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Nonceliac Gluten Sensitivity

2015; Elsevier BV; Volume: 148; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2014.12.049

1528-0012

Alessio Fasano, Anna Sapone, Victor F. Zevallos, Detlef Schuppan,

Eosinophilic Esophagitis

During the past decade there has been an impressive increase in popularity of the gluten-free diet (GFD)—now the most trendy alimentary habit in the United States and other countries. According to recent surveys, as many as 100 million Americans will consume gluten-free products within a year. Operating under the concept that the GFD benefits only individuals with celiac disease, health care professionals have struggled to separate the wheat from the chaff; there are claims that eliminating gluten from the diet increases health and helps with weight loss, or even that gluten can be harmful to every human being. However, apart from unfounded trends, a disorder related to ingestion of gluten or gluten-containing cereals, namely nonceliac gluten sensitivity (NCGS), has resurfaced in the literature, fueling a debate on the appropriateness of the GFD for people without celiac disease. Although there is clearly a fad component to the popularity of the GFD, there is also undisputable and increasing evidence for NCGS. However, we require a better understanding of the clinical presentation of NCGS, as well as its pathogenesis, epidemiology, management, and role in conditions such as irritable bowel syndrome, chronic fatigue, and autoimmunity. Before we can begin to identify and manage NCGS, there must be agreement on the nomenclature and definition of the disorder based on proper peer-reviewed scientific information. We review the most recent findings on NCGS and outline directions to dissipate some of the confusion related to this disorder. During the past decade there has been an impressive increase in popularity of the gluten-free diet (GFD)—now the most trendy alimentary habit in the United States and other countries. According to recent surveys, as many as 100 million Americans will consume gluten-free products within a year. Operating under the concept that the GFD benefits only individuals with celiac disease, health care professionals have struggled to separate the wheat from the chaff; there are claims that eliminating gluten from the diet increases health and helps with weight loss, or even that gluten can be harmful to every human being. However, apart from unfounded trends, a disorder related to ingestion of gluten or gluten-containing cereals, namely nonceliac gluten sensitivity (NCGS), has resurfaced in the literature, fueling a debate on the appropriateness of the GFD for people without celiac disease. Although there is clearly a fad component to the popularity of the GFD, there is also undisputable and increasing evidence for NCGS. However, we require a better understanding of the clinical presentation of NCGS, as well as its pathogenesis, epidemiology, management, and role in conditions such as irritable bowel syndrome, chronic fatigue, and autoimmunity. Before we can begin to identify and manage NCGS, there must be agreement on the nomenclature and definition of the disorder based on proper peer-reviewed scientific information. We review the most recent findings on NCGS and outline directions to dissipate some of the confusion related to this disorder. Anna SaponeView Large Image Figure ViewerDownload Hi-res image Download (PPT)Victor ZevallosView Large Image Figure ViewerDownload Hi-res image Download (PPT)Detlef SchuppanView Large Image Figure ViewerDownload Hi-res image Download (PPT) Gluten-related disorders are activated by the ingestion of gluten-containing grains by individuals with a genetic and/or immunologic predisposition to these conditions. Wheat is the most widely grown crop worldwide, with more than 25,000 different cultivars produced by plant breeders. Its popularity results from its simplicity of cultivation in different climates, high yield, nutritional value, organoleptic characteristics, and palatability. It can be processed into many foods, such as breads, pasta, pizza, bulgur, couscous, and drinks such as beer. Furthermore, the functional properties of gluten proteins have led to their addition to many foods and cosmetics. The same characteristics that make gluten so unique and desirable for human consumption also lead to diseases: the best known, wheat allergy and celiac disease, are mediated by the adaptive immune system (Figure 1). Each disorder is characterized by activation of T cells in the intestinal mucosa against gluten. In wheat allergy, immunoglobulin E (IgE) is cross-linked by repeat sequences in gluten peptides (eg, Ser-Gln-Gln-Gln-[Gln-]Pro-Pro-Phe), and nongluten proteins induce the release of immune mediators such as histamine from basophils and mast cells.1Tanabe S. Analysis of food allergen structures and development of foods for allergic patients.Biosci Biotechnol Biochem. 