Gluten sensitivity

Gluten sensitivity

Gluten sensitivity (GS) encompasses a collection of medical conditions in which gluten has an adverse effect. For individuals with gluten-sensitive enteropathy, removal of gluten generally results in the restoration of villus architecturecite journal | author = Thompson H | title = Necropsy studies on adult coeliac disease | journal = J. Clin. Pathol. | volume = 27 | issue = 9 | pages = 710–21 | year = 1974 | pmid = 4426981 | doi = ] or lower lymphocyte densities in the intestine.cite journal | author = Corazza GR, Frazzoni M, Gasbarrini G | title = Jejunal intraepithelial lymphocytes in coeliac disease: are they increased or decreased? | journal = Gut | volume = 25 | issue = 2 | pages = 158–62 | year = 1984 | pmid = 6693043 | doi = ] With some sensitivities, improvements may be seen in the neurological state, but a clinical finding may not be clear.cite journal | author = Wills AJ, Unsworth DJ | title = The neurology of gluten sensitivity: separating the wheat from the chaff | journal = Curr. Opin. Neurol. | volume = 15 | issue = 5 | pages = 519–23 | year = 2002 | pmid = 12351994 | doi = ] cite journal | author = Ventura A, Bouquet F, Sartorelli C, Barbi E, Torre G, Tommasini G | title = Coeliac disease, folic acid deficiency and epilepsy with cerebral calcifications | journal = Acta paediatrica Scandinavica | volume = 80 | issue = 5 | pages = 559–62 | year = 1991 | pmid = 1908173 | doi = ] GS also can affect blood chemistry,cite journal | author = Valdimarsson T, Löfman O, Toss G, Ström M | title = Reversal of osteopenia with diet in adult coeliac disease | journal = Gut | volume = 38 | issue = 3 | pages = 322–7 | year = 1996 | pmid = 8675082 | doi = ] treatability of certain autoimmune diseases,cite journal | author = Heading RC, Paterson WD, McClelland DB, Barnetson RS, Murray MS | title = Clinical response of dermatitis herpetiformis skin lesions to a gluten-free diet | journal = Br. J. Dermatol. | volume = 94 | issue = 5 | pages = 509–14 | year = 1976 | pmid = 773406 | doi = ] and/or an untreated improvement in autoimmune conditions.cite journal | author = Volta U, De Giorgio R, Granito A, "et al" | title = Anti-ganglioside antibodies in coeliac disease with neurological disorders | journal = Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | volume = 38 | issue = 3 | pages = 183–7 | year = 2006 | pmid = 16458087 | doi = 10.1016/j.dld.2005.11.013] cite journal | author = Amin R, Murphy N, Edge J, Ahmed ML, Acerini CL, Dunger DB | title = A longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and celiac disease | journal = Diabetes Care | volume = 25 | issue = 7 | pages = 1117–22 | year = 2002 | pmid = 12087007 | doi = ] cite journal | author = Kaukinen K, Halme L, Collin P, "et al" | title = Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure | journal = Gastroenterology | volume = 122 | issue = 4 | pages = 881–8 | year = 2002 | pmid = 11910339 | doi = ]

