iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://dx.doi.org/10.1038/nrgastro.2015.107
The spectrum of noncoeliac gluten sensitivity | Nature Reviews Gastroenterology & Hepatology
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The spectrum of noncoeliac gluten sensitivity

Nature Reviews Gastroenterology & Hepatology volume 12, pages 516–526 (2015)Cite this article

Subjects

Key Points

  • Individuals are increasingly self-reporting gluten sensitivity and placing themselves on a gluten-free diet outside a diagnosis of coeliac disease or IgE-mediated wheat allergy

  • This clinical entity has been termed noncoeliac gluten sensitivity (NCGS)

  • The symptoms evoked by gluten in NCGS include a constellation of intestinal and extraintestinal symptoms

  • Nongluten components of the grain can also be responsible for triggering symptoms in individuals with NCGS

  • No diagnostic biomarkers to differentiate between gluten and nongluten components currently exist; positive antigliadin antibodies support the diagnosis of NCGS but have limited sensitivity and specificity

  • Patients presenting with NCGS are a heterogeneous group and should be counselled about the uncertainties surrounding their diagnosis

Abstract

The past 5 years have seen an increase in the use of a gluten-free diet outside a diagnosis of coeliac disease or IgE-mediated wheat allergy. This trend has led to the identification of a new clinical entity termed noncoeliac gluten sensitivity (NCGS). In this Review, we discuss the evidence for NCGS as demonstrated by the results of double-blind, placebo-controlled dietary rechallenge studies. Furthermore, the characteristic phenotype of individuals with NCGS is described as well as the symptom manifestations commonly reported after gluten exposure, which include intestinal symptoms consistent with IBS, and extraintestinal symptoms such as neurological dysfunction, psychological disturbances, fibromyalgia and skin rash. Moreover, emerging evidence suggests that NCGS can be associated with organic gastrointestinal pathologies, such as IBD, in which its presence might be a reflection of severe or stricturing disease. However, NCGS is not without its controversies and uncertainties, in particular pertaining to whether it is gluten or nongluten components of the grain evoking symptoms; evidence suggests that fermentable carbohydrates, amylase trypsin inhibitors and wheat-germ agglutinin can also be responsible culprits. Finally, we discuss the novel techniques that might help diagnose NCGS in the future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MRS of the cerebellum in patients with gluten ataxia.
Figure 2: A head MRI of a 55-year-old patient with intractable headaches and positive AGA (gluten encephalopathy), but no evidence of enteropathy.
Figure 3: Proposed effects of wheat-based constituents that trigger clinical symptoms in NCGS.

Similar content being viewed by others

References

  1. Aziz, I., Branchi, F. & Sanders, D. S. The rise and fall of gluten! Proc. Nutr. Soc. http://dx.doi.org/10.1017/S0029665115000038.

  2. Mooney, P. D., Hadjivassiliou, M. & Sanders, D. S. Coeliac disease. BMJ 348, g1561 (2014).

    PubMed  Google Scholar 

  3. Hadithi, M. et al. Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease. Ann. Intern. Med. 147, 294–302 (2007).

    PubMed  Google Scholar 

  4. Rubio-Tapia, A., Hill, I. D., Kelly, C. P., Calderwood, A. H. & Murray, J. A. ACG clinical guidelines: diagnosis and management of celiac disease. Am. J. Gastroenterol. 108, 656–676 (2013).

    Article  CAS  Google Scholar 

  5. Ludvigsson, J. F. et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 63, 1210–1228 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Hall, N. J., Rubin, G. & Charnock, A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment. Pharmacol. Ther. 30, 315–330 (2009).

    CAS  PubMed  Google Scholar 

  7. Lee, A. R., Ng, D. L., Zivin, J. & Green, P. H. Economic burden of a gluten-free diet. J. Hum. Nutr. Diet. 20, 423–430 (2007).

    CAS  PubMed  Google Scholar 

  8. Singh, J. & Whelan, K. Limited availability and higher cost of gluten-free foods. J. Hum. Nutr. Diet. 24, 479–486 (2011).