2008; 72: 649-659Crossref PubMed Scopus (45) Google Scholar In contrast, celiac disease, which affects approximately 1% of most populations, has characteristics of an autoimmune disorder. It can be identified based on serologic markers such as serum antibodies against tissue transglutaminase-2 (TG2), followed by intestinal biopsy confirmation,2Tosco A. Auricchio R. Aitoro R. et al.In celiac disease intestinal titers of anti-tissue transglutaminase2 antibodies positively correlate with the mucosal damage degree and inversely with the gluten-free diet duration.Clin Exp Immunol. 2014; 177: 611-617Crossref PubMed Scopus (13) Google Scholar, 3Dieterich W. Laag E. Schöpper H. et al.Autoantibodies to tissue transglutaminase as predictors of celiac disease.Gastroenterology. 1998; 115: 1317-1321Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar and its link to autoimmune comorbidities.4Sollid L.M. Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease.Nat Rev Immunol. 2013; 13: 294-302Crossref PubMed Scopus (230) Google Scholar, 5Schuppan D. Junker Y. Barisani D. Celiac disease: from pathogenesis to novel therapies.Gastroenterology. 2009; 137: 1912-1933Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar In addition to celiac disease and wheat allergy, there have been cases of reactions to gluten-containing grains that involved neither allergic nor autoimmune mechanisms. These generally are termed nonceliac gluten sensitivity (NCGS) or simply gluten sensitivity (Figure 1).6Sapone A. Lammers K.M. Mazzarella G. et al.Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol. 2010; 152: 75-80Crossref PubMed Scopus (208) Google Scholar, 7Carroccio A. Mansueto P. Iacono G. et al.Non-celiac wheat sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity.Am J Gastroenterol. 2012; 107: 1898-1906Crossref PubMed Scopus (341) Google Scholar, 8Sapone A. Lammers K.M. Casolaro V. 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: 23Crossref PubMed Scopus (370) Google Scholar Individuals who experience distress when eating gluten-containing products and then improve on a gluten-free diet (GFD) might have NCGS instead of celiac disease. Patients with NCGS develop adverse reactions when eating gluten-containing foods. However, these do not lead to overt autoimmune enteropathy, which is characterized by villous atrophy and crypt hyperplasia, which develop in patients with celiac disease. Although the gastrointestinal (GI) symptoms of patients with NCGS can resemble those associated with celiac disease, NCGS is not accompanied by the development of autoantibodies to TG2. Typically, a diagnosis is made by exclusion; an elimination diet and then open challenge (monitored re-introduction of gluten-containing foods) can be used to confirm the diagnosis, based on the rapid reappearance of the intestinal or extraintestinal symptoms. Interest in NCGS has increased as studies defined it more clearly and proposed that its pathogenesis was distinct from that of celiac disease, which involves an innate immune response to gluten.6Sapone A. Lammers K.M. Mazzarella G. et al.Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol. 2010; 152: 75-80Crossref PubMed Scopus (208) Google Scholar, 8Sapone A. Lammers K.M. Casolaro V. 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: 23Crossref PubMed Scopus (370) Google Scholar However, an early description of NCGS dates to almost 40 years ago, when Ellis and Linaker9Ellis A. Linaker B.D. Non-coeliac gluten sensitivity?.Lancet. 1978; 1: 1358-1359Abstract PubMed Scopus (87) Google Scholar reported a case of a 43-year-old woman in January 1978. According to the investigators, she had the following:A 4-month history of loose motions, 3 times a day with no blood or mucus. The diarrhea was accompanied initially by periumbilical colic, which recurred intermittently, and abdominal distension, but she had not lost weight and had retained her appetite. She had been taking tetracycline for 6 years for acne conglobate. Investigations, which included examination of feces for ova, cysts, parasites, and occult blood, radiographs (barium meal, small-bowel meal, barium enema), sigmoidoscopy, and jejunal biopsy, were all normal except for a hiatus hernia. She did not improve when tetracycline was withdrawn or when antidiarrheal agents or tranquillizers were tried. Her symptoms