1 Nature Reviews Gastroenterology and Hepatology 2012 Vol: 9(5):295-299. DOI: 10.1038/nrgastro.2012.15

New understanding of gluten sensitivity

Among gluten-related disorders, gluten sensitivity is an emerging entity that is characterized by a wide array of manifestations. In particular, patients complain of IBS-like symptoms and extraintestinal manifestations that occur shortly after the ingestion of gluten. Symptoms improve or disappear when gluten is withdrawn from the diet, and recur if gluten is reintroduced. Laboratory tests are usually unhelpful for diagnosis, although ~50% of patients are positive for IgG antigliadin antibodies. The natural history of gluten sensitivity is unknown; in particular, it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity. The pathogenesis of gluten sensitivity is unclear; data so far demonstrate a predominant activation of innate immune responses. Further research is necessary to establish the main clinicopathological features of gluten sensitivity, thus enabling physicians to improve their management of the increasing number of patients who are sensitive to dietary gluten.

Mentions
Figures
Figure 1: Pathogenic mechanisms of gluten sensitivity and celiac disease.Enhanced neutrophil recruitment, gut inflammation (such as an increased number of intraepithelial lymphocytes) and an immune response to gliadin (AGAs) are features (orange field) common to gluten sensitivity and celiac disease. Decreased epithelial barrier function, intestinal mucosal damage and autoimmunity (that is, the presence of tTGA) are typical of celiac disease (red field), whereas enhanced epithelial barrier function has been demonstrated in gluten sensitivity (yellow field). Abbreviations: AGAs, antigliadin antibodies; tTGAs, tissue transglutaminase antibodies.
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References
  1. Catassi, C. et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann. Med. 42, 530-538 , .
    • . . . Worldwide, the growing consumption of the Mediterranean diet, which includes a wide range of gluten-containing foods (such as bread, pasta and pizza), has contributed to an alarming increase in the incidence of gluten-related disorders.1, 2 Gluten is the main structural protein in wheat and other cereals (such as barley, rye and spelt) and its components—gliadins and glutenins—create a 3D network when flours are mixed with water, giving dough elasticity and viscosity.3 New variants of wheat have arisen as a result of the mechanization of farming and the growing industrial use of pesticides and fertilizers that could have a leading role in the adverse immunologic reactions to gluten.4 Moreover, the process of bread leavening has been progressively shortened, which has resulted in an increased concentration of toxic gluten peptides in bakery products.5 . . .
    • . . . A wide array of disorders are related to gluten, ranging from well-known conditions such as celiac disease and wheat allergy to poorly defined illnesses (such as gluten ataxia and peripheral neuropathy) that are still a matter of clinical investigation.1 Over the years, a thorough and dramatic change has occurred in the definition of celiac disease, that is, the disorder has gone from being considered an essentially malabsorptive condition to being recognized as a widely heterogeneous syndrome with digestive and extradigestive symptoms.1 This improved definition of celiac disease and its clinical scenarios is largely attributable to improvements in diagnostic tests, such as the detection of autoantibodies and a superior appraisal of histopathology.10 Growing evidence indicates that gluten sensitivity is emerging as a new entity.11, 12, 13 Patients with gluten sensitivity do not have celiac disease, but they do experience symptoms when eating foods that contain gluten . . .
    • . . . Although both innate and adaptive immunity have a central role in the development of celiac disease, gluten sensitivity seems to be mainly associated with activation of the innate immune response.1, 17 The expression of the innate immunity marker Toll-like receptor (TLR)2 is considerably increased in the intestinal mucosa of patients with gluten sensitivity compared with patients who have celiac disease and control individuals.17 Moreover, patients with gluten sensitivity had higher expression of TLR1 and TLR4 transcripts at the mucosal level than did patients with celiac disease or control individuals.17 In addition, adaptive immune markers, including IL-6, T-helper-1 cytokine IFN-γ, IL-17 and IL-21, were expressed at increased levels in the small intestinal mucosa of patients with celiac disease, but not of those with gluten sensitivity.17 Another interesting finding that differentiates gluten sensitivity from celiac disease concerned the mucosal expression of genes associated with TREG cells . . .