    CAS  PubMed  Google Scholar 

  9. Karajeh, M. A., Hurlstone, D. P., Patel, T. M. & Sanders, D. S. Chefs' knowledge of coeliac disease (compared to the public): a questionnaire survey from the United Kingdom. Clin. Nutr. 24, 206–210 (2005).

    PubMed  Google Scholar 

  10. Addolorato, G. et al. Social phobia in coeliac disease. Scand. J. Gastroenterol. 43, 410–415 (2008).

    PubMed  Google Scholar 

  11. Aziz, I. et al. Change in awareness of gluten-related disorders among chefs and the general public in the UK: a 10-year follow-up study. Eur. J. Gastroenterol. Hepatol. 26, 1228–1233 (2014).

    CAS  PubMed  Google Scholar 

  12. Ferch, C. C. & Chey, W. D. Irritable bowel syndrome and gluten sensitivity without celiac disease: separating the wheat from the chaff. Gastroenterology 142, 664–666 (2012).

    PubMed  Google Scholar 

  13. Spence, D. Bad medicine: food intolerance. BMJ 346, f529 (2013).

    PubMed  Google Scholar 

  14. Tanpowpong, P. et al. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Child. 97, 12–16 (2012).

    PubMed  Google Scholar 

  15. Rubio-Tapia, A., Ludvigsson, J. F., Brantner, T. L., Murray, J. A. & Everhart, J. E. The prevalence of celiac disease in the United States. Am. J. Gastroenterol. 107, 1538–1544 (2012).

    PubMed  Google Scholar 

  16. Aziz, I. et al. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur. J. Gastroenterol. Hepatol. 26, 33–39 (2014).

    PubMed  Google Scholar 

  17. Lis, D., Stellingwerff, T., Shing, C. M., Ahuja, K. D. & Fell, J. W. Exploring the popularity, experiences and beliefs surrounding gluten-free diets in non-coeliac athletes. Int. J. Sport Nutr. Exerc. Metab. 25, 37–45 (2015).

    PubMed  Google Scholar 

  18. Golley, S., Corsini, N., Topping, D., Morell, M. & Mohr, P. Motivations for avoiding wheat consumption in Australia: results from a population survey. Public Health Nutr. 18, 490–499 (2015).

    PubMed  Google Scholar 

  19. Mardini, H. E., Westgate, P. & Grigorian, A. Y. Racial differences in the prevalence of celiac disease in the US population: National Health and Nutrition Examination Survey (NHANES) 2009–2012. Dig. Dis. Sci. 60, 1738–1742 (2015).

    PubMed  Google Scholar 

  20. Cooper, B. T., Holmes, G. K., Ferguson, R., Thompson, R. & Cooke, W. T. Proceedings: Chronic diarrhoea and gluten sensitivity. Gut 17, 398 (1976).

    CAS  PubMed  Google Scholar 

  21. Ellis, A. & Linaker, B. D. Non-coeliac gluten sensitivity? Lancet 1, 1358–1359 (1978).

    CAS  PubMed  Google Scholar 

  22. Cooper, B. T. et al. Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology 79, 801–806 (1980).

    CAS  PubMed  Google Scholar 

  23. Falchuk, Z. M. Gluten-sensitive diarrhea without enteropathy: fact of fancy? Gastroenterology 79, 953–955 (1980).

    CAS  PubMed  Google Scholar 

  24. Cooper, B. T. et al. “Gluten-sensitive diarrhea without evidence of celiac disease”. Gastroenterology 81, 192–194 (1981).

    CAS  PubMed  Google Scholar 

  25. Verdu, E. F., Armstrong, D. & Murray, J. A. Between celiac disease and irritable bowel syndrome: the “no man's land” of gluten sensitivity. Am. J. Gastroenterol. 104, 1587–1594 (2009).

    PubMed  PubMed Central  Google Scholar 

  26. Lovell, R. M. & Ford, A. C. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin. Gastroenterol. Hepatol. 10, 712–721.e4 (2012).