Gluten is composed of the sticky, storage proteins found in wheat. Gluten-sensitive enteropathy (GSE) can range from mild inflammation of mucosa the small intestine to severe coeliac disease. The term gluten-sensitive is applicable when a probable diagnosis of GSE based on conditions such as dermatitis herpetiformis. However, GS may be used in ambiguous situations when other conditions may be possible. For example, wheat allergies to gluten can result in anaphylaxis while others may be difficult to diagnose because of some of the cryptic inflammatory properties of wheat proteins. The term 'Gluten sensitivity' is typically applied when diagnostic testing is not done because of prolonged gluten-free diet and/or refusal of gluten-challenge prior to biopsy. The gluten-sensitive designation may not be appropriate in all cases, as wheat allergies are often directed toward albumins or globulins of wheat, or the person may have a sensitivity to proteins commonly found with wheat products (e.g. fungal amylase or bread-yeast mannins). Therefore diagnostic criteria are preferred. The relationship between gluten and these various sensitivities is complex. For gluten enteropathy, T-cell reactivity almost entirely restricted to prolamin-glutelin/species within the grass tribe "Triticeae", and especially α-gliadins of wheat.cite journal | author = Srinivasan U, Jones E, Carolan J, Feighery C | title = Immunohistochemical analysis of coeliac mucosa following ingestion of oats | journal = Clin. Exp. Immunol. | volume = 144 | issue = 2 | pages = 197–203 | year = 2006 | pmid = 16634791 | doi = 10.1111/j.1365-2249.2006.03052.x] cite journal | author = Anand BS, Piris J, Truelove SC | title = The role of various cereals in coeliac disease | journal = Q. J. Med. | volume = 47 | issue = 185 | pages = 101–110 | year = 1978 | pmid = 674547 | doi = ] For a tiny minority of GSE, inflammatory responses may extend to cover oats.cite journal | author = Silano M, Dessì M, De Vincenzi M, Cornell H | title = In vitro tests indicate that certain varieties of oats may be harmful to patients with coeliac disease | journal = J. Gastroenterol. Hepatol. | volume = 22 | issue = 4 | pages = 528–31 | year = 2007 | pmid = 17376046 | doi = 10.1111/j.1440-1746.2006.04512.x] Gluten allergies may extend over wide taxa or may be specific to certain wheat proteins and allergies may include oats.

wheat gluten flour, European spelt, barley corns, rolled rye]

Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should eventually fall into 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".cite journal | author = Hadjivassiliou M, Grünewald R, Sharrack B, "et al" | title = Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics | journal = Brain | volume = 126 | issue = Pt 3 | pages = 685–91 | year = 2003 | pmid = 12566288 | doi = ] This form of gluten sensitivity is controversial at the moment.

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 an inhibitor the alpha-amylase activities of other animals, particularly insects.cite journal |author=Bandani AR |title=Effect of plant a-amylase inhibitors on sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), alpha-amylase activity |journal=Commun. Agric. Appl. Biol. Sci. |volume=70 |issue=4 |pages=869–73 |year=2005 |pmid=16628930 |doi= |url=] It is also known that wheat gliadins creates intestinal disease when fed to very young rodents.cite journal |author=Stepánková R, Kofronová O, Tucková L, Kozáková H, Cebra JJ, Tlaskalová- Hogenová H |title=Experimentally induced gluten enteropathy and protective effect of epidermal growth factor in artificially fed neonatal rats |journal=J. Pediatr. Gastroenterol. Nutr. |volume=36 |issue=1 |pages=96–104 |year=2003 |month=January |pmid=12500003 |doi= |url=] One recent publication even raises the question 'is wheat safe for anyone to eat?'.cite journal | author = Bernardo D, Garrote JA, Fernández-Salazar L, Riestra S, Arranz E | title = Is gliadin really safe for non-coeliac individuals? Production of interleukin 15 in biopsy culture from non-coeliac individuals challenged with gliadin peptides | journal = Gut | volume = 56 | issue = 6 | pages = 889–90 | year = 2007 | pmid = 17519496 | doi = 10.1136/gut.2006.118265] Critically, pathology in insects or artificially fed rodents does not reflect what causes disease in humans, but it is interesting that toxicological effects of wheat are being uncovered that do have the potential to cause pathology in humans. One interesting consequence of these studies is that there may be a general gluten sensitivity that underlies various pathological manifestations, such as coeliac disease, urticaria, idiopathic sensitivity.

The rise of gluten sensitivity (particularly in adults) may reflect the convergence of many phenomena. An aging population, genetic risks associated with westernization, excesses in the diet, sensitizing chemicals (e.g.MSG, aspirin, NSAIDs), and allergy-enhancing chemical treatment of foods (e.g. enzymatic deamidation of gluten) may act together with natural defensive agents in foods to cross the threshold between normality and pathology.