  2. Troncone, R. & Jabri, B. Coeliac disease and gluten sensitivity. J. Intern. Med. 269, 582-590 , .
    • . . . Worldwide, the growing consumption of the Mediterranean diet, which includes a wide range of gluten-containing foods (such as bread, pasta and pizza), has contributed to an alarming increase in the incidence of gluten-related disorders.1, 2 Gluten is the main structural protein in wheat and other cereals (such as barley, rye and spelt) and its components—gliadins and glutenins—create a 3D network when flours are mixed with water, giving dough elasticity and viscosity.3 New variants of wheat have arisen as a result of the mechanization of farming and the growing industrial use of pesticides and fertilizers that could have a leading role in the adverse immunologic reactions to gluten.4 Moreover, the process of bread leavening has been progressively shortened, which has resulted in an increased concentration of toxic gluten peptides in bakery products.5 . . .
  3. Blomfeldt, T. O., Kuktaite, R., Johansson, E. & Hedenqvist, M. S. Mechanical properties and network structure of wheat gluten foams. Biomacromolecules 12, 1707-1715 , .
    • . . . Worldwide, the growing consumption of the Mediterranean diet, which includes a wide range of gluten-containing foods (such as bread, pasta and pizza), has contributed to an alarming increase in the incidence of gluten-related disorders.1, 2 Gluten is the main structural protein in wheat and other cereals (such as barley, rye and spelt) and its components—gliadins and glutenins—create a 3D network when flours are mixed with water, giving dough elasticity and viscosity.3 New variants of wheat have arisen as a result of the mechanization of farming and the growing industrial use of pesticides and fertilizers that could have a leading role in the adverse immunologic reactions to gluten.4 Moreover, the process of bread leavening has been progressively shortened, which has resulted in an increased concentration of toxic gluten peptides in bakery products.5 . . .
  4. Belderok, B. Developments in bread-making processes. Plant Food Hum. Nutr. 55, 1-86 , .
    • . . . Worldwide, the growing consumption of the Mediterranean diet, which includes a wide range of gluten-containing foods (such as bread, pasta and pizza), has contributed to an alarming increase in the incidence of gluten-related disorders.1, 2 Gluten is the main structural protein in wheat and other cereals (such as barley, rye and spelt) and its components—gliadins and glutenins—create a 3D network when flours are mixed with water, giving dough elasticity and viscosity.3 New variants of wheat have arisen as a result of the mechanization of farming and the growing industrial use of pesticides and fertilizers that could have a leading role in the adverse immunologic reactions to gluten.4 Moreover, the process of bread leavening has been progressively shortened, which has resulted in an increased concentration of toxic gluten peptides in bakery products.5 . . .
  5. Gobbetti, M., Rizzello, C. G., Di Cagno, R. & De Angelis, M. Sourdough lactobacilli and celiac disease. Food Microbiol. 24, 187-196 , .
  6. Gibert, A. et al. Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20,100 or 200 p.p.m.? Eur. J. Gastroenterol. Hepatol. 18, 1187-1195 , .
    • . . . For example, the mean daily gluten ingestion is 10–20 g in the Mediterranean area, and is even more in some populations.6 Gliadins, a group of proteins that are rich in proline and glutamine, have been identified as the main toxic component of gluten . . .
  7. Fraser, J. S. et al. Coeliac disease: in vivo toxicity of the putative immunodominant epitope. Gut 52, 1698-1702 , .
    • . . . These proteins, which are resistant to digestion in the gastrointestinal tract, are known to cause a rearrangement of the cellular cytoskeleton through the zonulin pathway and cause the loss of tight junctions, which results in an increase in paracellular permeability of the small intestinal mucosa.7, 8 Moreover, gliadin has a toxic effect as it reduces the F-actin content of small intestinal mucosal cells, inhibits epithelial cell growth and induces apoptosis, thereby altering mucosal homeostasis.9 . . .
