Gluten sensitivity (also gluten intolerance) is a spectrum of disorders including celiac disease in which gluten has an adverse effect on the body. Symptoms include bloating, abdominal discomfort or pain, diarrhea, muscular disturbances and bone or joint pain. It can also cause other unexpected symptoms such as headaches and vertigo, among many others.
Gluten gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet. It is a protein composite found in wheat and other grains, including barley and rye and processed foods thereof. Gluten is composed of a gliadin fraction (alcohol soluble) and a glutenin fraction (only soluble in dilute acids or alkali). Gluten is not naturally occurring in corn, rice, or oats.
- 1 Symptoms
- 2 Etiology
- 3 Causes of gluten sensitivity
- 4 Separating forms of gluten sensitivity
- 5 Idiopathic gluten sensitivity
- 6 Gluten sources
- 7 See also
- 8 References
- 9 External links
Symptoms of gluten sensitivity include bloating, abdominal discomfort or pain, constipation and diarrhea, and might present extraintestinal symptoms including muscular disturbances and bone or joint pain.
Gluten sensitivity can lead to neurological issues such as ataxia. This exhibits as balance, nystagmus or sleep disturbance.
Difference between idiopathic gluten sensitivity and celiac disease
In a 2009 paper, Verdu et al. defined gluten sensitivity as "one or more of a variety of immunological, morphological or symptomatic manifestations that may also be shared by celiac disease and irritable bowel syndrome (IBS)". In cases where there is reactivity to gluten, yet celiac disease and wheat allergy are eliminated as possibilities, non-celiac gluten sensitivity may be considered. While the general clinical picture for gluten sensitivity is similar to celiac disease in particular, it is usually less severe and neither anti-tissue transglutaminase antibodies nor autoimmune comorbidities are found.
It is believed[by whom?] that approximately 40-50% of gluten sensitivity patients may have IgG or IgA anti-gliadin antibodies (AGA). There is also a study identifying approximately 50% of gluten sensitivity patients, few more than the general population, carry either HLA DQ 2 or 8. On closer inspection, it has also been found that such gluten-sensitive subjects lack histological lesions; fall below Marsh 2 celiac disease score and indicating that there may be some infiltration of intraepithelial lymphocytes. In addition, it has been found that they have normal intestinal permeability and an increased expression of Toll Like receptors 2 (TLR2) but no change in the cytokines involved in adaptive immune responses Th1 and Th17 such as IL-6, IL-17 A, IL 21, which are increased only in patients with celiac disease. The types of responses indicate an innate immune system involvement, but not autoimmune disease.
Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should eventually fall into gluten-sensitive enteropathy (GSE) or wheat allergy. Only rarely should gluten sensitivity be idiopathic. Idiopathic gluten sensitivity (IGS) arises spontaneously or from an obscure or unknown cause and may involve neuropathy, myopathy, dermal, or intestinal abnormalities. Anti-gliadin antibodies are the primary link between gluten and idiopathic sensitivity in instances "in which enteropathy or allergy are not clearly involved".
When enteropathy develops in early childhood symptomatic disease is more rapidly evident. A survey of geriatrics with celiac disease in Finland revealed that the incidence of disease was much higher than the general population. Allergic disease may rise or fall with age; certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as an increased risk factor for urticaria or anaphylaxis, and the sensitizing dose may include low-dose aspirin therapy used in the treatment of heart disease. Idiopathic disease appears largely late onset.
Researchers reported extreme fatigue and pain in patients without celiac disease, with gliadin antibodies. They called this a "non-celiac gluten intolerance" for which there is no explanation as to the mechanisms involved.
Causes of gluten sensitivity
Triticeae and the potential role of selective evolution in gluten sensitivities
The fruiting bodies of plants contain genes as well as reserves of nutrients that allow seedlings to grow. The enrichment of nutrients is an attractant to herbivores and omnivores. For annual grasses that release seeds during a brief period each year there is a need to protect seeds during maturation from insects or animals, which might stock seeds for year round usage. For wheat, alpha-gliadins are seed-storage proteins, but also act as inhibitors of alpha-amylase activity in some animals, particularly in insects. Stepánková et al. (2003) found that wheat gliadins causes intestinal disease when fed to young rats.
