Skip to main content

Advertisement

Log in

Is Gluten a Cause of Gastrointestinal Symptoms in People Without Celiac Disease?

Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

The avoidance of wheat- and gluten-containing products is a worldwide phenomenon. While celiac disease is a well-established entity, the evidence base for gluten as a trigger of symptoms in patients without celiac disease (so-called ‘non-celiac gluten sensitivity’ or NCGS) is limited. The problems lie in the complexity of wheat and the ability of its carbohydrate as well as protein components to trigger gastrointestinal symptoms, the potentially false assumption that response to a gluten-free diet equates to an effect of gluten withdrawal, and diagnostic criteria for coeliac disease. Recent randomized controlled re-challenge trials have suggested that gluten may worsen gastrointestinal symptoms, but failed to confirm patients with self-perceived NCGS have specific gluten sensitivity. Furthermore, mechanisms by which gluten triggers symptoms have yet to be identified. This review discusses the most recent scientific evidence and our current understanding of NCGS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fry L. Dermatitis herpetiformis. In: Marsh M, editor. Coeliac disease. Oxford: Blackwell Scientific Publications; 1992.

    Google Scholar 

  2. Hadjivassiliou M, Grunewald RA, Davies-Jones GAB. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002;72(5):560–3.

    Article  PubMed  CAS  Google Scholar 

  3. Dickey W, Kearney N. Overweight in celiac disease: prevalence, clinical characteristics, and effect of a gluten-free diet. Am J Gastoenterol. 2006;101(10):2356–9.

    Article  CAS  Google Scholar 

  4. Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, et al. Food allergy and infantile autism. Panminerva Medica. 1995;37(3):137–41.

    Google Scholar 

  5. Hadley SK, Gaarder SM. Treatment of irritable bowel syndrome. Am Fam Physician. 2005;72(12):2501–6.

    PubMed  Google Scholar 

  6. Wieser H. Chemistry of gluten proteins. Food Microbiol. 2007;24(2):115–9.

    Article  PubMed  CAS  Google Scholar 

  7. • Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med. 2012;209(13):2395–408. Demonstration of a proinflammatory effect of a non-gluten protein in wheat.

  8. • Eswaran S, Muir J, Chey WD. Fiber and functional gastrointestinal disorders. Am J Gastroenterol. 2013;108:718–27. Up-to-date review of fibre and its potential in symptom induction and therapy in functionial gastrointestinsl disorders.

    Article  PubMed  CAS  Google Scholar 

  9. Kelly G. Inulin-type prebiotics: a review. (Part 2). Altern Med Rev. 2009;14:36–55.

    PubMed  Google Scholar 

  10. Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther. 2007;25(4):349–63.

    Article  PubMed  CAS  Google Scholar 

  11. Barrett JS, Gearry RB, Muir JG, Irving PM, Rose R, Rosella O, et al. Dietary poorly absorbed, short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon. Aliment Pharmacol Ther. 2010;31(8):874–82.

    PubMed  CAS  Google Scholar 

  12. • Shepherd SJ, Lomer MC, Gibson PR. Short-chain carbohydrates and functional gastrointestinal disorders. Am JGastroenterol. 2013;108(5):707–17. Up-to-date review of short-chain carbohydrates on functional gastrointestinal disorders focussing mostly on fodmaps.

    Article  CAS  Google Scholar 

  13. • Monash University Low FODMAP App (homepage on the internet). Melbourne, Monash University. Available from: http://www.med.monash.edu/cecs/gastro/fodmap/iphone-app.html. Recently released app containing up-to-date listing of the fodmap content of foods as found on the Monash University database.

  14. •• Biesiekierski JR, Rosella O, Rose R, Liels K, Barrett JS, Shepherd SJ, et al. Quantification of fructans, galacto-oligosacharides and other short-chain carbohydrates in processed grains and cereals. J Hum Nutr Diet 2011;24(2):154–76. Demonstration that gluten-containing grains are rich in fructans and vice-versa.

  15. • de Punder K, Pruimboom L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutritents. 2013;5:771–87. Useful review with particular reference to wheat germ agglutinin to remind that potentially pathogenic lectins are also present in wheat.

    Article  Google Scholar 

  16. Quigley EM, Abdel-Hamid H, Barbara G, Bhatia SJ, Boeckxstaens G, De Giorgio R, et al. A global perspective on irritable bowel syndrome: a consensus statement of the World Gastroenterology Organisation Summit Task Force on irritable bowel syndrome. J Clin Gastroenterol. 2012;46:356–66.