  8. Drago, S. et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand. J. Gastroenterol. 41, 408-419 , .
    • . . . These proteins, which are resistant to digestion in the gastrointestinal tract, are known to cause a rearrangement of the cellular cytoskeleton through the zonulin pathway and cause the loss of tight junctions, which results in an increase in paracellular permeability of the small intestinal mucosa.7, 8 Moreover, gliadin has a toxic effect as it reduces the F-actin content of small intestinal mucosal cells, inhibits epithelial cell growth and induces apoptosis, thereby altering mucosal homeostasis.9 . . .
  9. Dolfini, E. et al. Cytoskeleton reorganization and ultrastructural damage induced by gliadin in a three-dimensional in vitro model. World J. Gastroenterol. 11, 7597-7601 , .
  10. Caja, S., Mäki, M., Kaukinen, K. & Lindfors, K. Antibodies in coeliac disease: implications beyond diagnostics. Cell. Mol. Immunol. 8, 103-109 , .
    • . . . A wide array of disorders are related to gluten, ranging from well-known conditions such as celiac disease and wheat allergy to poorly defined illnesses (such as gluten ataxia and peripheral neuropathy) that are still a matter of clinical investigation.1 Over the years, a thorough and dramatic change has occurred in the definition of celiac disease, that is, the disorder has gone from being considered an essentially malabsorptive condition to being recognized as a widely heterogeneous syndrome with digestive and extradigestive symptoms.1 This improved definition of celiac disease and its clinical scenarios is largely attributable to improvements in diagnostic tests, such as the detection of autoantibodies and a superior appraisal of histopathology.10 Growing evidence indicates that gluten sensitivity is emerging as a new entity.11, 12, 13 Patients with gluten sensitivity do not have celiac disease, but they do experience symptoms when eating foods that contain gluten . . .
  11. Verdu, E. F., Armstrong, D. & Murrat, J. A. Between celiac disease and irritable bowel syndrome: the “no man's land” of gluten sensitivity. Am. J. Gastroenterol. 104, 1587-1594 , .
  12. 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 , .
    • . . . A wide array of disorders are related to gluten, ranging from well-known conditions such as celiac disease and wheat allergy to poorly defined illnesses (such as gluten ataxia and peripheral neuropathy) that are still a matter of clinical investigation.1 Over the years, a thorough and dramatic change has occurred in the definition of celiac disease, that is, the disorder has gone from being considered an essentially malabsorptive condition to being recognized as a widely heterogeneous syndrome with digestive and extradigestive symptoms.1 This improved definition of celiac disease and its clinical scenarios is largely attributable to improvements in diagnostic tests, such as the detection of autoantibodies and a superior appraisal of histopathology.10 Growing evidence indicates that gluten sensitivity is emerging as a new entity.11, 12, 13 Patients with gluten sensitivity do not have celiac disease, but they do experience symptoms when eating foods that contain gluten . . .
    • . . . The clinical features of gluten sensitivity include intestinal symptoms, commonly misdiagnosed as IBS,14 and extraintestinal manifestations, which occur soon after gluten has been ingested and rapidly disappear once the patient is on a gluten-free diet.12, 13 . . .
    • . . . Although the epidemiology of gluten sensitivity is far from being established, its presumed prevalence is higher than that of celiac disease.12, 13 Although it can occur at any age, gluten sensitivity seems to be more frequent in adults than in children, with a median age of onset of 40 years (range 17–63 years), and as with functional bowel disorders (including IBS), gluten sensitivity is more prevalent in females than in males (male to female ratio 1:2.5).25 . . .
    • . . . Gluten withdrawal is associated with a dramatic improvement or even the disappearance of IBS-like and extraintestinal symptoms, and reintroducing gluten causes symptom recurrence.11, 12, 13, 25 Symptom cessation or reoccurrence attributable to the absence or presence of dietary gluten should be considered a test indicative of gluten sensitivity . . .
    • . . . Serological analyses of patients with gluten sensitivity have found a high prevalence (40–50%) of first-generation antigliadin antibodies (AGAs).12, 13, 25 AGA positivity is almost always confined to the IgG class, while only occasionally occurring in the IgA class . . .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
  13. Bizzaro, N., Tozzoli, R., Villalta, D., Fabris, M. & Tonutti, E. Cutting-edge issues in celiac disease and in gluten intolerance. Clin. Rev. Allergy Immunol. , .