One study examined the effect of ω-5 gliadin, the primary cause of wheat dependent exercise/aspirin induced anaphylaxis, and found increased permeability of intestinal cells caused by this gliadin and another wheat albumin.
Another line of research shows gliadin binds a chemoattractant receptor and causes increases of a factor that destroys tight junctions. These junctions prevent leakage around the cells that line the small intestine, resulting in the leaking of food proteins into the body.
Immunochemistry of glutens
Triticeae glutens are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), class II mediated presentation (HLA DQ), class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In enteropathy, there are at least 3 types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ and antibody recognition of gliadin and transglutaminase.
The three dominant sequences responsible for the antibody reaction have been identified. With idiopathic disease only antibody recognition to gliadin has been resolved. In wheat allergy, there appears to be an innate component and the response pathways are mediated through IgE against gliadin and other wheat proteins.
Separating forms of gluten sensitivity
People suspected of having celiac disease may be tested for anti-transglutaminase antibodies followed by duodenal biopsy; this test will confirm or refute active celiac disease. The study that recommends this has some ATA positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology.
One study recommended biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of celiac disease can generally be done by adding HLA-DQ typing, in which DQ2 and DQ8 are found in enteropathy 98% of the time in Caucasians, DQ7.5 the remaining 1.6% and 0.4% not found with either of these 3. Without ATA or HLA-DQ2/8 positivity, celiac disease is not likely the cause of the sensitivity. In either case, other avenues of diagnostics, such as allergy testing are available.
Rarely gluten sensitivity may be idiopathic, a potential that wheat proteins play a role in other disease, in these instances DQ1 may be associated with sensitivity. There is research showing that in certain patients with gluten ataxia early diagnosis and treatment with a GFD can improve ataxia and prevent its progression.
Idiopathic gluten sensitivity
Depending on testing somewhere between 3 and 15% of the normal population have anti-gliadin antibodies (AGA). Studies using anti-gliadin antibodies (AGA) reveal that in undiagnosed or untreated individuals with AGA, have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.
Antibodies to α-gliadin have been significantly increased in non-celiacs individuals with oral ulceration. Anti-α-gliadin antibodies are frequently found in celiac disease (CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. The 1991 reference comes from a period when testing for subclinical CD was undeveloped. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA. One fourth of people with Sjögren's syndrome had responses to gluten, of 5 that had positive response to gluten, only one could be confirmed as CD and another was potentially GSE, the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.
Treatment to produce remission of Crohns disease (CrD) symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy. A later paper showed little IgE mediated response except to the dairy, while another paper showed no significant anti-food IgE association.
From the perspective of gluten sensitivity there is no single definition of gluten that concisely defines all potentially pathogenic glutens. With wheat allergies, there can be a wide spectrum of species that may trigger allergies with similar proteins, the omega-gliadin proteins have similar proteins found in oats at high frequency, but omega-gliadin allergy is not a predictor of oat allergy or intolerance. A person can have an allergy to wheat, but not rye.
Glutelins have not been characterized over broad taxa. With idiopathic gluten sensitivity, the antibodies that correlate with disease are anti-gliadin antibodies. Whether these antibodies are pathogenic or are indicators of circulating gliadin is unknown. For gluten-sensitive enteropathy, gliadin and homologous proteins from rye and barley cause disease. T-cell epitopes implicated in disease have been found in glutinous protein genes in all species sequenced within the tribe Triticeae.
The oat controversy
Oats are a species within the grass tribe Aveneae, which is in the Pooideae subfamily along with Triticeae (contains wheat, rye, barley and many other genera). Oats are the most closely related cereal species to Triticeae cereals. Some, but not all, cultivars of oat contain the pathogenic proteins that provoke a response in gluten sensitive individuals and those with celiac disease.
Origin of controversy
After World War II, wheat was suspected as the cause of celiac disease, and the gluten from wheat was identified as a cause soon after. At the time, duodenal biopsy—the current "gold standard" of diagnosis—had not yet been developed; indirect measures of disease were used. In two studies, three children were fed 75 to 150 grams of oats per day and developed symptoms. In three concurrent studies, 10 children and two adults were allowed to eat 28 to 60 grams of oats and developed no symptoms. Since wheat, barley and sometimes rye are common contaminants in oats, until this was investigated, oats were considered to be toxic to celiacs.