continued for 2 years. However, when a gluten-free diet was tried the diarrhea stopped within 4 days and the patient felt very much better. Jejunal biopsy was repeated after 6-week gluten challenge (accompanied by recurrence of diarrhea) but was normal in every way including normal intraepithelial lymphocyte counts. Resumption of the gluten-free diet was followed by a rapid disappearance of all her symptoms. We consider it very likely that this woman’s symptoms were due to gluten sensitivity. Her recovery is unlikely to be a placebo response because other treatments had failed; moreover, relapse during the gluten challenge was followed by remission after the second withdrawal of gluten from the diet.9Ellis A. Linaker B.D. Non-coeliac gluten sensitivity?.Lancet. 1978; 1: 1358-1359Abstract PubMed Scopus (87) Google Scholar After this publication, NCGS disappeared from the literature with the exception of a few reports.10Cooper B.T. Holmes G.K. Ferguson R. et al.Gluten-sensitive diarrhea without evidence of celiac disease.Gastroenterology. 1980; 79: 801-806PubMed Scopus (154) Google Scholar, 11Kaukinen K. Turjanmaa K. Mäki M. et al.Intolerance to cereals is not specific for coeliac disease.Scand J Gastroenterol. 2000; 35: 942-946Crossref PubMed Scopus (96) Google Scholar, 12Campanella J. Biagi F. Bianchi P.I. et al.Clinical response to gluten withdrawal is not an indicator of coeliac disease.Scand J Gastroenterol. 2008; 43: 1311-1314Crossref PubMed Scopus (45) Google Scholar A study in 20106Sapone A. Lammers K.M. Mazzarella G. et al.Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol. 2010; 152: 75-80Crossref PubMed Scopus (208) Google Scholar showed celiac disease and NCGS to be separate entities with different mechanisms of pathogenesis. NCGS was proposed to result from an innate immune response to gluten-containing foods, whereas celiac disease was associated with the adaptive immune response.4Sollid L.M. Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease.Nat Rev Immunol. 2013; 13: 294-302Crossref PubMed Scopus (230) Google Scholar, 5Schuppan D. Junker Y. Barisani D. Celiac disease: from pathogenesis to novel therapies.Gastroenterology. 2009; 137: 1912-1933Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar, 8Sapone A. Lammers K.M. Casolaro V. 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: 23Crossref PubMed Scopus (370) Google Scholar Since this report, there have been several articles published regarding NCGS, attempting to define its clinical presentation, assess its epidemiology, and describe its pathogenesis. Notably, NCGS does not seem to be limited to intestinal symptoms—it includes extraintestinal pathology. We review our limited knowledge about NCGS and the challenges to defining it. Since 2010, the definition of NCGS has been discussed at 3 consensus conferences, which led to 3 publications.13Sapone A. Bai J.C. Ciacci C. et al.Spectrum of gluten-related disorders: consensus on new nomenclature and classification.BMC Med. 2012; 10: 13Crossref PubMed Scopus (833) Google Scholar, 14Catassi C. Bai J.C. Bonaz B. et al.Non-celiac gluten sensitivity: the new frontier of gluten related disorders.Nutrients. 2013; 5: 3839-3853Crossref PubMed Scopus (370) Google Scholar, 15Ludvigsson J.F. Leffler D.A. Bai J.C. et al.The Oslo definitions for coeliac disease and related terms.Gut. 2013; 62: 43-52Crossref PubMed Scopus (1089) Google Scholar Given the uncertainties about this clinical entity and the lack of diagnostic biomarkers, all 3 reports concluded that NCGS should be defined by the following exclusionary criteria: a clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that resolve once the gluten-containing foodstuff is eliminated from the diet, and when celiac disease and wheat allergy have been ruled out. One of the most controversial and highly debated discussions concerns the role of gluten in causing NCGS. Recent reports have indicated that gluten might not be the cause of NCGS, and some investigators still question whether NCGS as a real clinical entity. Therefore, to avoid further confusion, it is important to clearly define the difference between food sensitivity and food intolerance. According to the US National Institute of Allergy and Infectious Diseases,16Boyce J.A. Assa’ad A. Burks A.W. et al.Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.J Allergy Clin Immunol. 