    • . . . A wide array of disorders are related to gluten, ranging from well-known conditions such as celiac disease and wheat allergy to poorly defined illnesses (such as gluten ataxia and peripheral neuropathy) that are still a matter of clinical investigation.1 Over the years, a thorough and dramatic change has occurred in the definition of celiac disease, that is, the disorder has gone from being considered an essentially malabsorptive condition to being recognized as a widely heterogeneous syndrome with digestive and extradigestive symptoms.1 This improved definition of celiac disease and its clinical scenarios is largely attributable to improvements in diagnostic tests, such as the detection of autoantibodies and a superior appraisal of histopathology.10 Growing evidence indicates that gluten sensitivity is emerging as a new entity.11, 12, 13 Patients with gluten sensitivity do not have celiac disease, but they do experience symptoms when eating foods that contain gluten . . .
    • . . . Although the epidemiology of gluten sensitivity is far from being established, its presumed prevalence is higher than that of celiac disease.12, 13 Although it can occur at any age, gluten sensitivity seems to be more frequent in adults than in children, with a median age of onset of 40 years (range 17–63 years), and as with functional bowel disorders (including IBS), gluten sensitivity is more prevalent in females than in males (male to female ratio 1:2.5).25 . . .
    • . . . As no clues exist as to whether gluten sensitivity is a permanent or a transient condition, the reintroduction of gluten after 1–2 years on a gluten-free diet might be advised.13, 25 . . .
    • . . . Gluten withdrawal is associated with a dramatic improvement or even the disappearance of IBS-like and extraintestinal symptoms, and reintroducing gluten causes symptom recurrence.11, 12, 13, 25 Symptom cessation or reoccurrence attributable to the absence or presence of dietary gluten should be considered a test indicative of gluten sensitivity . . .
    • . . . Wheat allergy should be ruled out by testing patients for serum IgE antibodies that are specific to gluten and wheat fractions as well as by skin prick tests.13 Another diagnostic prerequisite is the lack of highly specific markers of celiac disease, that is, IgA tissue transglutaminase antibodies (tTGAs), IgA endomysial antibodies (EmA) and IgG deamidated gliadin (DGP) antibodies.17, 25 . . .
    • . . . Serological analyses of patients with gluten sensitivity have found a high prevalence (40–50%) of first-generation antigliadin antibodies (AGAs).12, 13, 25 AGA positivity is almost always confined to the IgG class, while only occasionally occurring in the IgA class . . .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
    • . . . Positivity for HLA-DQ2 and/or HLA-DQ8 has been reported in ~40% of patients with gluten sensitivity.13, 17, 25 This figure is much lower than that found in patients with celiac disease (99%) and is comparable to the general population (~30%).17,25 Thus, data acquired so far indicate that gluten sensitivity is unrelated to the genetic pattern that is found in the vast majority of patients with celiac disease . . .
  14. Verdu, E. F. Can gluten contribute to irritable bowel syndrome? Am. J. Gastroenterol. 106, 516-518 , .
    • . . . The clinical features of gluten sensitivity include intestinal symptoms, commonly misdiagnosed as IBS,14 and extraintestinal manifestations, which occur soon after gluten has been ingested and rapidly disappear once the patient is on a gluten-free diet.12, 13 . . .
  15. Cooper, B. T. et al. Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterology 79, 801-806 , .
    • . . . Indeed, data published in 1980 and in 2000 suggested the existence of a syndrome caused by the ingestion of gluten in a subset of patients who did not have celiac disease or wheat allergy.15, 16 For many years, these patients continued to consume gluten-containing foods because gluten was not considered to be the cause of their symptoms . . .
  16. Kaukinen, K. et al. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 35, 942-946 , .
    • . . . Indeed, data published in 1980 and in 2000 suggested the existence of a syndrome caused by the ingestion of gluten in a subset of patients who did not have celiac disease or wheat allergy.15, 16 For many years, these patients continued to consume gluten-containing foods because gluten was not considered to be the cause of their symptoms . . .