A study published in February 2011 uncovered differing levels of toxicity amongst different varieties of oat, indicating that cross-contamination is not the only reason why some oats provoke reactions in some people with a gluten intolerance. A study published in June 2008 found that of 109 sources of oats screened, 85 had unacceptable levels of gluten from wheat, barley or rye.
Tolerable levels of gluten
In August 2013, the U.S. Food and Drug Administration (FDA)approved regulations  that allow food manufacturers to label products "gluten-free" if they contain less than 20 parts per million (ppm) of gluten. These regulations brought the U.S. in line with Canada, the U.K., and European Union countries, which also allow up to 20ppm in products labeled "gluten-free." However, the FDA also acknowledged in its Health Hazard Risk Assessment for Gluten Exposure  that some people react to far less gluten than 20ppm. Various manufacturers test their products to ensure they contain less than specified levels of gluten, such as 20, 10, or 5ppm. 
Oats can be tolerated in a gluten-free diet for most people, but oat products should be limited in contamination from Triticeae derived gluten to less than 20ppm (20 mg per kg) in order to meet the "gluten-free" standards of the U.S. and other countries. 
As of February 2011, G12, the newest monoclonal antibody (moAb) available, was the only one proven to detect both cross-contamination in oats and also the inherent gluten / avenin that is found in some varieties of oat.
A barley-sensitive ELISA called the R5 sandwich assay does not detect gluten in any of 25 pure oat varieties, but it does detect barley, wheat and rye. Disease-sensitive farming practices, antibody testing and species specific genetic testing are capable of producing pure oats. In the United States, 3 domestic GF-brands are available and one brand imported from Ireland 'reckons' to be 99.95% pure oats. Two brands in the United States use the R5 antibody test and claim to be below 20 PPM in defined gluten.
Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates. Recent studies show that gluten-sensitive individuals on a gluten-free diet often get too much simple carbohydrate, too little fiber and vitamin B. Currently most guidelines do not include oats in a gluten-free diet. While this is likely to change, oats are not recommended within a year of diagnosis because of the oat-sensitive enteropathy (ASE) risk, the desire to establish a clinical baseline and complexity of the contamination issue.
Consuming oats when anti-gliadin antibodies or gliadin are present increases anti-avenin antibodies, and may promote ASE. Duodenal biopsy may be recommended after oat consumption is initiated. The DQ phenotype of all 3 ASE individuals studied so far indicated DQ2 homozygotes are at risk for ASE. Preferably, newly diagnosed celiacs seek the help of a dietician. Guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet.
- List of allergies
- Vomitoxin, a mycotoxin which currently occurs abundantly in grains in Norway due to climate change. It might give rise to somewhat comparable symptoms.
- Sapone A et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. International Archives of Allergy and Immunology. 2010;152:75-80
- Hadjivassiliou M et al. Myopathy associated with gluten sensitivity. Muscle Nerve. 2007;35:443-450
- Verdu EF, Armstrong D, Murray JA. Between celiac disease and irritable bowel syndrome: The ‘No Man’s Land’ of Gluten Sensitivity. The American Journal of Gastroenterology. 2009;104(6):1587-1594
- Sapone A et al. (2010). Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. International Archives of Allergy & Immunology; 152: 75-80
- Bizzaro N et al. (2010) Cutting edge issues in celiac disease and in gluten intolerance. Clinical Reviews in Allergy & immunology.
- Sapone A et al. (2010). Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. International Archives of Allergy & Immunology; 152: 75-80.
- Hadjivassiliou M, Grünewald R, Sharrack B, et al. (2003). "Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics". Brain 126 (Pt 3): 685–91. doi:10.1093/brain/awg050. PMID 12566288.
- A. Vilpulla, P. Collin, M. Maki et al (2008) "Undetected coeliac disease in the elderly. A biopsy-proven population-based study." Digestive and Liver Disease 40 (2008) 809-813
- Biesiekierski, Jessica R et al (March 2011). "Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial". Am J Gastroenterol 106 (3): 508–514. doi:10.1038/ajg.2010.487. PMID 21224837.
- Bandani AR (2005). "Effect of plant a-amylase inhibitors on sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), alpha-amylase activity". Commun. Agric. Appl. Biol. Sci. 70 (4): 869–73. PMID 16628930.
