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Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness

Cellular & Molecular Immunology volume 10, pages 383–392 (2013)Cite this article

Abstract

Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related syndrome defined as non-celiac gluten sensitivity. Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%. From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced. Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten challenge is currently the diagnostic method with the highest accuracy. Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a condition that has global acceptance but has only a few certainties and many unresolved issues.

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References

  1. Volta U, de Giorgio R . New understanding of gluten sensitivity. Nat Rev Gastroenterol Hepatol 2012; 9: 295–299.

    Article  CAS  PubMed  Google Scholar 

  2. Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadijvassiliou M et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 2012; 10: 13.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gibert A, Espadaler M, Angel Canela M, Sánchez A, Vaqué C, Rafecas M . Consumption of gluten-free products: should be the threshold value for traces amounts of gluten be at 20, 100 or 200 p.p.m.? Eur J Gastroenterol Hepatol 2006; 18: 1187–1195.

    Article  CAS  PubMed  Google Scholar 

  4. Belderok B . Developments in bread-making processes. Plant Food Hum Nutr 2000; 55: 1–86.

    Article  CAS  Google Scholar 

  5. Gobbetti M, Rizzello CG, Di Cagno R, de Angelis M . Sordough lactobacilli and coeliac disease. Food Microbiol 2007; 24: 187–196.

    Article  CAS  PubMed  Google Scholar 

  6. Volta U, Villanacci V . Celiac disease: diagnostic criteria in progress. Cell Mol Immunol 2011; 8: 96–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Inonata N . Wheat allergy. Cur Opin Aller Clin Immunol 2009; 9: 238–243.

    Article  Google Scholar 

  8. Blomfeldt TO, Kuktaite R, Johansson E, Hedenqvist MS . Mechanical properties and network structure of wheat gluten forms. Biomacromolecules 2011; 12: 1707–1715.

    Article  CAS  PubMed  Google Scholar 

  9. Fraser JS, Engel W, Ellis HJ, Moodie SJ, Pollock EL, Wieser H et al. Coeliac disease: in vivo toxicity of the putative immunodominant epitope. Gut 2003; 52: 1698–1702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Drago S, El Asmar R, Di Pierro M, Clemente MG, Tripathi A, Sapone A et al. Gliadin, zonulin, and gut permeability: effects on celiac and non-celiac mucosa and intestinal cell lines. Scand J Gastroenterol 2006; 41: 408–419.

    Article  CAS  PubMed  Google Scholar 

  11. Dolfini E, Roncoroni L, Elli L, Fumagalli C, Colombo R, Ramponi S et al. Cytoskeleton reorganization and ultrastructural damage induced by gliadin in a three-dimensional in vitro model. World J Gastroenterol 2005; 11: 7597–7601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cooper BT, Holmes GK, Ferguson R, Thompson RA, Allan RN, Cooke WT . Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology 1980; 79: 801–806.

    CAS  PubMed  Google Scholar 

  13. Kaukinen K, Turjanmaa K, Mäki M, Partanen J, Venäläinen R, Reunala T et al. Intolerance to cerealsis not specific for celiac disease. Scand J Gastroenterol 2000; 35: 942–946.

    Article  CAS  PubMed  Google Scholar 

  14. Verdu EF, Armstrong D, Murray JA . Between celiac disease and irritable bowel syndrome: the ‘no man's land’ of gluten sensitivity. Am J Gastroenterol 2009; 104: 1587–1594.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Troncone R, Jabri B . Coeliac disease and gluten sensitivity. J Intern Med 2011; 269: 582–590.

    Article  CAS  PubMed  Google Scholar 

  16. Di Sabatino A, Corazza GR . Non-celiac gluten sensitivity: sense or sensibility? Ann Intern Med 2012; 156: 309–311.

    Article  PubMed  Google Scholar 

  17. Lundin KEA, Alaedini A . Non-celiac gluten sensitivity. Gastrointest Endoscopy Clin N Am 2012; 22: 723–734.

    Article  Google Scholar 

  18. Brown AC . Gluten sensitivity: problems of an emerging condition separate from celiac disease. Expert Rev Gastroenterol Hepatol 2012; 6: 41–53.

    Google Scholar 

  19. Godlee F . Gluten sensitivity: real or not? BMJ 2012; 345: e8450.

    Article  Google Scholar 

  20. Anonymus patient, Rostami K, Hogg-Kollars S . Non-coeliac gluten sensitivity: a patient's journey. BMJ 2012; 345: e7982.

    Article  Google Scholar 

  21. Sollid LM, Jabri B . Triggers and drivers of autoimmunity: lessons from celiac disease. Nat Rev Immunol 2013; 13: 294–302.

    Article  CAS  PubMed  Google Scholar 

  22. Marietta EV, Murray JA . Animal models in gluten sensitivity. Semin Immunopathol 2012; 34: 497–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Turvet SE, Broide DH . Innate immunity. J Allergy Clin Immunol 2010; 125( Suppl 2): S24–S32.

    Article  Google Scholar 

  24. Bendelac A, Savage PB, Teyton L . The biology of NKT cells. Annu Rev Immunol 2007; 25: 297–336.

    Article  CAS  PubMed  Google Scholar 

  25. Bonilla FA, Oettgen HC . Adaptive immunity. J Allergy Clin Immunol 2010; 125( Suppl 2): S33–S40.

    Article  PubMed  Google Scholar 

  26. Zhu J, Yamane H, Paul WE . Differentiation of effector CD4T cell populations. Annu Rev Immunol 2010; 28: 445–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Crotty S . Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011; 29: 621–623.

    Article  CAS  PubMed  Google Scholar 

  28. Crome SQ, Wang AY, Levings MK . Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2010; 159: 109–119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bilate AM, Lafaille JJ . Induced CD4+ FoxP3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012: 30: 733–758.