Gluten toxicity

An increasing number of studies on gliadin indicate gluten has direct and modifying effect on the cells of the small intestine. Two different lines of research show that different gliadins can increase permeability of the epithelial cells (outermost cells of the villus) allowing food proteins to enter. One study examined the effect of ω-5 gliadin, the primary cause of exercise/aspirin induced anaphylaxis, and found increased permeability of intestinal cells caused by this gliadin and another wheat albumin.cite journal |author=Bodinier M, Legoux MA, Pineau F, "et al" |title=Intestinal translocation capabilities of wheat allergens using the Caco-2 cell line |journal=J. Agric. Food Chem. |volume=55 |issue=11 |pages=4576–83 |year=2007 |month=May |pmid=17477542 |doi=10.1021/jf070187e |url=] Another line of research shows gliadin binds a receptor and causes increases of a factor that destroys of tight junctions.cite journal |author=Thomas KE, Sapone A, Fasano A, Vogel SN |title=Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease |journal=J. Immunol. |volume=176 |issue=4 |pages=2512–21 |year=2006 |month=February |pmid=16456012 |doi= |url=] These junctions prevent leakage around the cells that line the small intestine, resulting in the leaking of food proteins into the body.cite journal |author=Lammers KM, Lu R, Brownley J, "et al" |title=Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3 |journal=Gastroenterology |volume= |issue= |pages= |year=2008 |month=March |pmid=18485912 |doi=10.1053/j.gastro.2008.03.023 |url=] These toxicities of gluten that are not apart of the adaptive immune response may be the link between wheat and gluten sensitivity, possibly type 1 diabetes.

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.cite journal |author=van Heel DA, West J |title=Recent advances in coeliac disease |journal=Gut |volume=55 |issue=7 |pages=1037–46 |year=2006 |month=July |pmid=16766754 |doi=10.1136/gut.2005.075119 |url=] With idiopathic disease only antibody recognition to gliadin has been resolved. In wheat allergy, there appears to be an innate components and the response pathways are mediated through IgE against gliadin and other wheat proteins.cite journal |author=Bittner C, Grassau B, Frenzel K, Baur X |title=Identification of wheat gliadins as an allergen family related to baker's asthma |journal=J. Allergy Clin. Immunol. |volume=121 |issue=3 |pages=744–9 |year=2008 |month=March |pmid=18036646 |doi=10.1016/j.jaci.2007.09.051 |url=] cite journal |author=Matsuo H, Dahlström J, Tanaka A, "et al" |title=Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis |journal=Allergy |volume=63 |issue=2 |pages=233–6 |year=2008 |month=February |pmid=18186814 |doi=10.1111/j.1398-9995.2007.01504.x |url=] cite journal |author=Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K |title=Proteomic analysis of wheat flour allergens |journal=J. Agric. Food Chem. |volume=55 |issue=17 |pages=6863–70 |year=2007 |month=August |pmid=17655322 |doi=10.1021/jf070843a |url=]

