Gluten sensitivity

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Gluten-related disorders

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, constipation, muscular disturbances, headaches, migraines, severe acne, fatigue, and bone or joint pain.[1][2]

However, self-reported non-celiac gluten sensitivity may not be a discrete entity or part of this spectrum disorder bringing its role in functional bowel disorders like irritable bowel syndrome into question.[3]

Gluten, named from the Latin gluten meaning glue,[4] is a substance that gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet.


More than 250 symptoms of gluten sensitivity have been reported, including bloating, abdominal discomfort or pain, constipation and diarrhea. [5] Sensitivity may also present with extraintestinal symptoms, including headache, “brain fog,” tingling and/or numbness in hands and feet, fatigue, as well as muscular disturbances and bone or joint pain.[1][2][6]

Difference between idiopathic gluten sensitivity and celiac disease[edit]

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)".[7] 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.

However, in 2013, Biesiekierski JR et al. concluded that NCGS (non-celiac gluten sensitivity), as currently defined, might not be a discrete entity (or its effects might be confounded by FODMAP restriction), and that gluten might not cause functional gut symptoms once dietary FODMAPs are reduced.[3] An editorial in Gastroenterology calls into question the existence of NCGS as a discrete entity.[8] The authors suggest that reduction of FODMAPs, rather than gluten or other wheat proteins, might be mechanism by which low-gluten diets improve gastrointestinal symptoms. These findings suggest that gluten sensitivity may not play a significant role in the etiology of functional gastrointestinal disorders like irritable bowel syndrome.

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".[9]


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.[10] 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.

A double-blind placebo-controlled trial found that gluten caused significantly worse pain, tiredness, bloating and stool consistency than a placebo diet in IBS patients. There was no difference in celiac or gliadin antibodies between the gluten and control groups.[11] However a more detailed follow-up trial by the same authors found no difference between gluten or placebo groups.[3]

Causes of gluten sensitivity[edit]

Immunochemistry of glutens[edit]

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.[12] 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.[13][14][15]

Separating forms of gluten sensitivity[edit]

A recent literature review found that patients suffering from non-coeliac gluten sensitivity "are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis and clinical history, and, probably, clinical course" and that non-coeliac gluten sensitivity diagnosis can be reached only by excluding celiac disease and wheat allergy.[16] Another review article emphasizes that a final confirmation of NCGS diagnosis requires, additionally, a positive oral gluten challenge after at least three weeks of gluten-free diet.[17]

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.[18] The study that recommends this has some ATA positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology.[19][20]

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.[21]

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.[22]

Idiopathic gluten sensitivity[edit]

Further information: Anti-gliadin antibodies

Studies using anti-gliadin antibodies (AGA) reveal that diagnosed or untreated individuals with AGA have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.[23]


Other conditions[edit]

Antibodies to α-gliadin have been significantly increased in non-celiacs individuals with oral ulceration.[24] 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.[25] 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.[26]


Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates.[27] 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.[28]

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.[28]

Sensitivity to other proteins in wheat[edit]

Some patients' may have a reaction not (or not only) to gluten as such, but to other substances present in wheat.

Specifically, in a publication of 2012, α-amylase/trypsin inhibitors (ATIs) from wheat were identified as a cause of non-celiac non-allergy wheat sensitivity.[29] The ATIs are proteins that are part of the plant's natural defense against insects, but in humans they can cause Toll-like receptor 4 (TLR4)-mediated intestinal inflammation.[29][30] This can be the case for both celiac and non-celiac patients. Detlef Schuppan, whose research team discovered this role of the ATIs, emphasizes that modern wheat cultivations are bred to have a high ATI content and that this may play a role in the onset and course of disorders such as celiac disease and gluten sensitivity.[31]


Recent studies indicate that AGA IgG is high in roughly half of NCGS patients[32] and that for these patients, unlike for coeliac disease patients, the IgG AGA decreases strongly over 6 months of gluten-free diet; AGA IgA is usually very low in NGCS patients.[17][33][34]

There are many open question on gluten sensitivity and, as stated in a review article, "there is general agreement in the scientific community that additional studies are needed to shed light on NCGS".[34] In another review, it is emphasized that "it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity".[35] The need for developing biomarkers for NCGS is frequently emphasized;[17][36] for example, the authors of a recent review article indicate: "There is a desperate need for reliable biomarkers and/or an algorithm that include clinical, biochemical and histopathological findings which support the diagnosis of NCGS."[6]

See also[edit]


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  37. ^