  17. 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 , .
    • . . . The pathogenesis of gluten sensitivity is still largely unsettled, although current data, mainly derived from a single study by Sapone et al.,17 suggest that the mechanisms involved are different from those underlying celiac disease (Figure 1) . . .
    • . . . Although both innate and adaptive immunity have a central role in the development of celiac disease, gluten sensitivity seems to be mainly associated with activation of the innate immune response.1, 17 The expression of the innate immunity marker Toll-like receptor (TLR)2 is considerably increased in the intestinal mucosa of patients with gluten sensitivity compared with patients who have celiac disease and control individuals.17 Moreover, patients with gluten sensitivity had higher expression of TLR1 and TLR4 transcripts at the mucosal level than did patients with celiac disease or control individuals.17 In addition, adaptive immune markers, including IL-6, T-helper-1 cytokine IFN-γ, IL-17 and IL-21, were expressed at increased levels in the small intestinal mucosa of patients with celiac disease, but not of those with gluten sensitivity.17 Another interesting finding that differentiates gluten sensitivity from celiac disease concerned the mucosal expression of genes associated with TREG cells . . .
    • . . . Although both innate and adaptive immunity have a central role in the development of celiac disease, gluten sensitivity seems to be mainly associated with activation of the innate immune response.1, 17 The expression of the innate immunity marker Toll-like receptor (TLR)2 is considerably increased in the intestinal mucosa of patients with gluten sensitivity compared with patients who have celiac disease and control individuals.17 Moreover, patients with gluten sensitivity had higher expression of TLR1 and TLR4 transcripts at the mucosal level than did patients with celiac disease or control . . .
    • . . . The expression of TREG marker FOXP3 was found to be notably reduced in patients with gluten sensitivity compared with those who had celiac disease.17 The expression of these messengers represents a quite controversial aspect of autoimmunity, as both downregulation and upregulation of FOXP3 and other TREG-dependent molecules have been reported in patients with celiac disease and related conditions (such as type 1 diabetes mellitus).18, 19, 20 Taken together, these preliminary data suggest that innate, rather than adaptive, immunity has a prominent pathogenetic role in gluten sensitivity. . . .
    • . . . Loss of intestinal barrier function, which has been clearly established in celiac disease, represents a key mechanism for the development of autoimmunity through the continuous aberrant passage of antigens across the intestinal epithelium.21 However, in contrast to celiac disease, the study by Sapone et al.17 showed that patients with gluten sensitivity did not have changes in intestinal mucosal permeability as assessed by the lactulose–mannitol test . . .
    • . . . In particular, an increased lactulose to mannitol urinary ratio, which is indicative of enhanced permeability of the small intestine, was detected in patients with celiac disease, but not in those with gluten sensitivity.17 Nonetheless, it should be noted that the lactulose–mannitol test might not be reliable enough to identify subtle abnormalities of the intestinal barrier function in patients with gluten sensitivity . . .
    • . . . As increased CLDN4 expression is indicative of reduced intestinal permeability, this finding suggests that patients with gluten sensitivity might have a less permeable mucosa than those with celiac disease.17 Clearly, further studies are necessary to confirm this result and to establish whether mucosal epithelial barrier function is actually increased in patients with gluten sensitivity. . . .
    • . . . Despite having a normal small intestinal mucosa, relatives of patients with celiac disease often display evidence of immune responsiveness to gluten.11 This observation has been confirmed by the demonstration that 10 of 78 (12.8%) patients with gluten sensitivity were first-degree relatives of patients with celiac disease.25 Local instillation of gluten in the rectum can be a useful test for identifying mucosal evidence of gluten sensitivity at an early stage in asymptomatic first-degree relatives of patients with celiac disease.26, 27 At variance with celiac disease, patients with gluten sensitivity do not seem to show major autoimmune comorbidities.17 Indeed, in the study of 78 patients with gluten sensitivity none had type 1 diabetes mellitus and only one (1.3%) had autoimmune thyroiditis, compared with 5% and 19%, respectively, of 80 patients with celiac disease.25 Natural history data on gluten sensitivity are still lacking and it is therefore difficult to draw firm conclusions on the outcome of this condition . . .