    PubMed  Google Scholar 

  27. Böhn, L., Störsrud, S., Törnblom, H., Bengtsson, U. & Simrén, M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am. J. Gastroenterol. 108, 634–641 (2013).

    PubMed  Google Scholar 

  28. Lind, R. et al. Subjective health complaints and modern health worries in patients with subjective food hypersensitivity. Dig. Dis. Sci. 50, 1245–1251 (2005).

    PubMed  Google Scholar 

  29. Berstad, A., Undseth, R., Lind, R. & Valeur, J. Functional bowel symptoms, fibromyalgia and fatigue: a food-induced triad? Scand. J. Gastroenterol. 47, 914–919 (2012).

    PubMed  PubMed Central  Google Scholar 

  30. Boettcher, E. & Crowe, S. E. Dietary proteins and functional gastrointestinal disorders. Am. J. Gastroenterol. 108, 728–736 (2013).

    CAS  PubMed  Google Scholar 

  31. Young, E., Stoneham, M. D., Petruckevitch, A., Barton, J. & Rona, R. A population study of food intolerance. Lancet 343, 1127–1130 (1994).

    CAS  PubMed  Google Scholar 

  32. Carroccio, A. et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am. J. Gastroenterol. 107, 1898–1906 (2012).

    PubMed  Google Scholar 

  33. Biesiekierski, J. R. et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 106, 508–514 (2011).

    CAS  PubMed  Google Scholar 

  34. Carroccio, A., Mansueto, P., D'Alcamo, A. & Iacono, G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am. J. Gastroenterol. 108, 1845–1852 (2013).

    PubMed  Google Scholar 

  35. Sapone, A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 10, 13 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Catassi, C. et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 5, 3839–3853 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. Biesiekierski, J. R. 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 145, 320–328 (2013).

    CAS  PubMed  Google Scholar 

  38. Francavilla, R. et al. Clinical, serologic, and histologic features of gluten sensitivity in children. J. Pediatr. 164, 463–467 (2014).

    PubMed  Google Scholar 

  39. 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. 12, 85 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. Volta, U. et al. Serological tests in gluten sensitivity (nonceliac gluten intolerance). J. Clin. Gastroenterol. 46, 680–685 (2012).

    CAS  PubMed  Google Scholar 

  41. 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. 59, 1255–1261 (2014).

    CAS  PubMed  Google Scholar 

  42. Carroccio, A. et al. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. BMC Med. 12, 230 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Kabbani, T. A. et al. Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am. J. Gastroenterol. 109, 741–746 (2014).

    CAS  PubMed  Google Scholar 

  44. Troncone, R. et al. In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA. Gastroenterology 111, 318–324 (1996).

    CAS  PubMed  Google Scholar 

  45. Caio, G., Volta, U., Tovoli, F. & De Giorgio, R. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 14, 26 (2014).

    PubMed  PubMed Central  Google Scholar 

  46. Sapone, A. et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 9, 23 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sapone, A. et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int. Arch. Allergy Immunol. 152, 75–80 (2010).

    CAS  PubMed  Google Scholar 

  48. Volta, U. & De Giorgio, R. New understanding of gluten sensitivity. Nat. Rev. Gastroenterol. Hepatol. 9, 295–299 (2012).

    CAS  PubMed  Google Scholar 

  49. Villanacci, V., Lanzini, A., Lanzarotto, F. & Ricci, C. Observations on the paper of Carroccio. et al. “Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity”. Am. J. Gastroenterol. 108, 619–620 (2013).

    PubMed  Google Scholar 

  50. Carroccio, A., Mansueto, P., Tripodo, C. & Florena, A. M. Response to Villanacci. et al. Am. J. Gastroenterol. 108, 620 (2013).

    PubMed  Google Scholar 

  51. Volta, U., Caio, G., Tovoli, F. & De Giorgio, R. Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness. Cell. Mol. Immunol. 10, 383–392 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Brottveit, M. et al. Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am. J. Gastroenterol. 108, 842–850 (2013).