eparating forms of gluten sensitivity

Only rarely should gluten sensitivity be without cause. Generally the sensitivity can be split between gluten-sensitive enteropathy and wheat allergy. Since individuals with GSE can also have wheat allergy, a finding of wheat allergy does not eliminate the possibility of enteropathy. Individuals highly suspect of gluten-sensitive enteropathy maybe given anti-transglutaminase antibodies test followed by duodenal biopsy, this will confirm or refute active coeliac disease.cite journal |author=Hopper AD, Cross SS, Hurlstone DP, "et al" |title=Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool |journal=BMJ |volume=334 |issue=7596 |pages=729 |year=2007 |month=April |pmid=17383983 |pmc=1847864 |doi=10.1136/bmj.39133.668681.BE |url=] The study that recommends this, however, has a number of ATA positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology.cite journal |author=Hopper AD, Cross SS, Sanders DS |title=Patchy villous atrophy in adult patients with suspected gluten-sensitive enteropathy: is a multiple duodenal biopsy strategy appropriate? |journal=Endoscopy |volume=40 |issue=3 |pages=219–24 |year=2008 |month=March |pmid=18058655 |doi=10.1055/s-2007-995361 |url=] cite journal |author=Kaukinen K, Peräaho M, Collin P, "et al" |title=Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study |journal=Scand. J. Gastroenterol. |volume=40 |issue=5 |pages=564–72 |year=2005 |month=May |pmid=16036509 |doi=10.1080/00365520510023422 |url=] One current study recommended at biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of GSE 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, GSE is not likely the cause of the sensitivity.In either case, other avenues of diagnostics, such as allergy testing are available.cite journal |author=Kaukinen K, Turjanmaa K, Mäki M, "et al" |title=Intolerance to cereals is not specific for coeliac disease |journal=Scand. J. Gastroenterol. |volume=35 |issue=9 |pages=942–6 |year=2000 |month=September |pmid=11063153 |doi= |url=] Rarely gluten sensitivity maybe idiopathic, a potential that wheat proteins play a role in other disease, in these instances DQ1 may be associated with sensitivity, but for neurological issues, a gluten-free diet has not been shown to positively effect the outcome of patients as in enteropathy or allergy.

Gluten-sensitive enteropathy

Coeliac disease is the classically defined gluten-sensitivity and dermatitis herpetiformis was appended to a broadening definition of gluten sensitivity. The diagnostic "gold standard" of coeliac disease as the villus atrophy detected in duodenal biopsies. However, it is now recognized that inflammation of the epithelial tissue of the small intestine precedes atrophy. Early in the disease, gluten elicits T-lymphocyte recognition of gluten hydrolysates (polypeptides of gluten) and gluten peptides bind to mammalian tissue transglutaminase (tTG). This second interaction results in the production of "self" antibodies to tTG. This increases lymphocytes within the epithelia of the small intestine (Marsh grade 1 and 2) and antibody-tTG complexes seen as deposits. This usually progresses to coeliac disease (Marsh grade 3 and 4). The dietary cause of GSE is not limited to wheat gluten, 'glutens' from all known edible cultivars of "Triticeae" can induce GSE in susceptible individuals (see: Gluten immunochemistry).

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.cite journal | author = Baldo BA, Krilis S, Wrigley CW | title = Hypersensitivity to inhaled flour allergens. Comparison between cereals | journal = Allergy | volume = 35 | issue = 1 | pages = 45–56 | year = 1980 | pmid = 6154431 | doi = ] A person can have an allergy to wheat, but not rye.cite journal | author = Karatay S, Erdem T, Kiziltunc A, "et al" | title = General or personal diet: the individualized model for diet challenges in patients with rheumatoid arthritis | journal = Rheumatol. Int. | volume = 26 | issue = 6 | pages = 556–60 | year = 2006 | pmid = 16025333 | doi = 10.1007/s00296-005-0018-y]

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 simply 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".cite journal | author = Kupper C | title = Dietary guidelines and implementation for celiac disease | journal = Gastroenterology | volume = 128 | issue = 4 Suppl 1 | pages = S121–7 | year = 2005 | pmid=15825119 | doi = 10.1053/j.gastro.2005.02.024] Also, since barley is distantly related to wheat, but carries pathogenic epitopes it can be assumed that all members of "Triticeae" should carry T-cell sites capable of sustaining disease (see also Genetics of Triticeae). While often not explicitly stated in some standards, pathogenic glutens found in wheat are also found in Spelt and Kamut®(both types of wheat), Triticale (a trans-species Triticeae hybrid).