    • . . . Wheat allergy should be ruled out by testing patients for serum IgE antibodies that are specific to gluten and wheat fractions as well as by skin prick tests.13 Another diagnostic prerequisite is the lack of highly specific markers of celiac disease, that is, IgA tissue transglutaminase antibodies (tTGAs), IgA endomysial antibodies (EmA) and IgG deamidated gliadin (DGP) antibodies.17, 25 . . .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
    • . . . Positivity for HLA-DQ2 and/or HLA-DQ8 has been reported in ~40% of patients with gluten sensitivity.13, 17, 25 This figure is much lower than that found in patients with celiac disease (99%) and is comparable to the general population (~30%).17,25 Thus, data acquired so far indicate that gluten sensitivity is unrelated to the genetic pattern that is found in the vast majority of patients with celiac disease . . .
  18. Granzotto, M. et al. Regulatory T-cell function is impaired in celiac disease. Dig. Dis. Sci. 54, 1513-1519 , .
    • . . . The expression of TREG marker FOXP3 was found to be notably reduced in patients with gluten sensitivity compared with those who had celiac disease.17 The expression of these messengers represents a quite controversial aspect of autoimmunity, as both downregulation and upregulation of FOXP3 and other TREG-dependent molecules have been reported in patients with celiac disease and related conditions (such as type 1 diabetes mellitus).18, 19, 20 Taken together, these preliminary data suggest that innate, rather than adaptive, immunity has a prominent pathogenetic role in gluten sensitivity. . . .
  19. Vorobjova, T. et al. Increased FOXP3 expression in small-bowel mucosa of children with coeliac disease and type I diabetes mellitus. Scand. J. Gastroenterol. 44, 422-430 , .
    • . . . The expression of TREG marker FOXP3 was found to be notably reduced in patients with gluten sensitivity compared with those who had celiac disease.17 The expression of these messengers represents a quite controversial aspect of autoimmunity, as both downregulation and upregulation of FOXP3 and other TREG-dependent molecules have been reported in patients with celiac disease and related conditions (such as type 1 diabetes mellitus).18, 19, 20 Taken together, these preliminary data suggest that innate, rather than adaptive, immunity has a prominent pathogenetic role in gluten sensitivity. . . .
  20. Hansson, T. et al. Transforming growth factor-β (TGF-β) and tissue transglutaminase expression in the small intestine in children with coeliac disease. Scand. J. Immunol. 56, 530-537 , .
    • . . . The expression of TREG marker FOXP3 was found to be notably reduced in patients with gluten sensitivity compared with those who had celiac disease.17 The expression of these messengers represents a quite controversial aspect of autoimmunity, as both downregulation and upregulation of FOXP3 and other TREG-dependent molecules have been reported in patients with celiac disease and related conditions (such as type 1 diabetes mellitus).18, 19, 20 Taken together, these preliminary data suggest that innate, rather than adaptive, immunity has a prominent pathogenetic role in gluten sensitivity. . . .
  21. Schuppan, D., Junker, Y. & Barisani, D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 137, 1912-1933 , .
    • . . . Loss of intestinal barrier function, which has been clearly established in celiac disease, represents a key mechanism for the development of autoimmunity through the continuous aberrant passage of antigens across the intestinal epithelium.21 However, in contrast to celiac disease, the study by Sapone et al.17 showed that patients with gluten sensitivity did not have changes in intestinal mucosal permeability as assessed by the lactulose–mannitol test . . .
  22. 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 , .
    • . . . Indeed, Biesiekierski et al., using the dual sugar absorption test, did not find any significant difference in the intestinal barrier function of two randomly treated groups of patients who had gluten sensitivity (one challenged by gluten, the other by placebo).22 In addition, PCR analysis of tight junction components, that is claudins (CLDN), tight junction protein 1 and occludin, showed a notably higher expression of CLDN4 mRNA in duodenal biopsy samples from patients with gluten sensitivity than those with celiac disease . . .