    CAS  PubMed  Google Scholar 

  53. Vazquez-Roque, M. I. et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology 144, 903–911 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hollon, J. et al. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients 7, 1565–1576 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bucci, C. et al. Gliadin does not induce mucosal inflammation or basophil activation in patients with nonceliac gluten sensitivity. Clin. Gastroenterol. Hepatol. 11, 1294–1299 (2013).

    CAS  PubMed  Google Scholar 

  56. Verdu, E. F. et al. Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G217–G225 (2008).

    CAS  PubMed  Google Scholar 

  57. Aziz, I. & Hadjivassiliou, M. Coeliac disease: noncoeliac gluten sensitivity—food for thought. Nat. Rev. Gastroenterol. Hepatol. 11, 398–399 (2014).

    CAS  PubMed  Google Scholar 

  58. Hadjivassiliou, M. et al. Gluten sensitivity: from gut to brain. Lancet Neurol. 9, 318–330 (2010).

    CAS  PubMed  Google Scholar 

  59. Hadjivassiliou, M. et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 80, 1740–1745 (2013).

    CAS  PubMed  Google Scholar 

  60. Hadjivassiliou, M., Davies-Jones, G. A., Sanders, D. S. & Grünewald, R. A. Dietary treatment of gluten ataxia. J. Neurol. Neurosurg. Psychiatry 74, 1221–1224 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hadjivassiliou, M. et al. Neuropathy associated with gluten sensitivity. J. Neurol. Neurosurg. Psychiatry 77, 1262–1266 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hadjivassiliou, M. et al. Dietary treatment of gluten neuropathy. Muscle Nerve 34, 762–766 (2006).

    CAS  PubMed  Google Scholar 

  63. Hadjivassiliou, M. et al. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 56, 385–388 (2001).

    CAS  PubMed  Google Scholar 

  64. Peters, S. L., Biesiekierski, J. R., Yelland, G. W., Muir, J. G. & Gibson, P. R. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity—an exploratory clinical study. Aliment. Pharmacol. Ther. 39, 1104–1112 (2014).

    CAS  PubMed  Google Scholar 

  65. Aziz, I., Hadjivassiliou, M. & Sanders, D. S. Editorial: Noncoeliac gluten sensitivity—a disease of the mind or gut? Aliment. Pharmacol. Ther. 40, 113–114 (2014).

    CAS  PubMed  Google Scholar 

  66. Brottveit, M. et al. Absence of somatization in non-coeliac gluten sensitivity. Scand. J. Gastroenterol. 47, 770–777 (2012).

    CAS  PubMed  Google Scholar 

  67. Kalaydjian, A. E., Eaton, W., Cascella, N. & Fasano, A. The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr. Scand. 113, 82–90 (2006).

    CAS  PubMed  Google Scholar 

  68. Dickerson, F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol. Psychiatry 68, 100–104 (2010).

    CAS  PubMed  Google Scholar 

  69. Cascella, N. G. et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr. Bull. 37, 94–100 (2011).

    PubMed  Google Scholar 

  70. Cascella, N. G. et al. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull. 39, 867–871 (2013).

    PubMed  Google Scholar 

  71. Isasi, C. et al. Fibromyalgia and non-celiac gluten sensitivity: a description with remission of fibromyalgia. Rheumatol. Int. 34, 1607–1612 (2014).

    PubMed  PubMed Central  Google Scholar 

  72. Rodrigo, L., Blanco, I., Bobes, J. & de Serres, F. J. Effect of one year of a gluten-free diet on the clinical evolution of irritable bowel syndrome plus fibromyalgia in patients with associated lymphocytic enteritis: a case-control study. Arthritis Res. Ther. 16, 421 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. Michaëlsson, G. et al. Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Br. J. Dermatol. 142, 44–51 (2000).

    PubMed  Google Scholar 

  74. Biesiekierski, J. R., Newnham, E. D., Shepherd, S. J., Muir, J. G. & Gibson, P. R. Characterization of adults with a self-diagnosis of nonceliac gluten sensitivity. Nutr. Clin. Pract. 29, 504–509 (2014).