    Article  PubMed  Google Scholar 

  17. Anonymous. Therapeutic Guidelines: Gastrointestinal Version 5, 2011, Therapeutic Guidelines Limited: Melbourne, Australia.

  18. Catassi C, Anderson RP, Hill ID, Koletzko S, Lionetti E, Mouane N, Schumann M, Yachha SK. World perspective on celiac disease. J Pediatr Gastroenterol Nutr 2012;55(5):494–9.

    Google Scholar 

  19. Anderson RP et al. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 2000;6(3):337–42.

    Article  PubMed  CAS  Google Scholar 

  20. Haines ML, Anderson RP, Gibson PR. Systematic review: the evidence base for long-term management of coeliac disease. Aliment Pharmacol Ther. 2008;28(9):1042–66.

    Article  PubMed  CAS  Google Scholar 

  21. • Kupfer SS, Jabri B. Pathophysiology of celiac disease. Gastrointest Endosc Clin N Am. 2012;22:639–60. Up-to-date review on developments in the pathogenesis of celaic disease in terms of genetics, immunology and environment.

    Article  PubMed  Google Scholar 

  22. Kagnoff MF. Two genetic loci control the murine immune response to A-gliadin, a wheat protein that activates coeliac sprue. Nature. 1982;296(5853):158–60.

    Article  PubMed  CAS  Google Scholar 

  23. Lundin KE, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, et al. Gliadin-specific, HLA-DQ(alpha 1*0501, beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med. 1993;178(1):187–96.

    Google Scholar 

  24. Lundin KE, Gjertsen HA, Scott H, Sollid LM, Thorsby E. T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease patient preferentially recognize gliadin when presented by DQ8. Hum Immunol. 1994;41(4):285–91.

    Google Scholar 

  25. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol. 2002;2(9):647–55.

    Article  PubMed  CAS  Google Scholar 

  26. Catassi C, Kryszak D, Bhatti B, Sturgeon C, Helzlsouer K, Clipp SL, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010;42(7):530–8.

    Google Scholar 

  27. Holtmeier W, Caspary WF. Celiac disease. Orphanet J Rare Dis. 2006;1:3.

    Article  PubMed  Google Scholar 

  28. •• Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13. Important international effort to provide consensus opinion on a classification of gluten-related disorders.

  29. •• Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62(1):43–52. Important international effort to define various issues in celiac disease.

  30. http://www.bsg.org.uk/sections/small-bowel-nutrition-articles/bsg-guidance-on-coeliac-disease-2010.html

  31. Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136–60.

    Article  PubMed  CAS  Google Scholar 

  32. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656–76.

    Article  PubMed  CAS  Google Scholar 

  33. Bai JC, Fried M, Corazza GR, Schuppan D, Farthing M, Catassi C, et al. World gastroenterology organisation global guidelines on celiac disease. J Clin Gastroenterol. 2013;47(2):121–6.

    Article  PubMed  Google Scholar 

  34. Catassi C, Fabiani E, Iacono G, D'Agate C, Francavilla R, Biagi F, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007;85(1):160–6.

    Google Scholar 

  35. Tanabe S. Analysis of food allergen structures and development of foods for allergic patients. Biosci Biotechnol Biochem. 2008;72(3):649–59.

    Article  PubMed  CAS  Google Scholar 

  36. Brandtzaeg P. Food allergy: separating the science from the mythology. Nat Rev Gastroenterol Hepatol. 2010;7(7):380–400.

    Article  PubMed  CAS  Google Scholar 

  37. •• Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012;107(12):1898–906. Provocative study suggesting that many patients with irritable bowel syndrome have wheat hypersensitivity, many having specific histopathological findings. The findings need to be reproduced at other centres.

    Article  PubMed  Google Scholar 

  38. Carroccio A, Brusca I, Mansueto P, Pirrone G, Barrale M, Di Prima L, et al. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2010;8(3):254–60.

    Article  PubMed  Google Scholar 

  39. Carroccio A, Brusca I, Mansueto P, Soresi M, D’Alcamo A, Ambrosiano G, et al. Fecal assays detect hypersensitivity to cow’s milk protein and gluten in adults with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2011;9(11):965–71.

    Article  PubMed  CAS  Google Scholar 

  40. • Carroccio A, Brusca I, Mansueto P, D’alcamo A, Barrale M, Soresi M, et al. A comparison between two different in vitro basophil activation tests for gluten- and cow’s milk protein sensitivity in irritable bowel syndrome (IBS)-like patients. Clin Chem Lab Med. 2013;51(6):1257–63. Study confirming the potential value of the basophil activation test in identifying patients with wheat intolerance and irritable bowel syndrome.