2010; 126: S1-S58Abstract Full Text Full Text PDF PubMed Scopus (1158) Google Scholar food intolerance occurs when the body lacks a particular enzyme to digest nutrients, nutrients are too abundant to be digested completely, or a particular nutrient cannot be digested properly. Therefore, symptoms are exclusively GI and mostly secondary to sugar fermentation by the intestinal microbiota, leading to the production of gas, which causes abdominal distention, abdominal pain, and irregular bowel movements. Common examples include lactose intolerance, or intolerance to excess fermentable oligo- and disacchararides, monosaccharides and polyols (FODMAPs) or lactulose. Food sensitivities are immune-mediated reactions to some nutrients; these reactions (intestinal and extraintestinal) do not always occur in the same way when people ingest that particular nutrient. NCGS is an example of food sensitivity. There have been reports that FODMAPs, rather than gluten, induce the abdominal symptoms attributed to NCGS. These findings indicate that NCGS might not be a separate entity from irritable bowel syndrome (IBS),17Biesiekierski J.R. Peters S.L. Newnham E.D. et al.No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.Gastroenterology. 2013; 145: 320-328Abstract Full Text Full Text PDF PubMed Scopus (615) Google Scholar, 18Vanga R. Leffler D.A. Gluten sensitivity: not celiac and not certain.Gastroenterology. 2014; 145: 276-279Abstract Full Text Full Text PDF Scopus (14) Google Scholar but rather a subgroup of IBS. However, keeping in mind the difference between the definition of food intolerance (GI symptoms secondary to fermentation of sugars by the colonic microbiota) and food sensitivity (an immune response to nutrient-derived antigens that causes GI and extra-GI symptoms), as well as the definition of NCGS (characterized by intestinal and/or extraintestinal symptoms, after ingestion of gluten-containing grains, that resolve upon elimination of these grains from the diet), it should be clear that IBS and NCGS are distinct entities with some overlapping features. Moreover, although FODMAPs can cause GI symptoms such as bloating, they inhibit, rather than cause, intestinal inflammation, inducing beneficial alterations to intestinal microbiota and generation of short-chain fatty acids.19Halmos E.P. Christophersen C.T. Bird A.R. et al.Diets that differ in their FODMAP content alter the colonic luminal microenvironment.Gut. 2015; 64: 93-100Crossref PubMed Scopus (459) Google Scholar, 20Puertollano E. Kolida S. Yaqoob P. Biological significance of short-chain fatty acid metabolism by the intestinal microbiome.Curr Opin Clin Nutr Metab Care. 2014; 17: 139-144Crossref PubMed Scopus (164) Google Scholar, 21Vulevic J. Juric A. Tzortzis G. et al.A mixture of trans-galactooligosaccharides reduces markers of metabolic syndrome and modulates the fecal microbiota and immune function of overweight adults.J Nutr. 2013; 143: 324-331Crossref PubMed Scopus (241) Google Scholar, 22Neyrinck A.M. Van Hée V.F. Piront N. et al.Wheat-derived arabinoxylan oligosaccharides with prebiotic effect increase satietogenic gut peptides and reduce metabolic endotoxemia in diet-induced obese mice.Nutr Diabetes. 2012; 2: e28Crossref PubMed Scopus (153) Google Scholar, 23Koleva P.T. Valcheva R.S. Sun X. et al.Inulin and fructo-oligosaccharides have divergent effects on colitis and commensal microbiota in HLA-B27 transgenic rats.Br J Nutr. 2012; 108: 1633-1643Crossref PubMed Scopus (74) Google Scholar, 24Holma R. Juvonen P. Asmawi M.Z. et al.Galacto-oligosaccharides stimulate the growth of bifidobacteria but fail to attenuate inflammation in experimental colitis in rats.Scand J Gastroenterol. 2002; 37: 1042-1047Crossref PubMed Scopus (64) Google Scholar Cereals such as wheat and rye, when consumed in normal quantities, are only minor sources of FODMAPs in the daily diet (Table 1). Therefore, gluten-containing grains are not likely to induce IBS exclusively via FODMAPs. In contrast, there is growing evidence that other proteins that are unique to gluten-containing cereals can elicit an innate immune response that leads to NCGS, raising a nomenclature issue. For this reason, wheat sensitivity, rather than gluten sensitivity, seems to be a more appropriate term, keeping in mind that other gluten-containing grains such as barley and rye also can trigger the symptoms.Table 1Sources of FODMAPsFODMAPExcess fructoseLactoseOligosaccharides (fructans and/or galactans)PolyolsProblem high FODMAP food sourceFruits: apples, pears, nashi pears, clingstone peaches, mango, sugar snap peas, watermelon, tinned fruit in natural juiceHoneySweeteners: fructose, high-fructose corn syrupLarge total fructose dose: concentrated fruit sources; large servings of fruit, dried fruit, fruit juiceMilk: cow, goat, and sheep (regular and low fat ice cream)Yogurt (regular and low fat)Cheeses: soft and fresh (eg, ricotta and cottage)Vegetables: artichokes, asparagus, beetroot, Brussels