23209313. 
  33. ^ Junker, Y.; Zeissig, S.; Kim, S.-J.; Barisani, D.; Wieser, H.; Leffler, D. A.; Zevallos, V.; Libermann, T. A.; Dillon, S.; Freitag, T. L.; Kelly, C. P.; Schuppan, D. (2012). "Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4". Journal of Experimental Medicine 209 (13): 2395–2408. doi:10.1084/jem.20102660. ISSN 0022-1007. PMID 23209313. more recent breeding of high yielding and highly pest-resistant wheat […] has led to a drastic increase of ATI content. […] Our finding of ATI as a potent stimulator of TLR4 in the intestine might not only be relevant to celiac disease, but is likely to have implications for patients with so-called gluten sensitivity and possibly for patients with irritable bowel syndrome, inflammatory bowel disease, and even nonintestinal inflammation. 
  34. ^ Caio, Giacomo; Volta, Umberto; Tovoli, Francesco; De Giorgio, Roberto (2014). "Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity". BMC Gastroenterology (Research Support, Non-U.S. Gov't) 14 (1): 26. doi:10.1186/1471-230X-14-26. ISSN 1471-230X. PMID 24524388. 
  35. ^ a b Volta, Umberto; Caio, Giacomo; Tovoli, Francesco; De Giorgio, Roberto (2013). "Non-celiac gluten sensitivity: an emerging syndrome with many unsettled issues". Italian Journal of Medicine 8 (4): 225. doi:10.4081/itjm.2013.461. ISSN 1877-9352. 
  36. ^ Volta, Umberto; De Giorgio, Roberto (2012). "New understanding of gluten sensitivity". Nature Reviews Gastroenterology & Hepatology (Review) 9 (5): 295–299. doi:10.1038/nrgastro.2012.15. ISSN 1759-5045. PMID 22371218. 
  37. ^ Mansueto, Pasquale; Seidita, Aurelio; D’Alcamo, Alberto; Carroccio, Antonio (2014). "Non-Celiac Gluten Sensitivity: Literature Review". Journal of the American College of Nutrition (Review) 33 (1): 39–54. doi:10.1080/07315724.2014.869996. ISSN 0731-5724. PMID 24533607. 
  38. ^