- Stepánková, R.; Kofronová, O.; Tucková, L.; Kozáková, H; Cebra, J. J.; Tlaskalová; Hogenová, H. (January 2003). "Experimentally induced gluten enteropathy and protective effect of epidermal growth factor in artificially fed neonatal rats". J. Pediatr. Gastroenterol. Nutr. 36 (1): 96–104. doi:10.1097/00005176-200301000-00018. PMID 12500003.
- Bodinier M, Legoux MA, Pineau F, et al. (May 2007). "Intestinal translocation capabilities of wheat allergens using the Caco-2 cell line". Journal of Agricultural and Food Chemistry 55 (11): 4576–83. doi:10.1021/jf070187e. PMID 17477542.
- Thomas KE, Sapone A, Fasano A, Vogel SN (February 2006). "Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease". J. Immunol. 176 (4): 2512–21. PMID 16456012.
- Lammers KM, Lu R, Brownley J, et al. (March 2008). "Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3". Gastroenterology 135 (1): 194–204.e3. doi:10.1053/j.gastro.2008.03.023. PMC 2653457. PMID 18485912.
- van Heel DA, West J (July 2006). "Recent advances in coeliac disease". Gut 55 (7): 1037–46. doi:10.1136/gut.2005.075119. PMC 1856316. PMID 16766754.
- Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A, Henderson K, Mannering SI, Gianfrani C, Jewell DP, Hill AV, McCluskey J, Rossjohn J, Anderson RP (2010). "Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease". Sci Transl Med 2 (41): 41ra51. doi:10.1126/scitranslmed.3001012. PMID 20650871.
- Bittner C, Grassau B, Frenzel K, Baur X (March 2008). "Identification of wheat gliadins as an allergen family related to baker's asthma". The Journal of Allergy and Clinical Immunology 121 (3): 744–9. doi:10.1016/j.jaci.2007.09.051. PMID 18036646.
- Matsuo H, Dahlström J, Tanaka A, et al. (February 2008). "Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis". Allergy 63 (2): 233–6. doi:10.1111/j.1398-9995.2007.01504.x. PMID 18186814.
- Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K (August 2007). "Proteomic analysis of wheat flour allergens". Journal of Agricultural and Food Chemistry 55 (17): 6863–70. doi:10.1021/jf070843a. PMID 17655322.
- Hopper AD, Cross SS, Hurlstone DP, et al. (April 2007). "Pre-endoscopy serological testing for celiac disease: evaluation of a clinical decision tool". BMJ 334 (7596): 729. doi:10.1136/bmj.39133.668681.BE. PMC 1847864. PMID 17383983.
- Hopper AD, Cross SS, Sanders DS (March 2008). "Patchy villous atrophy in adult patients with suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy appropriate?". Endoscopy 40 (3): 219–24. doi:10.1055/s-2007-995361. PMID 18058655.
- Kaukinen K, Peräaho M, Collin P, et al. (May 2005). "Small-bowel mucosal transglutaminase 2-specific IgA deposits in celiac disease without villous atrophy: a prospective and randomized clinical study". Scand. J. Gastroenterol. 40 (5): 564–72. doi:10.1080/00365520510023422. PMID 16036509.
- Kaukinen K, Turjanmaa K, Mäki M, et al. (September 2000). "Intolerance to cereals is not specific for coeliac disease". Scand. J. Gastroenterol. 35 (9): 942–6. doi:10.1080/003655200750022995. PMID 11063153.
- Hadjivassiliou M, Sanders DS, Woodroofe N et al. (2008). Gluten ataxia. The Cerebellum; 494-498
- Anderson LA, McMillan SA, Watson RG, et al. (2007). "Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity"". World J. Gastroenterol. 13 (1): 146–51. PMID 17206762.
- O'Farrelly C, O'Mahony C, Graeme-Cook F, Feighery C, McCartan BE, Weir DG (1991). "Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy". J. Oral Pathol. Med. 20 (10): 476–8. doi:10.1111/j.1600-0714.1991.tb00407.x. PMID 1753350.
- Ringvold A, Overgaard RG (1995). "Increased IgA antibodies to gluten and gliadin in serum of persons with ocular pseudo-exfoliation". Acta ophthalmologica Scandinavica 73 (2): 171–2. doi:10.1111/j.1600-0420.1995.tb00662.x. PMID 7656149.