    Article  CAS  PubMed  Google Scholar 

  30. Castellanos-Rubio A, Santin I, Irastorza I, Castaño L, Carlos Vitoria J, Ramon Bilbao J . TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity 2009; 42: 69–73.

    Article  CAS  PubMed  Google Scholar 

  31. Harris KM, Fasano A, Mann DL . Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the etiologic agent in celiac disease. J Immunol 2008; 181: 4457–4460.

    Article  CAS  PubMed  Google Scholar 

  32. Monteleone I, Pallone F, Monteleone G . Interleukin-23 and Th17 cells in the control of gut inflammation. Mediators Inflamm 2009; 2009: 297645.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Monteleone I, Sarra M, del Vecchio BG, Paoluzi OA, Franze E, Fina D et al. Characterization of IL-17A-producing cells in celiac disease mucosa. J Immunol 2010; 184: 2211–2218.

    Article  CAS  PubMed  Google Scholar 

  34. Sapone A, Lammers K, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Carteni M, Casolaro V et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch AllergyImmunol 2010; 152: 75–80.

    Article  CAS  Google Scholar 

  36. Vorobjova T, Uibo O, Heilman K, Rägo T, Honkanen J, Vaarala O et al. Increased FOXP3 expression in small-bowel mucosa of children with coeliac disease and type I diabetes mellitus. Scand J Gastroenterol 2009; 44: 422–430.

    Article  CAS  PubMed  Google Scholar 

  37. Hansson T, Ulfgren AK, Lindroos E, DannAEus A, Dahlbom I, Klareskog L . Transforming growth factor-beta (TGF-beta) and tissue transglutaminase expression in the small intestine in children with coeliac disease. Scand J Immunol 2002; 56: 530–537.

    Article  CAS  PubMed  Google Scholar 

  38. Schuppan D . Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119: 234–242.

    Article  CAS  PubMed  Google Scholar 

  39. 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: 508–514.

    Article  CAS  PubMed  Google Scholar 

  40. Vaquez-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: 903–911.

    Article  Google Scholar 

  41. 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: G217–G225.

    Article  CAS  PubMed  Google Scholar 

  42. Natividad JM, Huang X, Slack E, Jury J, Sanz Y, David C et al. Host responses to intestinal microbial antigensin gluten sensitive mice. PLos ONE 2009; 4: e6472.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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: 2395–2408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gibson PR, Sheperd SJ . Food choice as a key management strategy for functional gastrointestinal symptoms. Am J Gastroenterol 2012; 107: 657–666.

    Article  CAS  PubMed  Google Scholar 

  45. Corazza GR, Frazzoni M, Strocchi A, Prati C, Sarchielli P, Capelli M et al. Alimentary exorphin actions on motility and hormonal secretion of gastrointestinal tract. In: Fraioli F, Isidori A, Mazzetti M (ed.). Opioid Peptides in the Periphery. Amsterdam: Elsevier Sciences Publisher, 1984: 243–247.

    Google Scholar 

  46. Suarez FL . Savaiano DA, Levitt MD . A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med 1995; 333: 1–4.

    Article  CAS  PubMed  Google Scholar 

  47. 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: 1898–1906.

    Article  PubMed  Google Scholar 

  48. Volta U, Tovoli F, Cicola R, Parisi C, Fabbri A, Piscaglia M et al. Serological tests in gluten sensitività (nonceliac gluten intolerance). J Clin Gastroenterol 2012; 46: 680–685.

    Article  CAS  PubMed  Google Scholar 

  49. Volta U . Indagine su sensibilità al glutine non celiaca: risultati preliminari. Celiachia Notizie 2013, 1: 58–60.

    Google Scholar 

  50. Dezi R, Niveloni S, Sugai E, Pedreira S, Smecuol E, Vazquez H et al. Gluten sensitivity in the rectal mucosa of first-degree relatives of celiac disease patients. Am J Gastroenterol 1997; 92: 1326–1330.

    CAS  PubMed  Google Scholar 

  51. Bizzaro N, Tozzoli R, Villalta D, Fabris M, Tonutti E . Cutting-edge issues in celiac disease and in gluten intolerance. Clin Rev Allerg Immunol 2012; 42: 279–287.

    Article  CAS  Google Scholar 

  52. Volta U, Granito A, Parisi C, Fabbri A, Fiorini E, Piscaglia M et al. Deamidated gliadin peptide antibodies as a routine test for celiac disease: a prospective analysis. J Clin Gastroenterol 2010; 44: 186–190.

    Article  PubMed  Google Scholar 

  53. Volta U, Corazza GR, Frisoni M, Valentini RA, Molinaro N, Bianchi FB et al. IgA antigliadin antibodies and persistence of jejunal lesions in adult celiac disease. Digestion 1990; 47: 111–114.

    Article  CAS  PubMed  Google Scholar 

  54. Oberhuber G, Granditsch G, Vogelsang H . The histopathology of coeliac disease: time for a stndardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999; 11: 1185–1194.

    Article  CAS  Google Scholar 

  55. Not T, Ziberna F, Vatta S, Quaglia S, Martelossi S, Villanacci V et al. Cryptic genetic gluten intolerance revealed by intestinal antitransglutaminase antibodies and response to gluten-free diet. Gut 2011; 60: 1487–1493.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    Umberto Volta, Giacomo Caio, Francesco Tovoli & Roberto De Giorgio

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Correspondence to Umberto Volta.

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Volta, U., Caio, G., Tovoli, F. et al. Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness. Cell Mol Immunol 10, 383–392 (2013). https://doi.org/10.1038/cmi.2013.28

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