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. Oats may contain pathogenic proteins that sustain gluten-sensitive disease. Alternatively, oat seeds appear similar to seeds of wheat, barley and rye and cross-contamination between these grains is difficult to resolve.

Origin of controversy

After World war II wheat became suspect as the cause of coeliac disease, and, soon after, the gluten from wheat was identified as a cause. At the time, duodenal biopsy (the current "gold standard" of diagnosis) had not yet been developed.cite journal |author=SMITH RB, SPRINZ H, CROSBY WH, SULLIVAN BH |title=Peroral small bowel mucosal biopsy |journal=Am. J. Med. |volume=25 |issue=3 |pages=391–4 |year=1958 |month=September |pmid=13571252 |doi= |url=] As a consequence, 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 other studies from the same period, 10 children and 2 adults were allowd to eat moderate amounts (28 to 60 grams) of oats and developed no symptoms.cite journal |author=Garsed K, Scott BB |title=Can oats be taken in a gluten-free diet? A systematic review |journal=Scand. J. Gastroenterol. |volume=42 |issue=2 |pages=171–8 |year=2007 |month=February |pmid=17327936 |doi=10.1080/00365520600863944 |url=] Wheat, barley and sometimes rye are common contaminants in oats.cite journal |author=Thompson T |title=Gluten contamination of commercial oat products in the United States |journal=N. Engl. J. Med. |volume=351 |issue=19 |pages=2021–2 |year=2004 |month=November |pmid=15525734 |doi=10.1056/NEJM200411043511924 |url=] American Dietetic Association. Nutrition Care Manual: Celiac Disease. Available at: Accessed December 15, 2004.] Until this was investigated, oats were cautiously considered to be toxic to coeliacs. :further|History of coeliac disease

Current findings

While the problem of contamination has been known for several years, 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.cite journal |author=Hernando A, Mujico JR, Mena MC, Lombardía M, Méndez E |title=Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA |journal=Eur J Gastroenterol Hepatol |volume=20 |issue=6 |pages=545–54 |year=2008 |month=June |pmid=18467914 |doi=10.1097/MEG.0b013e3282f46597 |url=] "Triticeae" contaminated oats in the study came from many countries indicating that most sources of oats are unacceptable for GS based on contamination.

Tolerable levels of gluten

In summary of recent developments, oats can be tolerated in a gluten-free diet, but oat products should be limited in contamination from "Triticeae" derived gluten to 20 PPM (20 mg per kg). States are free to deny the GF-label standard for oat products, if warranted (see Politics of Gluten-Free and oats).

Gluten-free testing

A new 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.cite journal |author=Hernando A, Mujico JR, Mena MC, Lombardía M, Méndez E |title=Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States and Canada by Sandwich R5 ELISA |journal=Eur J Gastroenterol Hepatol |volume=20 |issue=6 |pages=545–54 |year=2008 |month=June |pmid=18467914 |doi=10.1097/MEG.0b013e3282f46597 |url=] 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. [ "Cleaning/Inspection Process" Gluten Free Oats®] ] ["Are McCann's Oat products gluten free?". URL: [ FAQ - Frequently asked questions] ] Two brands in the United States use the R5 antibody test and claim to be below 20 PPM in defined gluten. [ [ "GLUTEN FREE ROLLED OATS" Bob's Red Mill Natural Foods] ]

further|Antibody testing for gluten-free foods


Gluten-free oats in a gluten-free diet. Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates.cite journal |author=Størsrud S, Hulthén LR, Lenner RA |title=Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences |journal=Br. J. Nutr. |volume=90 |issue=1 |pages=101–7 |year=2003 |month=July |pmid=12844381 |doi= |url=] Recent studies show that gluten-sensitive individuals on a gluten-free diet often get too much simple starch, 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. However, guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet. [cite web
title=Guidelines for Consumption of Pure and Uncontaminated Oats by Individuals with Celiac Disease
publisher=Professional Advisory Board of Canadian Celiac Association

:Further|Oat sensitivity


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