    • . . . The clinical presentation of gluten sensitivity is a combination of IBS-like symptoms, including abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), and systemic manifestations such as 'foggy mind', headache, fatigue, joint and muscle pain, leg or arm numbness, dermatitis (eczema or skin rash), depression and anemia (Figure 2).25 In a double-blind, randomized, placebo-controlled trial by Biesiekierski et al.,22 IBS-like symptoms and tiredness reoccurred more frequently in the gluten rechallenged group than in patients on placebo (68% and 40%, respectively), thus suggesting a link between gluten and symptom generation . . .
    • . . . Although the frequency of intestinal IBS-like symptoms is higher than that of extraintestinal manifestations, all patients usually display two or more extraintestinal symptoms, the most common being fatigue (36%) and 'foggy mind' (42%), the latter defined as a sensation of lethargy that occurs after eating gluten-containing foods.25 However, Biesiekierski et al. reported that only one extraintestinal manifestation (that is, tiredness) was associated with IBS-like symptoms.22 Thus, other data are needed to establish the actual prevalence and type of extraintestinal symptoms in patients with gluten sensitivity. . . .
  23. 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 , .
    • . . . Both abnormalities improved upon gluten withdrawal.23 Moreover, luminal antigens, such as components of the intestinal microbiota, might contribute to enhanced inflammatory responses to dietary antigens such as gluten.24 Taken together, these results from animal models provide a proof of concept that neuromuscular abnormalities and gut microbiota can trigger gliadin-induced symptoms . . .
  24. Natividad, J. M. et al. Host responses to intestinal microbial antigens in gluten sensitive mice. PLoS ONE 4, e6472 , .
    • . . . Both abnormalities improved upon gluten withdrawal.23 Moreover, luminal antigens, such as components of the intestinal microbiota, might contribute to enhanced inflammatory responses to dietary antigens such as gluten.24 Taken together, these results from animal models provide a proof of concept that neuromuscular abnormalities and gut microbiota can trigger gliadin-induced symptoms . . .
  25. Volta, U. et al. Serological tests in gluten sensitivity (nonceliac gluten intolerance). J. Clin. Gastroenterol. , .
  26. Troncone, R. et al. In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA. Gastroenterology 111, 318-324 , .
    • . . . Despite having a normal small intestinal mucosa, relatives of patients with celiac disease often display evidence of immune responsiveness to gluten.11 This observation has been confirmed by the demonstration that 10 of 78 (12.8%) patients with gluten sensitivity were first-degree relatives of patients with celiac disease.25 Local instillation of gluten in the rectum can be a useful test for identifying mucosal evidence of gluten sensitivity at an early stage in asymptomatic first-degree relatives of patients with celiac disease.26, 27 At variance with celiac disease, patients with gluten sensitivity do not seem to show major autoimmune comorbidities.17 Indeed, in the study of 78 patients with gluten sensitivity none had type 1 diabetes mellitus and only one (1.3%) had autoimmune thyroiditis, compared with 5% and 19%, respectively, of 80 patients with celiac disease.25 Natural history data on gluten sensitivity are still lacking and it is therefore difficult to draw firm conclusions on the outcome of this condition . . .
  27. Dezi, R. et al. Gluten sensitivity in the rectal mucosa of first-degree relatives of celiac disease patients. Am. J. Gastroenterol. 92, 1326-1330 , .
    • . . . Despite having a normal small intestinal mucosa, relatives of patients with celiac disease often display evidence of immune responsiveness to gluten.11 This observation has been confirmed by the demonstration that 10 of 78 (12.8%) patients with gluten sensitivity were first-degree relatives of patients with celiac disease.25 Local instillation of gluten in the rectum can be a useful test for identifying mucosal evidence of gluten sensitivity at an early stage in asymptomatic first-degree relatives of patients with celiac disease.26, 27 At variance with celiac disease, patients with gluten sensitivity do not seem to show major autoimmune comorbidities.17 Indeed, in the study of 78 patients with gluten sensitivity none had type 1 diabetes mellitus and only one (1.3%) had autoimmune thyroiditis, compared with 5% and 19%, respectively, of 80 patients with celiac disease.25 Natural history data on gluten sensitivity are still lacking and it is therefore difficult to draw firm conclusions on the outcome of this condition . . .