sprout, broccoli, cabbage, fennel, garlic, leeks, okra, onions, peas, shallotsCereals: wheat and rye when eaten in large amounts (eg, bread, pasta, couscous, crackers, biscuits)Legumes: chickpeas, lentils, red kidney beans, baked beansFruits: watermelon, custard apple, white peaches, rambutan, persimmonFruits: apples, apricots, cherries, longan, lychee, nashi pears, nectarine pears, peaches, plums, prunes, watermelonVegetables: avocado, cauliflower, mushrooms, snow peasSweeteners: sorbitol (420), mannitol (421), xylitol (967), maltitol (965), isomalt (953), and others ending in “-ol”Suitable alternative low-FODMAP food sourceFruit: banana, blueberry, carambola, durian, grapefruit, grape, honeydew melon, kiwifruit, lemon, lime, mandarin, orange, passion fruit, paw paw, raspberry, rockmelon, strawberry, tangeloHoney substitutes: maple syrup, golden syrupSweeteners: any except polyolsMilk: lactose-free, rice milkCheese: “hard” cheeses including brie and camembertYogurt: lactose-freeIce cream substitutes: gelati, sorbetButterVegetables: bamboo shoots, bok choy, carrot, celery, capsicum, choko, choy sum, corn, eggplant, green beans, lettuce, chives, parsnip, pumpkin, silverbeet, spring onion (green only), tomatoOnion/garlic substitutes: garlic-infused oilCereals: gluten-free and spelt bread/cereal productsFruits: banana, blueberry, carambola, durian, grapefruit, grape, honeydew melon, kiwifruit, lemon, lime, mandarin, orange, passion fruit, paw paw, raspberry, rockmelonSweeteners: sugar (sucrose), glucose, other artificial sweeteners not ending in “-ol” Open table in a new tab Symptoms of NCGS usually occur within hours or days after ingestion of gluten-containing grains, and disappear rapidly when these grains are eliminated from the diet. NCGS most frequently produces a combination of intestinal and extraintestinal symptoms. IBS-like symptoms, such as abdominal pain, gas, distension, and irregular bowel movements, frequently are reported and therefore make it difficult to distinguish NCGS from IBS induced by other causes. The differential diagnosis is facilitated for patients who also experience extraintestinal symptoms, including headache or frank migraine, foggy mind, chronic fatigue, joint and muscle pain, tingling of the extremities, leg or arm numbness, eczema, anemia, depression,6Sapone A. Lammers K.M. Mazzarella G. et al.Differential mucosal IL-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease.Int Arch Allergy Immunol. 2010; 152: 75-80Crossref PubMed Scopus (208) Google Scholar, 8Sapone A. Lammers K.M. Casolaro V. 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: 23Crossref PubMed Scopus (370) Google Scholar or for patients who report a reduction in immune-mediated (including autoimmune) symptoms on a GFD. By the time the patient sees a specialist, most patients with NCGS already have detected a relationship between exposure to gluten-containing grains and onset or worsening of symptoms. Children with NCGS mainly have intestinal symptoms such as abdominal pain and chronic diarrhea without weight loss. Less frequently, they present with extraintestinal manifestations, including fatigue and attention-deficit disorders.25Francavilla R. Cristofori Castellaneta S. et al.Clinical, serologic, and histologic features of gluten sensitivity in children.Pediatr. 2014; 164: 463-467Abstract Full Text Full Text PDF Scopus (73) Google Scholar Of particular interest is the relationship between NCGS and neurologic and neuropsychiatric disorders, including autism, schizophrenia, and peripheral neuropathy.26Hadjivassiliou M. Grünewald R.A. Kandler R.H. et al.Neuropathy associated with gluten sensitivity.J Neurol Neurosurg Psychiatry. 2006; 77: 1262-1266Crossref PubMed Scopus (90) Google Scholar, 27Hadjivassiliou M. Sanders D.S. Woodroofe N. et al.Gluten ataxia.Cerebellum. 2008; 7: 494-498Crossref PubMed Scopus (108) Google Scholar, 28Hadjivassiliou M. Sanders D.S. Grünewald R.A. et al.Gluten sensitivity: from gut to brain.Lancet Neurol. 