    PubMed  Google Scholar 

  75. Leffler, D. et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 62, 996–1004 (2013).

    CAS  PubMed  Google Scholar 

  76. Tortora, R. et al. In vitro gliadin challenge: diagnostic accuracy and utility for the difficult diagnosis of celiac disease. Am. J. Gastroenterol. 107, 111–117 (2012).

    PubMed  Google Scholar 

  77. Aziz, I., Evans, K. E., Hopper, A. D., Smillie, D. M. & Sanders, D. S. A prospective study into the aetiology of lymphocytic duodenosis. Aliment. Pharmacol. Ther. 32, 1392–1397 (2010).

    CAS  PubMed  Google Scholar 

  78. Molina-Infante, J., Santolaria, S., Fernandez-Bañares, F., Montoro, M. & Esteve, M. Lymphocytic enteropathy, HLA-DQ2/DQ8 genotype and wheat-dependent symptoms: non-celiac wheat sensitivity or Marsh I celiac disease? Am. J. Gastroenterol. 108, 451 (2013).

    PubMed  Google Scholar 

  79. Carroccio, A. & Mansueto, P. Response to Molina-Infante. et al. Am. J. Gastroenterol. 108, 451–452 (2013).

    PubMed  Google Scholar 

  80. Carroccio, A. et al. Antiendomysium antibodies assay in the culture medium of intestinal mucosa: an accurate method for celiac disease diagnosis. Eur. J. Gastroenterol. Hepatol. 23, 1018–1023 (2011).

    CAS  PubMed  Google Scholar 

  81. Not, T. et al. Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet. Gut 60, 1487–1493 (2011).

    CAS  PubMed  Google Scholar 

  82. Aziz, I., Hadjivassiliou, M. & Sanders, D. S. Self-reported gluten sensitivity: an international concept in need of consensus? Am. J. Gastroenterol. 109, 1498–1499 (2014).

    CAS  PubMed  Google Scholar 

  83. Coburn, J. A. et al. Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet. J. Clin. Gastroenterol. 47, 828–833 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kaukinen, K. et al. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 35, 942–946 (2000).

    CAS  PubMed  Google Scholar 

  85. Campanella, J. et al. Clinical response to gluten withdrawal is not an indicator of coeliac disease. Scand. J. Gastroenterol. 43, 1311–1314 (2008).

    CAS  PubMed  Google Scholar 

  86. Catassi, C. et al. How the diagnosis of non-celiac gluten sensitivity (NCGS) should be confirmed: The Salerno Experts' Criteria. Nutrients (in press).

  87. Nijeboer, P., Bontkes, H. J., Mulder, C. J. & Bouma, G. Non-celiac gluten sensitivity. Is it in the gluten or the grain? J. Gastrointestin. Liver Dis. 22, 435–440 (2013).

    PubMed  Google Scholar 

  88. Shepherd, S. J., Parker, F. C., Muir, J. G. & Gibson, P. R. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin. Gastroenterol. Hepatol. 6, 765–771 (2008).

    CAS  PubMed  Google Scholar 

  89. Murray, K. et al. Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am. J. Gastroenterol. 109, 110–119 (2014).

    CAS  PubMed  Google Scholar 

  90. Halmos, E. P., Power, V. A., Shepherd, S. J., Gibson, P. R. & Muir, J. G. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 146, 67–75 (2014).

    CAS  PubMed  Google Scholar 

  91. Staudacher, H. M., Irving, P. M., Lomer, M. C. & Whelan, K. Mechanisms and efficacy of dietary FODMAP restriction in IBS. Nat. Rev. Gastroenterol. Hepatol. 11, 256–266 (2014).

    CAS  PubMed  Google Scholar 

  92. Biesiekierski, J. R. et al. Quantification of fructans, galacto-oligosacharides and other short-chain carbohydrates in processed grains and cereals. J. Hum. Nutr. Diet. 24, 154–176 (2011).

    CAS  PubMed  Google Scholar 

  93. Junker, Y. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 209, 2395–2408 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Tilg, H., Koch, R. & Moschen, A. R. Proinflammatory wheat attacks on the intestine: alpha-amylase trypsin inhibitors as new players. Gastroenterology 144, 1561–1563 (2013).