  28. Wahnschaffe, U., Schulzke, J., 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 , .
    • . . . Antibody titers of IgG AGAs in patients with gluten sensitivity are usually as high as those found in patients with celiac disease.25 Although lower than in patients with celiac disease (80–90%), the prevalence of IgG AGAs in patients with gluten sensitivity is much higher than in those with a variety of other conditions, for example, IBS (20%)28 or nongastrointestinal diseases (connective tissue disorders and autoimmune liver disease, 9% and 21.5%, respectively),29 and in the general population and healthy blood donors (ranging from 2% to 8%).30, 31 . . .
  29. Volta, U. et al. Usefulness of antibodies to deamidated gliadin peptides in celiac disease diagnosis and follow-up. Dig. Dis. Sci. 53, 1582-1588 , .
    • . . . Antibody titers of IgG AGAs in patients with gluten sensitivity are usually as high as those found in patients with celiac disease.25 Although lower than in patients with celiac disease (80–90%), the prevalence of IgG AGAs in patients with gluten sensitivity is much higher than in those with a variety of other conditions, for example, IBS (20%)28 or nongastrointestinal diseases (connective tissue disorders and autoimmune liver disease, 9% and 21.5%, respectively),29 and in the general population and healthy blood donors (ranging from 2% to 8%).30, 31 . . .
  30. Volta, U. et al. High prevalence of celiac disease in the general population. Dig. Dis. Sci. 46, 1500-1505 , .
    • . . . Antibody titers of IgG AGAs in patients with gluten sensitivity are usually as high as those found in patients with celiac disease.25 Although lower than in patients with celiac disease (80–90%), the prevalence of IgG AGAs in patients with gluten sensitivity is much higher than in those with a variety of other conditions, for example, IBS (20%)28 or nongastrointestinal diseases (connective tissue disorders and autoimmune liver disease, 9% and 21.5%, respectively),29 and in the general population and healthy blood donors (ranging from 2% to 8%).30, 31 . . .
  31. Hadjivassiliou, M. et al. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 347, 369-371 , .
  32. Volta, U. et al. IgA antigliadin antibodies and persistence of jejunal lesions in adult coeliac disease. Digestion 47, 111-114 , .
  33. Oberhüber, G., Granditsch, G. & Vogelsang, H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur. J. Gastroenterol. Hepatol. 11, 1185-1194 , .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
  34. Brown, I., Mino-Kenudson, M., Deshpande, V. & Lauwers, G. Y. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis. Arch. Pathol. Lab. Med. 130, 1020-1025 , .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
  35. Salmi, T. T. et al. Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease. Aliment. Pharmacol. Ther. 24, 541-552 , .
    • . . . About 60% of patients with gluten sensitivity have a normal intestinal mucosa that is composed of <25% intraepithelial lymphocytes (IELs)13, 17, 25 ('grade 0' according to the Marsh–Oberhüber modified classification).33 The remaining 40% of patients have a mild increase in the number of IELs of up to 40% ('grade 1'), which is less than the percentage of IELs usually found in patients with celiac disease.12, 25 Nonetheless, grade 1 lesions are known to occur not only in gluten-related conditions, but also in a wide array of diseases, that is, autoimmune disorders (such as Hashimoto thyroiditis and type 1 diabetes mellitus), intestinal infections (bacterial, viral and parasitic), Helicobacter pylori infection, lactose intolerance, food allergies and common variable immunodeficiency.34 When a grade 1 lesion is demonstrated, T-cell receptor γδ IELs should be assessed, as their levels are considerably increased in patients with celiac disease but not in those with gluten sensitivity.12 In the context of a grade 1 lesion, the detection of IgA tTGAs in the intestinal mucosa would suggest a diagnosis of potential celiac disease rather than gluten sensitivity.35, 36 . . .
  36. Maglio, M. et al. Intestinal deposits of anti-tissue transglutaminase IgA in childhood celiac disease. Dig. Liver Dis. 43, 604-608 , .
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