2010; 9: 318-330Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar However, it is not clear how gluten might contribute to these disorders. Given the vague, sometimes nonspecific, nature of NCGS symptoms, a differential diagnosis from other conditions, particularly other gluten-related disorders, can be challenging. Table 2 summarizes the major clinical and pathogenic differences between NCGS, celiac disease, and wheat allergy.Table 2Activities of ATIs in Gluten-Containing and Gluten-Free StaplesTime interval from gluten exposure to onset of symptomsCeliac disease, days to weeksGluten sensitivity, hours to daysWheat allergy, minutes to hoursPathogenesisAutoimmunity (adaptive immunity)Innate immunity?Allergic immune responseHLAHLA DQ2/8 restrictedNot-HLA DQ2/8 restrictedNot-HLA DQ2/8 restrictedAuto-antibodiesAlmost always presentAlways absentAlways absentEnteropathyAlmost always presentAlways absent (slight increase in IEL)Always absent (eosinophils in the lamina propria)SymptomsIntestinal and extraintestinalIntestinal and extraintestinalIntestinal and extraintestinalComplicationsComorbiditiesLong term complicationsComorbiditiesLong term complications?No comorbiditiesShort-term complications (anaphylaxis)NOTE. Activities were determined using a cell-based bioassay of TLR4 activation.IEL, intraepithelial lymphocyte. Open table in a new tab NOTE. Activities were determined using a cell-based bioassay of TLR4 activation. IEL, intraepithelial lymphocyte. IBS is a syndrome that appears to be a mixed bag of distinct entities with common clinical presentations. Therefore, it is possible to consider some subjects with NCGS to be typical IBS patients and vice versa: a subgroup of IBS patients may have NCGS. This last scenario was highlighted in subjects affected by the diarrhea-predominant variant of IBS29Vazquez-Roque M.I. Camilleri M. Smyrk T. 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: 903-911Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar—particularly those with HLA-DQ2 and/or DQ8 genotypes (associated with celiac disease). In these subjects, ingestion of gluten-containing grains increased gut permeability via reduced expression of intestinal epithelial tight junction proteins, without affecting intestinal transit time and histology.29Vazquez-Roque M.I. Camilleri M. Smyrk T. 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: 903-911Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar Fritscher-Ravens et al30Fritscher-Ravens A. Schuppan D. Ellrichmann M. et al.Confocal endomicroscopy reveals food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.Gastroenterology. 2014; 147: 1012-1020Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar studied 36 subjects who reported severe IBS with a clear yet undefined relation to food intake, but exclusion of celiac disease or common food allergies. By using in vivo confocal laser endomicroscopy, Fritscher-Ravens et al30Fritscher-Ravens A. Schuppan D. Ellrichmann M. et al.Confocal endomicroscopy reveals food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.Gastroenterology. 2014; 147: 1012-1020Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar detected breaks in tight junctions and infiltration of the intestinal epithelium by immune cells in 22 of 36 patients with NCGS, within 2–3 minutes after duodenal instillation of the offending food extract. Most of these subjects (13 of 22) reacted to wheat (the other subjects reacted to milk, soy, and yeast). Importantly, exclusion of the offending food reduced clinical symptom scores by an average of 74%, which persisted for the 12 months of follow-up evaluation, ruling out a placebo effect.30Fritscher-Ravens A. Schuppan D. Ellrichmann M. et al.Confocal endomicroscopy reveals food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.Gastroenterology. 2014; 147: 1012-1020Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Apart from showing the rapid activation of the innate immune response in the intestine, this study showed that confocal laser endomicroscopy might be used in the diagnosis of NCGS. However, apart from NCGS, some patients also might have had a form of food allergy that was not detected with conventional serologic or skin tests.31Soares-Weiser K. Takwoingi Y. Panesar S.S. et al.The diagnosis of food allergy: a systematic review and meta-analysis.Allergy. 2014; 69: 76-86Crossref PubMed Scopus (164) Google Scholar, 32Lieberman J.A. Sicherer S.H. Diagnosis of food allergy: epicutaneous skin tests, in vitro tests, and oral food challenge.Curr Allergy Asthma Rep. 2011; 11: 58-64Crossref PubMed Scopus (67) Google Scholar, 33Carroccio A. Mansueto P. Morfino G. et al.Oligo-antigenic diet in the treatment of chronic anal fissures. Evidence for a relationship between food hypersensitivity and anal fissures.Am J Gastroenterol. 2013; 108: 825-832Crossref PubMed Scopus (18) Google Scholar Some patients with NCGS have disorders such as schizophrenia, autism spectrum disorders, allergies, or autoimmune disorders. GFDs can have positive effects in some of these patients and help them manage NCGS and extraintestinal disorders. Patients with schizophrenia who produced high levels of anti-gliadin IgGs and anti-TG6, but were excluded from having celiac disease, had reduced symptoms on a GFD.34Cascella N.G. Santora D.