Background: While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. Key Messages: Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non-starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re-challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of ‘non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed. Conclusions: Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world.

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 2014;1-10.
Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV: In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med 2000;6:337-342.
Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A, Henderson K, Mannering SI, Gianfrani C, Jewell DP, Hill AV, McCluskey J, Rossjohn J, Anderson RP: Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med 2010;2:41ra51.
Carroccio A, Rini G, Mansueto P: Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology 2014;146:320-321.
Volta U, Bardella MT, Calabrò A, Troncone R, Corazza GR; Study Group for Non-Celiac Gluten Sensitivity: An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med 2014;12:85.
Lu W, Gwee KA, Siah KT, Kang JY, Lee R, Ngan CC: Prevalence of anti-deamidated gliadin peptide antibodies in Asian patients with irritable bowel syndrome. J Neurogastroenterol Motil 2014;20:236-241.
Kabbani TA, Vanga RR, Leffler DA, Villafuerte-Galvez J, Pallav K, Hansen J, Mukherjee R, Dennis M, Kelly CP: Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am J Gastroenterol 2014;109:741-746.
Volta U, Tovoli F, Cicola R, Parisi C, Fabbri A, Piscaglia M, Fiorini E, Caio G: Serological tests in gluten sensitivity (nonceliac gluten intolerance). J Clin Gastroenterol 2012;46:680-685.
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 2013;108:1845-1852.
Peters SL, Biesiekierski JR, Yelland GW, Muir JG, Gibson PR: Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory clinical study. Aliment Pharmacol Ther 2014;39:1104-1112.
Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR: Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 2011;106:508-514.
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;145:320-328.
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;5:844-850.
Ontiveros N, Tye-Din JA, Hardy MY, Anderson RP: Ex-vivo whole blood secretion of interferon (IFN)-γ and IFN-γ-inducible protein-10 measured by enzyme-linked immunosorbent assay are as sensitive as IFN-γ enzyme-linked immunospot for the detection of gluten-reactive T cells in human leucocyte antigen (HLA)-DQ2·5(+)-associated coeliac disease. Clin Exp Immunol 2014;175:305-315.
Uvackova L, Skultety L, Bekesova S, McClain S, Hajduch M: The MS(E)-proteomic analysis of gliadins and glutenins in wheat grain identifies and quantifies proteins associated with celiac disease and baker's asthma. J Proteomics 2013;93:65-73.
Kaukinen K, Lindfors K, Mäki M: Advances in the treatment of coeliac disease: an immunopathogenic perspective. Nat Rev Gastroenterol Hepatol 2014;11:36-44.
Šramkováa Z, Gregováb E, Šturdíka E: Chemical composition and nutritional quality of wheat grain. Acta Chimica Slovaca 2009;2:115-138.
Koehler P, Wieser H: Chemistry of cereal grains; in Boetti M, Ganzle M (eds): Handbook on Sourdough Biotechnology. Springer, New York, 2013, pp 11-45.
Stevenson L, Phillips F, O'Sullivan K, Walton J: Wheat bran: its composition and benefits to health, a European perspective. Int J Food Sci Nutr 2012;63:1001-1013.
Wieser H: Chemistry of gluten proteins. Food Microbiol 2007;24:115-119.
Altenbach SB, Vensel WH, Dupont FM: The spectrum of low molecular weight alpha-amylase/protease inhibitor genes expressed in the US bread wheat cultivar Butte 86. BMC Res Notes 2011;4:242.
Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, Zevallos V, Libermann TA, Dillon S, Freitag TL, Kelly CP, Schuppan D: Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 2012;209:2395-2408.
Pusztai A, Ewen SW, Grant G, Brown DS, Stewart JC, Peumans WJ, Van Damme EJ, Bardocz S: Antinutritive effects of wheat-germ agglutinin and other N-acetylglucosamine-specific lectins. Br J Nutr 1993;70:313-321.
Carroccio A, Brusca I, Mansueto P, Pirrone G, Barrale M, Di Prima L, Ambrosiano G, Iacono G, Lospalluti ML, La Chiusa SM, Di Fede G: A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2010;8:254-260.
de Punder K, Pruimboom L: The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients 2013;5:771-787.
Tchernychev B, Wilchek M: Natural human antibodies to dietary lectins. FEBS Lett 1996;397:139-142.
Sollid LM, Kolberg J, Scott H, Ek J, Fausa O, Brandtzaeg P: Antibodies to wheat germ agglutinin in coeliac disease. Clin Exp Immunol 1986;63:95-100.
Dalla Pellegrina C, Perbellini O, Scupoli MT, Tomelleri C, Zanetti C, Zoccatelli G, Fusi M, Peruffo A, Rizzi C, Chignola R: Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol 2009;237:146-153.
Teschemacher H: Opioid receptor ligands derived from food proteins. Curr Pharm Design 2003;9:1331-1344.
Zioudrou C, Streaty RA, Klee WA: Opioid peptides derived from food proteins. The exorphins. J Biol Chem 1979;254:2446-2449.
Huebner FR, Lieberman KW, Rubino RP, Wall JS: Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides 1984;5:1139-1147.
Trivedi MS, Shah JS, Al-Mughairy S, Hodgson NW, Simms B, Trooskens GA, Van Criekinge W, Deth RC: Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences. J Nutr Biochem 2014;25:1011-1018.
Fukudome S, Jinsmaa Y, Matsukawa T, Sasaki R, Yoshikawa M: Release of opioid peptides, gluten exorphins by the action of pancreatic elastase. FEBS Lett 1997;412:475-479.
Kost NV, Sokolov OY, Kurasova OB, Dmitriev AD, Tarakanova JN, Gabaeva MV, Zolotarev YA, Dadayan AK, Grachev SA, Korneeva EV, Mikheeva IG, Zozulya AA: Beta-casomorphins-7 in infants on different type of feeding and different levels of psychomotor development. Peptides 2009;30:1854-1860.
Pennington CL, Dufresne CP, Fanciulli G, Wood TD: Detection of gluten exorphin B4 and B5 in human blood by liquid chromatography-mass spectrometry/mass spectrometry. Open Spectroscopy J 2007;1:9-16.
Boutrou R, Gaudichon C, Dupont D, Jardin J, Airinei G, Marsset-Baglieri A, Benamouzig R, Tomé D, Leonil J: Sequential release of milk protein-derived bioactive peptides in the jejunum in healthy humans. Am J Clin Nutr 2013;97:1314-1323.
Barnett MP, McNabb WC, Roy NC, Woodford KB, Clarke AJ: Dietary A1 β-casein affects gastrointestinal transit time, dipeptidyl peptidase-4 activity, and inflammatory status relative to A2 β-casein in Wistar rats. Int J Food Sci Nutr 2014;65:720-727.
Ho S, Woodford K, Kukuljan S, Pal S: Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr 2014;68:994-1000.
Vazquez-Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O'Neill J, Carlson P, Lamsam J, Janzow D, Eckert D, Burton D, Zinsmeister AR: 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.
Muir JG, Gibson PR: Manipulating dietary carbohydrates to treat irritable bowel syndrome; in Simren M (ed): Clinical Insights. London, Future Medicine, pp 81-103.
Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG: Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015;64:93-100.
Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG: A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 2014;146:67-75.
Tuck CJ, Muir JG, Barrett JS, Gibson PR: Fermentable oligosaccharides, disaccharides, monosaccharides and polyols: role in irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 2014;8:819-834.
Biesiekierski JR, Newnham ED, Shepherd SJ, Muir JG, Gibson PR: Characterization of adults with a self-diagnosis of nonceliac gluten sensitivity. Nutr Clin Pract 2014;29:504-509.
Biesiekierski JR, Rosella O, Rose R, Liels K, Barrett JS, Shepherd SJ, Gibson PR, Muir JG: Quantification of fructans, galacto-oligosaccharides and other short-chain carbohydrates in processed grains and cereals. J Hum Nutr Diet 2011;24:154-176.
Gibson PR, Muir JG: Not all effects of a gluten-free diet are due to removal of gluten. Gastroenterology 2013;145:693.
Vrancken G, Rimaux T, Weckx S, Leroy F, De Vuyst L: Influence of temperature and backslopping time on the microbiota of a type I propagated laboratory wheat sourdough fermentation. Appl Environ Microbiol 2011;77:2716-2726.
Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, 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;10:13.
Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C: The Oslo definitions for coeliac disease and related terms. Gut 2013;62:43-52.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.