- Lidén M, Kristjánsson G, Valtýsdóttir S, Hällgren R (2007). "Gluten sensitivity in patients with primary Sjögren's syndrome". Scand. J. Gastroenterol. 42 (8): 962–7. doi:10.1080/00365520701195345. PMID 17613926.
- Workman EM, Alun Jones V, Wilson AJ, Hunter JO (1984). "Diet in the management of Crohn's disease". Human nutrition. Applied nutrition 38 (6): 469–73. PMID 6526690.
- Frieri M, Claus M, Boris M, Zitt M, Scalise D, Harris N (1990). "Preliminary investigation on humoral and cellular immune responses to selected food proteins in patients with Crohn's disease". Annals of allergy 64 (4): 345–51. PMID 2321808.
- Huber A, Genser D, Spitzauer S, Scheiner O, Jensen-Jarolim E (1998). "IgE/anti-IgE immune complexes in sera from patients with Crohn's disease do not contain food-specific IgE". Int. Arch. Allergy Immunol. 115 (1): 67–72. doi:10.1159/000023832. PMID 9430498.
- Baldo BA, Krilis S, Wrigley CW (1980). "Hypersensitivity to inhaled flour allergens. Comparison between cereals". Allergy 35 (1): 45–56. doi:10.1111/j.1398-9995.1980.tb01716.x. PMID 6154431.
- Karatay S, Erdem T, Kiziltunc A, et al. (2006). "General or personal diet: the individualized model for diet challenges in patients with rheumatoid arthritis". Rheumatol. Int. 26 (6): 556–60. doi:10.1007/s00296-005-0018-y. PMID 16025333.
- Kupper C (2005). "Dietary guidelines and implementation for celiac disease". Gastroenterology 128 (4 Suppl 1): S121–7. doi:10.1053/j.gastro.2005.02.024. PMID 15825119.
- Comino, Isabel; Ana Real, Laura de Lorenzo, Hugh Cornell, Miguel Ángel López-Casado, Francisco Barro, Pedro Lorite, Ma Isabel Torres, Ángel Cebolla, Carolina Sousa (12). "Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease". Gut 60 (First Online): 915–22. doi:10.1136/gut.2010.225268. PMC 3112367. PMID 21317420. Retrieved 12 March 2011.
- SMITH RB, SPRINZ H, CROSBY WH, SULLIVAN BH (September 1958). "Peroral small bowel mucosal biopsy". Am. J. Med. 25 (3): 391–4. doi:10.1016/0002-9343(58)90077-9. PMID 13571252.
- Garsed K, Scott BB (February 2007). "Can oats be taken in a gluten-free diet? A systematic review". Scand. J. Gastroenterol. 42 (2): 171–8. doi:10.1080/00365520600863944. PMID 17327936.
- American Dietetic Association. Nutrition Care Manual: Celiac Disease. Available at: http://www.nutritioncaremanual.org. Accessed December 15, 2004.
- Thompson T (November 2004). "Gluten contamination of commercial oat products in the United States". N. Engl. J. Med. 351 (19): 2021–2. doi:10.1056/NEJM200411043511924. PMID 15525734.
- Hernando A, Mujico JR, Mena MC, Lombardía M, Méndez E (June 2008). "Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA". Eur J Gastroenterol Hepatol 20 (6): 545–54. doi:10.1097/MEG.0b013e3282f46597. PMID 18467914.
- Catassi C et al (2007) "A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with coeliac disease." American Journal of Clinical Nutrition, Vol 85, No 1, 160-166
- Cleaning/Inspection Process Gluten Free Oats
- "Are McCann's Oat products gluten free?". URL:FAQ - Frequently asked questions
- GLUTEN FREE ROLLED OATS Bob's Red Mill Natural Foods
- Størsrud S, Hulthén LR, Lenner RA (July 2003). "Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences". Br. J. Nutr. 90 (1): 101–7. doi:10.1079/BJN2003872. PMID 12844381.
- Rashid, Mohsin (2007-06-08). "Guidelines for Consumption of Pure and Uncontaminated Oats by Individuals with Celiac Disease". Professional Advisory Board of Canadian Celiac Association. Retrieved 2008-08-14.
- Celiac Disease & Gluten Sensitivity Detailed information on gluten sensitivity, including amounts (in parts per million) of gluten in various foods.
- Gluten Free WorldWide International gluten-free food directory