    Article  PubMed  Google Scholar 

  41. Jones VA. Food intolerance: A major factor in the pathogenesis of irritable bowel syndrome. Lancet. 1982;2(8308):1115–7.

    Article  PubMed  CAS  Google Scholar 

  42. Dickerson JWT, Ballantine L, Hastrop K. Food allergy. Lancet. 1978;1(8061):773.

    Article  Google Scholar 

  43. Ellis A, Linaker BD. Non-coeliac gluten sensitivity? Lancet. 1978;1(8061):1358.

    Article  PubMed  CAS  Google Scholar 

  44. Cooper BT, Holmes GK, Ferguson R, Thompson RA, Allan RN, Cooke WT Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology. 1980;79:801–6.

    Google Scholar 

  45. Suter D, Fleming F. Cereal food allergy issues, opportunities and the way forward for industry. in 41st AIFST Convention. 2008. Sydney, Australia.

  46. Vinning G,McMahon G. Gluten-free Grains. A demand-and-supply analysis of prospects for the Australian grains industry. Rural industries Research and Development Corporation: Canberra. 2006. 21(5): p. 359–65.

  47. Sander GR, Cummins AG, Powell BC. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett. 2005;579(21):4851–5.

    Article  PubMed  CAS  Google Scholar 

  48. Giovannini C, Sanchez M, Straface E, Scazzocchio B, Silano M, De Vincenzi M. Induction of apoptosis in Caco-2 cells by wheat gliadin peptides. Toxicology. 2000;145(1):63–71.

    Google Scholar 

  49. Hadjivassiliou M, Williamson CA, Woodroofe N. The immunology of gluten sensitivity: Beyond the gut. Trends Immunol. 2004;25(11):578–82.

    Article  PubMed  CAS  Google Scholar 

  50. Rivabene R, Mancini E, DeVincenzi M. In vitro cytotoxic effect of wheat gliadin-derived peptides on the Caco-2 intestinal cell line is associated with intracellular oxidative imbalance: implications for coeliac disease. Biochim Biophys Acta. 1999;1453:152–60.

    Article  PubMed  CAS  Google Scholar 

  51. Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, et al. Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G217–25.

    Google Scholar 

  52. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001;121:1329–38.

    Google Scholar 

  53. Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2007;5(7):844–50.

    Google Scholar 

  54. Picarelli A, Maiuri L, Mazzilli MC, Coletta S, Ferrante P, Di Giovambattista F, et al. Gluten-sensitive disease with mild enteropathy. Gastroenterology. 1996;111:608–16.

    Google Scholar 

  55. •• Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508–14. The first randomised controlled parallel-group re-challenge trial of fodmap-deplete gluten in patients with self-perceived non-celiac gluten sensitivity showing gluten-specific induction of gastrointestinal symptoms and tiredness. Mechansism were not identified.

  56. Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: Celiac disease and gluten sensitivity. BMC Med. 2011;9:23.

    Google Scholar 

  57. Volta U, Tovoli F, Cicola R, Parisi C, Fabbri A, Piscaglia M, et al. Serological tests in gluten sensitivity (nonceliac gluten intolerance). J Clin Gastroenterol. 2012;46(8):680–5.

    Google Scholar 

  58. • Vazquez-Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O'Neill J, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013;144(5):903–11. Detailed study of gluten-containing and gluten-free diets in patients with diarrhea-predominant irrtiable bowel sydnrome, indicating that intestinal permeability is higher on the gluten-containing diet. However, the effect was not defined as gluten-specific.

  59. •• Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. 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(2):320–328. Cross-over, re-challenge study of fodmap-deplete gluten in patients with self-perceived non-celiac gluten sensitivity on a low fodmap background. Diets were rigorously controlled. While patients did improve on initial fodmap restriction, no gluten-specific effect on gastrointestinal symtpoms was identified.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Jessica R. Biesiekierski, Jane G. Muir, and Peter R. Gibson declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with animal subjects performed by the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter R. Gibson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biesiekierski, J.R., Muir, J.G. & Gibson, P.R. Is Gluten a Cause of Gastrointestinal Symptoms in People Without Celiac Disease?. Curr Allergy Asthma Rep 13, 631–638 (2013). https://doi.org/10.1007/s11882-013-0386-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-013-0386-4

Keywords

Navigation