    CAS  PubMed  Google Scholar 

  95. Dalla Pellegrina, C. et al. Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol. Appl. Pharmacol. 237, 146–153 (2009).

    CAS  PubMed  Google Scholar 

  96. Miyake, K., Tanaka, T. & McNeil, P. L. Lectin-based food poisoning: a new mechanism of protein toxicity. PLoS ONE 2, e687 (2007).

    PubMed  PubMed Central  Google Scholar 

  97. Carroccio, A., Rini, G. & Mansueto, P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology 146, 320–321 (2014).

    PubMed  Google Scholar 

  98. Di Sabatino, A. 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. http://dx.doi.org/10.1016/j.cgh.2015.01.029.

  99. Sanders, D. S. et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 358, 1504–1508 (2001).

    CAS  PubMed  Google Scholar 

  100. Sanders, D. S. et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur. J. Gastroenterol. Hepatol. 15, 407–413 (2003).

    CAS  PubMed  Google Scholar 

  101. Cash, B. D. et al. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology 141, 1187–1193 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Wahnschaffe, U., Ullrich, R., Riecken, E. O. & Schulzke, J. D. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 121, 1329–1338 (2001).

    CAS  PubMed  Google Scholar 

  103. Wahnschaffe, U., Schulzke, J. D., Zeitz, M. & Ullrich, R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 5, 844–850 (2007).

    PubMed  Google Scholar 

  104. Ludvigsson, J. F. et al. The Oslo definitions for coeliac disease and related terms. Gut 62, 43–52 (2013).

    PubMed  Google Scholar 

  105. Vazquez-Roque, M. I. et al. HLA-DQ genotype is associated with accelerated small bowel transit in patients with diarrhea-predominant irritable bowel syndrome. Eur. J. Gastroenterol. Hepatol. 23, 481–487 (2011).

    PubMed  PubMed Central  Google Scholar 

  106. Herfarth, H. H., Martin, C. F., Sandler, R. S., Kappelman, M. D. & Long, M. D. Prevalence of a gluten-free diet and improvement of clinical symptoms in patients with inflammatory bowel diseases. Inflamm. Bowel Dis. 20, 1194–1197 (2014).

    PubMed  PubMed Central  Google Scholar 

  107. Aziz, I., Branchi, F., Pearson, K., Priest, J. & Sanders, D. S. A study evaluating the bidirectional relationship between inflammatory bowel disease and self-reported non-celiac gluten sensitivity. Inflamm. Bowel Dis. 21, 847–853 (2015).

    PubMed  Google Scholar 

  108. Carroccio, A. et al. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 8, 254–260 (2010).

    PubMed  Google Scholar 

  109. Carroccio, A. 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. 51, 1257–1263 (2013).

    CAS  PubMed  Google Scholar 

  110. Carroccio, A. et al. Fecal assays detect hypersensitivity to cow's milk protein and gluten in adults with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 9, 965–971 (2011).

    CAS  PubMed  Google Scholar 

  111. Valerii, M. C. et al. Responses of peripheral blood mononucleated cells from non-celiac gluten sensitive patients to various cereal sources. Food Chem. 176, 167–174 (2015).

    CAS  PubMed  Google Scholar 

  112. Fritscher-Ravens, A. et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 147, 1012–1020 (2014).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Royal Hallamshire Hospital, Glossop Road, S10 2JF, Sheffield, UK

    Imran Aziz & David S. Sanders

  2. Department of Neurosciences, Royal Hallamshire Hospital, Glossop Road, S10 2JF, Sheffield, UK

    Marios Hadjivassiliou

Authors
  1. Imran Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marios Hadjivassiliou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Sanders
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects in the production of this article.

Corresponding author

Correspondence to Imran Aziz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aziz, I., Hadjivassiliou, M. & Sanders, D. The spectrum of noncoeliac gluten sensitivity. Nat Rev Gastroenterol Hepatol 12, 516–526 (2015). https://doi.org/10.1038/nrgastro.2015.107

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2015.107

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing