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The rise and fall of gluten!

Published online by Cambridge University Press:  17 February 2015

Imran Aziz*
Affiliation:
Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK
Federica Branchi
Affiliation:
Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
David S. Sanders
Affiliation:
Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK
*
*Corresponding author: Dr I. Aziz, fax +44 114 2712692, email imran.aziz@sth.nhs.uk
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Abstract

Mankind has existed for 2·5 million years but only in the last 10 000 years have we been exposed to wheat. Wheat was first cultivated in the Fertile Crescent (South Western Asia) with a farming expansion that lasted from about 9000BC to 4000BC. Thus it could be considered that wheat (and gluten) is a novel introduction to man's diet! Prior to 1939 the rationing system had already been devised. This led to an imperative to try to increase agricultural production. Thus it was agreed in 1941 that there was a need to establish a Nutrition Society. The very roots of the society were geared towards necessarily increasing the production of wheat. This goal was achieved and by the end of the 20th century, global wheat output had expanded 5-fold. Perhaps as a result the epidemiology of coeliac disease (CD) or gluten sensitive enteropathy has changed. CD is a state of heightened immunological responsiveness to ingested gluten in genetically susceptible individuals. CD now affects 1 % or more of all adults, for which the treatment is a strict lifelong gluten-free diet. However, there is a growing body of evidence to show that a far greater proportion of individuals without coeliac disease are taking a gluten-free diet of their own volition. This clinical entity has been termed non-coeliac gluten sensitivity (NCGS), although the condition is fraught with complexities due to overlap with other gluten-based constituents that can also trigger similar clinical symptoms. This review will explore the relationship between gluten, the rising prevalence of modern coeliac disease, and the new entity of NCGS along with its associated uncertainties.

Type
Conference on ‘Carbohydrates in health: friends or foes’
Copyright
Copyright © The Authors 2015 

What is gluten?

Gluten is the main storage protein used by some classes of flowering plants to nourish seeds during development and germination( Reference Shewry, Napier and Tatham 1 ). It is a high molecular weight protein found in the endosperm of grass-related grains, including wheat, barley and rye. It is the composite of two classes of protein, a glutenin and a prolamin (gliadin in wheat), which can be fractionated to produce α, β and γ peptides. As plant seeds are the plant tissue most consumed by men, seed storage proteins have been long studied and characterised. Wheat gluten was first isolated in 1745( Reference Beccari 2 ) and since then further advances in the knowledge of protein structure have established that the prolamin components of gluten are responsible for the ability to process wheat to form dough by means of creating a viscoelastic network( Reference Field, Shewry and Miflin 3 , Reference Shewry, Halford and Belton 4 ).

History of gluten and mankind

Mankind has existed for about 2·5 million years but cereal crops were introduced as a component of the human diet about 10 000 years ago during the Neolithic Revolution. This saw a transition from hunting and gathering of food to settled agriculture. The first signs of cultivation have been found in the Fertile Crescent in South West Asia and the subsequent farming expansion lasted until 4000 BC( Reference Harlan and Zohary 5 ).

Cereal harvesting and consumption has gradually increased since then, until its major outbreak in the 20th century. Between the two World Wars, the need to develop a more efficient rationing system and increased agricultural production became evident. The improvement of wheat cultivation became one of the main objectives of the Nutrition Society which was founded in 1941 in Britain to advance the scientific study of nutrition and its application to the maintenance of health( Reference Copping 6 ). This goal was achieved, with modern day global wheat production amounting to over 700 million tonnes per year (http://faostat.fao.org).

Moreover, the need to ensure an efficient agricultural production has led to the artificial breeding and selection of wheat variants with better adaption to extreme climate conditions, bread-making qualities and resistance to diseases( Reference van den Broeck, de Jong and Salentijn 7 ). This has contributed to a dramatic change in the genetic variety and possibly immunogenic qualities of wheat over time( Reference van den Broeck, de Jong and Salentijn 7 ). Currently, about 95 % of the wheat grown worldwide is bread wheat (Triticum aestivum), a hexaploid species which resulted from the spontaneous hybridisations between more ancient tetraploid (Emmer) and diploid species (Wild grass) and was then selected by farmers for its superior qualities and yields, such as higher number and bigger seeds( Reference Dubcovsky and Dvorak 8 ). Furthermore, the awareness of the potential role of gluten in processing food has led to the industrial extraction of gluten from plant seeds and its use in the baking industry as an additive with various functions, such as increasing elasticity and stability of food products or as protein supplement to low-protein food( Reference Kasarda 9 ).

It is therefore believed that the rate of increase in gluten exposure, from the development of wheat cultivation to modern intensive farming, along with its genetic modification, has been too high to give our immune system the time to develop optimal adaptive mechanisms, though this ‘evolutionary theory’ has yet to be fully clarified( Reference Catassi 10 ). Nevertheless, perhaps as a result of all these factors has come the changing epidemiology of coeliac disease (CD) and other gluten-related disorders (Fig. 1).

Fig. 1. (Colour online) Timeline of the history of gluten and mankind.

Gluten-related disorders: not only coeliac disease

As a counterpart of its nutritional properties and wide availability, the consumption of cereals has been associated with the development of several symptoms and disorders, whose responsibility have been attributed to the gluten component contained in wheat and related grains. A recent consensus has classified gluten-related disorders into three broad categories: allergic reactions, such as wheat allergy; autoimmune, which includes coeliac disease, dermatitis herpetiformis and gluten ataxia; immune-mediated, in the form of non-coeliac gluten sensitivity (NCGS)( Reference Sapone, Bai and Ciacci 11 ). The purpose of this review is to specifically focus on CD and NCGS.

Coeliac disease

CD is a chronic inflammatory enteropathy caused by dietary exposure to gluten( Reference Mooney, Hadjivassiliou and Sanders 12 ). Although the manifestations of CD may have been described more than 100 years ago, it is only from the 1940s that the relationship between gluten and CD has been established( Reference van Berge-Henegouwen and Mulder 13 ). However, more than 70 years later, the pathogenesis of CD has yet to be fully elucidated, but it is agreed that the ingestion of gluten in genetically predisposed individuals carrying the human leucocyte antigen DQ2 and/or DQ8 alleles can arise in a T-cell mediated immune reaction, leading to small bowel villous atrophy and subsequent clinical manifestations( Reference Marsh 14 , Reference Sollid, Markussen and Ek 15 ).

Historically, CD was rare with an incidence of one in 8000 being reported in the 1950s( Reference Davidson and Fountain 16 ). However, contemporary epidemiological studies estimate a worldwide prevalence of approximately one in 100 or 1 %( Reference Fasano, Berti and Gerarduzzi 17 , Reference Volta, Bellentani and Bianchi 18 ). Nevertheless, a considerable proportion of patients still remain undiagnosed with estimates that for every patient diagnosed with CD approximately eight cases are yet to be detected. Furthermore, our understanding of the coeliac patient has drastically changed. In fact previously most of the cases that were diagnosed were children, whereas now it has been shown that adult cases (characteristically presenting between the fourth and sixth decades) are more frequently occurring at a ratio of 9:1 compared with the paediatric cohort.

The clinical manifestations of CD are heterogeneous. The classical presentation of malabsorption characterised by chronic diarrhoea, weight loss and failure to thrive is relatively rare. Far more commonly, patients present with non-classical symptoms which include irritable bowel type syndrome (IBS)( Reference Sanders, Carter and Hurlstone 19 ), iron deficiency anaemia( Reference Corazza, Valentini and Andreani 20 ), osteoporosis( Reference Kemppainen, Kröger and Janatuinen 21 ), ataxia or peripheral neuropathy( Reference Hadjivassiliou, Gibson and Davies-Jones 22 ). Indeed, given that IBS is extremely common affecting about 11 % of the population national guidelines now propose that all patients presenting with such symptoms should have CD excluded( Reference Kemppainen, Kröger and Janatuinen 21 ). In fact, a recent meta-analysis has shown that CD accounts for 4 % of those cases presenting with IBS( Reference Richey, Howdle and Shaw 23 , Reference Ford, Chey and Talley 24 ).

To date, the only therapy for CD is a lifelong gluten-free diet (GFD)( Reference Rubio-Tapia, Hill and Kelly 25 ). Adherence to a restrictive GFD leads to gradual healing of the mucosa of the small bowel and to the resolution of malabsorptive symptoms( Reference Lee, Lo and Memeo 26 ), although there is a consistent proportion of patients who continue to show a low grade of mucosal inflammation even on a GFD( Reference Lanzini, Lanzarotto and Villanacci 27 ). The Codex standard (which is used in the UK and Europe), and similarly the Food and Drug Administration in the United States, suggest that foods containing ≤20 mg/kg or 20 parts per million (ppm) gluten can be labelled as ‘gluten-free’ and that foods containing between 21 and 100 ppm gluten can be labelled as ‘very low gluten’.

Gluten-free diet in the absence of coeliac disease

Historically, gluten-free products have been of limited availability with knowledge of CD among the general population shown to be lacking( Reference Karajeh, Hurlstone and Patel 28 ). This inevitably contributed to the social phobia that individuals with CD experienced when dining out( Reference Sverker, Hensing and Hallert 29 ). However, over the last decade there has been a paradigm shift with a drastic rise in the availability of gluten-free products paralleled by an increase in awareness among the public( Reference Aziz, Karajeh and Zilkha 30 ). Such findings are not only as a consequence of a rise in the incidence and recognition of CD. In fact, surveys conducted among the general population confirm that a greater number of consumers worldwide are following a GFD irrespective of the presence of CD( Reference Aziz, Lewis and Hadjivassiliou 31 , Reference Tanpowpong, Ingham and Lampshire 32 ). Observational studies have reported that up to 13 % of the population may self-report sensitivity to gluten-based products and that up to 5 % of the population may be taking a GFD of their own volition( Reference Aziz, Lewis and Hadjivassiliou 31 , Reference Tanpowpong, Ingham and Lampshire 32 ). In some, the avoidance of gluten-containing food is viewed as a healthier lifestyle change rather than an actual treatment, whereas in others it is a consequence of reporting ill-effects to ingestion of gluten-based products. In fact, the relationship between the ingestion of gluten-containing products and the development of clinical symptoms even in the absence of CD has been described since the late 1970s( Reference Cooper, Holmes and Ferguson 33 , Reference Ellis and Linaker 34 ). However, it is only in the last few years that the scientific community has focused its attention on this field, prompted by patient demands and by the sudden media pressure regarding the ‘gluten-free lifestyle’.

Why is non-coeliac gluten sensitivity different?

The definition of NCGS encompasses a spectrum of gastrointestinal and extra-intestinal symptoms which are triggered by the ingestion of gluten-containing food, even in the absence of the serologic and histological hallmarks of CD or wheat allergy( Reference Sapone, Bai and Ciacci 11 , Reference Catassi, Bai and Bonaz 35 ). This terminology was defined following double-blind placebo-controlled studies showing gluten per se to induce symptoms in the absence of CD( Reference Biesiekierski, Newnham and Irving 36 ). The symptoms reported include abdominal pain, diarrhoea, constipation and bloating, as well as chronic fatigue, behavioural changes, bone or joint pain and muscle cramps( Reference Sapone, Bai and Ciacci 11 , Reference Catassi, Bai and Bonaz 35 , Reference Biesiekierski, Newnham and Irving 36 ). Symptoms typically occur shortly after the ingestion of gluten, resolve on a GFD and relapse after gluten challenge.

NCGS is often self-reported or suspected by the patients themselves and then confirmed by physicians after other forms of gluten-related disorders have been excluded( Reference Catassi, Bai and Bonaz 35 ). In fact, whilst the diagnosis of CD can be made in most patients on the basis of positive serology (presence of endomysial and/or tissue transglutaminase antibodies) and villous atrophy at duodenal biopsy( Reference Rubio-Tapia, Hill and Kelly 25 , Reference Ludvigsson, Bai and Biagi 37 ); patients with NCGS present with negative serology and absence of villous atrophy( Reference Sapone, Bai and Ciacci 11 ). However, the presence of antigliadin antibodies has been described in up to 50 % patients with NCGS( Reference Carroccio, Mansueto and Iacono 38 Reference Volta, Bardella and Calabrò 40 ), and an increase in duodenal intraepithelial lymphocytes, corresponding to the grade 1 of the Marsh–Oberhuber histologic classification, has been observed in a subset of patients with NCGS in the absence of other criteria for CD( Reference Carroccio, Mansueto and Iacono 38 ). Moreover, the prevalence of NCGS seem to be higher in first-degree relatives of subjects with CD, and carriers of human leucocyte antigen DQ2 and/or DQ8 seem to be at greater risk of experiencing symptoms related to NCGS than the general population although these data have not been confirmed in different epidemiological studies( Reference Carroccio, Mansueto and Iacono 38 , Reference Volta, Bardella and Calabrò 40 ).

The growing interest in this clinical entity has led to the advancing of several hypotheses about NCGS pathogenesis, yet all of them still remain to be fully elucidated. Altered intestinal permeability similar to that involved in the pathogenesis of CD and activation of the innate immune system following gluten exposure have been considered and are under investigation( Reference Sapone, Bai and Ciacci 11 , Reference Sapone, Lammers and Mazzarella 41 Reference Brottveit, Beitnes and Tollefsen 43 ).

How to diagnose non-coeliac gluten sensitivity

In the absence of clear serologic or histopathologic criteria to orient towards a diagnosis, NCGS has often been perceived as being an IBS-like entity, mainly due to an evident overlap of clinical features between those two syndromes( Reference Verdu, Armstrong and Murray 44 ). Furthermore, it has also been observed that IBS patients, previously naive to the effects of gluten, may benefit from a GFD( Reference Vazquez-Roque, Camilleri and Smyrk 45 ). To date, the reference standard for the diagnosis of ‘true’ NCGS is an elimination diet followed by double-blind placebo-controlled gluten challenge, a method which could hardly be introduced into clinical practice( Reference Sapone, Bai and Ciacci 11 ). Recently, a diagnostic algorithm based on the absence or presence of clinical, serologic and histological criteria has been proposed to diagnose and differentiate NCGS from CD( Reference Kabbani, Vanga and Leffler 46 ). This novel study provides a clinically pragmatic approach as it takes into consideration the difficulties that arise when evaluating patients who present with gluten-based sensitivity and are already taking a GFD, which in cases of CD can lead to negative coeliac serology and normal duodenal biopsies( Reference Kabbani, Vanga and Leffler 46 ). It has been suggested that where available negative human leucocyte antigen DQ2 and DQ8 genotype is useful, in that in can exclude CD with certainty given its 100 % negative predictive value; this will account for almost half of presenting cases( Reference Aziz, Lewis and Hadjivassiliou 31 ). However, if human leucocyte antigen-DQ typing is not readily available, or is positive, then a gluten challenge followed by coeliac investigations is required( Reference Kabbani, Vanga and Leffler 46 ). Traditionally, a gluten challenge has been suggested to be ≥10 g gluten (equivalent to about 4 slices of bread) daily for 6 weeks, prior to formalised testing. More recently this could be as little as ≥3 g gluten (equivalent to 1·5 slices of bread) daily for 2 weeks( Reference Leffler, Schuppan and Pallav 47 ), which may be more suited to patients specifically presenting with gluten sensitivity. By adopting this approach in secondary-care gastrointestinal practice only a minority of adult patients will have a diagnosis of CD (7 %), with the remaining 93 % subsequently diagnosed as NCGS( Reference Aziz, Lewis and Hadjivassiliou 31 ). Furthermore, individuals with NCGS do not appear to suffer the nutritional deficiencies (anaemia and haematinic deficiencies) and low mean BMI commonly associated with CD, which is a reflection of the state of normal villi as seen in NCGS as opposed to the villous atrophy in CD( Reference Aziz, Lewis and Hadjivassiliou 31 ).

The controversies surrounding non-coeliac gluten sensitivity

Given the scattered data regarding the pathogenesis of NCGS, it is unclear when faced with a patient diagnosed with NCGS whether gluten is genuinely responsible for their symptom complaint. Firstly, there are no diagnostic biomarkers for NCGS and as previously mentioned carrying out double-blind placebo-controlled gluten challenges is impractical and cumbersome in routine clinical practice. Secondly, evidence concerning the efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) in controlling IBS symptoms has disclosed the concept that other components of wheat may be responsible for triggering symptoms instead (Table 1)( Reference Shepherd, Parker and Muir 48 , Reference Gibson and Shepherd 49 ). In fact, FODMAP such as fructans, largely contained in wheat and related grains, can trigger gastrointestinal symptoms by means of a combination of osmotic effect and increased gas production from bacterial fermentation( Reference Gibson and Shepherd 50 , Reference Murray, Wilkinson-Smith and Hoad 51 ). It has recently been demonstrated that individuals with NCGS on a self-imposed GFD show further improvement when placed on a low FODMAP diet and that subsequent blinded gluten re-introduction shows no specific or dose-dependent effect( Reference Biesiekierski, Peters and Newnham 52 ). This has led to the concept of NCGS being challenged although this study actually demonstrated a nocebo response to low-dose gluten, high-dose gluten, or whey protein which may be as a consequence of an anticipatory effect in view of the crossover design of the study rather than dismiss the effects of gluten( Reference Biesiekierski, Peters and Newnham 52 ). Moreover, it has also been suggested that other proteins contained in wheat, such as lectins, agglutinins and amylase-trypsin inhibitors can trigger the innate immune response and therefore lead to the development of symptoms after ingestion of wheat( Reference Junker, Zeissig and Kim 53 Reference Dalla Pellegrina, Perbellini and Scupoli 55 ). For these reasons, it has been advised that in clinical practice it may be more appropriate to describe patients with NCGS using the preface ‘self-reported’, or alternatively use the term non-coeliac wheat sensitivity( Reference Carroccio, Rini and Mansueto 56 , Reference Sanders and Aziz 57 ). Nevertheless, this complex field opens a gateway for future studies to identify means of delineating which gluten-based component is responsible for triggering any particular individual's symptoms.

Table 1. Main characteristics of the gluten-free diet and the low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet

ppm, parts per million.

Conclusion

The rise in gluten production and consumption has led to the recognition of gluten-related disorders. CD affects 1 % of the population. However, there is a growing body of evidence to show that individuals without CD are taking a GFD of their own volition. This clinical entity is defined as NCGS, although it is not without its controversy and uncertainty given the lack of diagnostic biomarkers and associated conflicting substrates which can provoke similar symptoms.

Conflict of interest

None.

Financial Support

None.

Authorship

I. A. and F. B. are joint first authors. D. S. S. is senior author.

Footnotes

These two authors contributed jointly to the paper.

J Waterlow Lecture presented by Professor David S Sanders at the Nutrition Society Summer Meeting 2014.

References

1. Shewry, PR, Napier, JA & Tatham, AS (1995) Seed storage proteins: structures and biosynthesis. Plant Cell 7, 945956.Google Scholar
2. Beccari, B (1745). De frumento. In: De Bononiensi Scientiarum et Artium Instituto atque Academia Commentarii: Bononiae : ex typographia Laelii a Vulpe; 1745.Google Scholar
3. Field, JM, Shewry, PR & Miflin, BJ (1983) Solubilisation and characterisation of wheat gluten proteins: correlations between the amount of aggregated proteins and baking quality. J Sci Food Agric 34, 370377.CrossRefGoogle ScholarPubMed
4. Shewry, PR, Halford, NG, Belton, PS et al. (2002) The structure and properties of gluten: an elastic protein from wheat grain. Philos Trans R Soc Lond B Biol Sci 357, 133142.CrossRefGoogle ScholarPubMed
5. Harlan, JR & Zohary, D (1966) Distribution of wild wheats and barley. Science 153, 10741080.Google Scholar
6. Copping, AM (1978) The history of the nutrition society. Proc Nutr Soc 37, 105139.Google Scholar
7. van den Broeck, HC, de Jong, HC, Salentijn, EM et al. (2010) Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease. Theor Appl Genet 121, 15271539.Google Scholar
8. Dubcovsky, J & Dvorak, J (2007) Genome plasticity a key factor in the success of polyploid wheat under domestication. Science 316, 18621866.Google Scholar
9. Kasarda, DD (2013) Can an increase in celiac disease be attributed to an increase in the gluten content of wheat as a consequence of wheat breeding? J Agric Food Chem 61, 11551159.Google Scholar
10. Catassi, C (2005) Where is celiac disease coming from and why? J Pediatr Gastroenterol Nutr 40, 279282.Google Scholar
11. Sapone, A, Bai, JC, Ciacci, C et al. (2012) Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 10, 13.CrossRefGoogle Scholar
12. Mooney, PD, Hadjivassiliou, M & Sanders, DS (2014) Coeliac disease. Br Med J 348, 1561.Google Scholar
13. van Berge-Henegouwen, GP & Mulder, CJ (1993) Pioneer in the gluten free diet: Willem-Karel Dicke 1905–1962, over 50 years of gluten free diet. Gut 34, 14731475.Google Scholar
14. Marsh, MN (1992) Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 102, 330354.Google Scholar
15. Sollid, LM, Markussen, G, Ek, J et al. (1989) Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med 169, 345350.CrossRefGoogle ScholarPubMed
16. Davidson, LS & Fountain, JR (1950) Incidence of the sprue syndrome; with some observations on the natural history. Br Med J 1, 11571161.Google Scholar
17. Fasano, A, Berti, I, Gerarduzzi, T et al. (2003) Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 163, 286292.CrossRefGoogle ScholarPubMed
18. Volta, U, Bellentani, S, Bianchi, FB et al. (2001) High prevalence of celiac disease in Italian general population. Dig Dis Sci 46, 15001505.CrossRefGoogle ScholarPubMed
19. Sanders, DS, Carter, MJ, Hurlstone, DP et al. (2001) 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, 15041508.CrossRefGoogle ScholarPubMed
20. Corazza, GR, Valentini, RA, Andreani, ML et al. (1995) Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia. Scand J Gastroenterol 30, 153156.CrossRefGoogle ScholarPubMed
21. Kemppainen, T, Kröger, H, Janatuinen, E et al. (1999) Osteoporosis in adult patients with celiac disease. Bone 24, 249255.Google Scholar
22. Hadjivassiliou, M, Gibson, A, Davies-Jones, GA et al. (1996) Does cryptic gluten sensitivity play a part in neurological illness? Lancet 347, 369371.Google Scholar
23. Richey, R, Howdle, P, Shaw, E et al. (2009) Recognition and assessment of coeliac disease in children and adults: summary of NICE guidance. Br Med J 338, 1684.Google Scholar
24. Ford, AC, Chey, WD, Talley, NJ et al. (2009) Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med 169, 651658.Google Scholar
25. Rubio-Tapia, A, Hill, ID, Kelly, CP et al. (2013) ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 108, 656676.CrossRefGoogle ScholarPubMed
26. Lee, SK, Lo, W, Memeo, L et al. (2003) Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc 57, 187191.Google Scholar
27. Lanzini, A, Lanzarotto, F, Villanacci, V et al. (2009) Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther 29, 12991308.CrossRefGoogle ScholarPubMed
28. Karajeh, MA, Hurlstone, DP, Patel, TM et al. (2005) Chefs' knowledge of coeliac disease (compared to the public): a questionnaire survey from the United Kingdom. Clin Nutr 24, 206210.CrossRefGoogle Scholar
29. Sverker, A, Hensing, G & Hallert, C (2005) ‘Controlled by food'- lived experiences of coeliac disease. J Hum Nutr Diet 18, 171180.Google Scholar
30. Aziz, I, Karajeh, MA, Zilkha, J et al. (2014) 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, 12281233.Google Scholar
31. Aziz, I, Lewis, NR, Hadjivassiliou, M et al. (2014) A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur J Gastroenterol Hepatol 26, 3339.Google Scholar
32. Tanpowpong, P, Ingham, TR, Lampshire, PK et al. (2012) Coeliac disease and gluten avoidance in New Zealand children. Arch Dis Child 97, 1216.Google Scholar
33. Cooper, BT, Holmes, GK, Ferguson, R et al. (1976) Proceedings: chronic diarrhoea and gluten sensitivity. Gut 17, 398.Google Scholar
34. Ellis, A & Linaker, BD (1978) Non-coeliac gluten sensitivity? Lancet 1, 13581359.Google Scholar
35. Catassi, C, Bai, JC, Bonaz, B et al. (2013) Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients 5, 38393853.Google Scholar
36. Biesiekierski, JR, Newnham, ED, Irving, PM et al. (2011) Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 106, 508514.Google Scholar
37. Ludvigsson, JF, Bai, JC, Biagi, F et al. (2014) Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 63, 12101228.Google Scholar
38. Carroccio, A, Mansueto, P, Iacono, G et al. (2012) Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol 107, 18981906.Google Scholar
39. Volta, U, Tovoli, F, Cicola, R et al. (2012) Serological tests in gluten sensitivity (nonceliac gluten intolerance). J Clin Gastroenterol 46, 680685.Google Scholar
40. Volta, U, Bardella, MT, Calabrò, A et al. (2014) An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med 12, 85.Google Scholar
41. 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 152, 7580.CrossRefGoogle ScholarPubMed
42. Sapone, A, Lammers, KM, Casolaro, V et al. (2011) Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med 9, 23.Google Scholar
43. Brottveit, M, Beitnes, AC, Tollefsen, S et al. (2013) Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity. Am J Gastroenterol 108, 842850.Google Scholar
44. Verdu, EF, Armstrong, D & Murray, JA (2009) Between celiac disease and irritable bowel syndrome: the “no man's land” of gluten sensitivity. Am J Gastroenterol 104, 15871594.Google Scholar
45. Vazquez-Roque, MI, Camilleri, M, Smyrk, T et al. (2013) A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology 144, 903911.Google Scholar
46. Kabbani, TA, Vanga, RR, Leffler, DA et al. (2014) Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am J Gastroenterol 109, 741746.Google Scholar
47. Leffler, D, Schuppan, D, Pallav, K et al. (2013) Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 62, 9961004.Google Scholar
48. Shepherd, SJ, Parker, FC, Muir, JG et al. (2008) Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin Gastroenterol Hepatol 6, 765771.Google Scholar
49. Gibson, PR & Shepherd, SJ (2010) Evidence-based dietary management of functional gastrointestinal symptoms: the FODMAP approach. J Gastroenterol Hepatol 25, 252258.CrossRefGoogle ScholarPubMed
50. Gibson, PR & Shepherd, SJ (2012) Food choice as a key management strategy for functional gastrointestinal symptoms. Am J Gastroenterol 107, 657666.Google Scholar
51. Murray, K, Wilkinson-Smith, V, Hoad, C et al. (2014) 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, 110119.CrossRefGoogle ScholarPubMed
52. Biesiekierski, JR, Peters, SL, Newnham, ED et al. (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 145, 320328.Google Scholar
53. Junker, Y, Zeissig, S, Kim, SJ et al. (2012) Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 209, 23952408.Google Scholar
54. Haas, H, Falcone, FH, Schramm, G et al. (1999) Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol 29, 918927.Google Scholar
55. Dalla Pellegrina, C, Perbellini, O, Scupoli, MT et al. (2009) Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol Appl Pharmacol 237, 146153.CrossRefGoogle ScholarPubMed
56. Carroccio, A, Rini, G & Mansueto, P (2014) Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology 146, 320321.CrossRefGoogle ScholarPubMed
57. Sanders, DS & Aziz, I (2012) Non-celiac wheat sensitivity: separating the wheat from the chat! Am J Gastroenterol 107, 19081912.Google Scholar
Figure 0

Fig. 1. (Colour online) Timeline of the history of gluten and mankind.

Figure 1

Table 1. Main characteristics of the gluten-free diet and the low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet