Non-celiac gluten sensitivity
Non-celiac gluten sensitivity (NCGS) or gluten sensitivity[14] is a controversial disorder which can cause both gastrointestinal and other problems.
Non-celiac gluten sensitivity
Gluten sensitivity
Any age[8]
lifelong[9]
Exclusion of celiac disease and wheat allergy, improvement with gluten withdrawal and worsening after gluten consumption[6][11][12]
0.5–13%[13]
NCGS is included in the spectrum of gluten-related disorders.[3][4] The definition and diagnostic criteria of non-celiac gluten sensitivity were debated and established by three consensus conferences.[4][14][15][16][17] However, as of 2019, there remained much debate in the scientific community as to whether NCGS was a distinct clinical disorder.[18]
The pathogenesis of NCGS is not well understood, but the activation of the innate immune system, the direct cytotoxic effects of gluten and probably other wheat components, are implicated.[3][19][20] There is evidence that not only gliadin (the main cytotoxic antigen of gluten), but also other proteins named ATIs which are present in gluten-containing cereals (wheat, rye, barley, and their derivatives) may have a role in the development of symptoms. ATIs are potent activators of the innate immune system.[3][21] FODMAPs, especially fructans, are present in small amounts in gluten-containing grains and have been identified as a possible cause of some gastrointestinal symptoms in NCGS patients.[3][10][22][21] As of 2019, reviews have concluded that although FODMAPs may play a role in NCGS, they explain only certain gastrointestinal symptoms, such as bloating, but not the extra-digestive symptoms that people with NCGS may develop, such as neurological disorders, fibromyalgia, psychological disturbances, and dermatitis.[21][9][3]
For these reasons, NCGS is a controversial clinical condition[23] and some authors still question it.[24][25] It has been suggested that "non-celiac wheat sensitivity" is a more appropriate term, without forgetting that other gluten-containing cereals are implicated in the development of symptoms.[11][24]
NCGS is the most common syndrome of gluten-related disorders[4][26] with prevalence rates between 0.5–13% in the general population.[13] As no biomarker for diagnosing this condition is available, its diagnosis is made by exclusion of other gluten-related disorders such as celiac disease and wheat allergy.[23][27] Many people have not been diagnosed following strict criteria, and there is a "fad component" to the recent rise in popularity of the gluten-free diet, leading to debate surrounding the evidence for this condition and its relationship to celiac disease and irritable bowel syndrome.[3][5] People with NCGS are often unrecognized by specialists and lack adequate medical care and treatment.[28] They often have a long history of health complaints and unsuccessful consultations with physicians, and thus many resort to a gluten-free diet and a self-diagnosis of gluten sensitivity.[29]
Research[edit]
There are many open questions on gluten sensitivity,[10] emphasized in one review that "it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity".[69] It has not yet been established whether innate or adaptive immune responses are involved in NCGS, nor whether the condition relates specifically to gluten or rather relates to other components of grains.[31][70]
Studies indicate that AGA IgG is high in slightly more than half of NCGS patients[4] and that, unlike for celiac disease patients, the IgG AGA decreases strongly over 6 months of gluten-free diet; AGA IgA is usually low or absent in NCGS patients.[4][71]
The need for developing biomarkers for NCGS is frequently emphasized;[4][29][72] for example, one review indicated: "There is a desperate need for reliable biomarkers ... that include clinical, biochemical and histopathological findings which support the diagnosis of NCGS."[31]
Research has also attempted to discern, by double-blind placebo-controlled trials, between a "fad component" to the recent popularity of the gluten-free diet and an actual sensitivity to gluten or other components of wheat.[3][4][73] In a 2013 double-blind, placebo-controlled challenge (DBPC) by Biesiekierski et al. in a few people with IBS, the authors found no difference between gluten or placebo groups and the concept of NCGS as a syndrome was questioned. However, it is possible the reintroduction of both gluten and whey protein had a nocebo effect similar in all people, and this could have masked the true effect of gluten/wheat reintroduction.[39] In a 2015 double-blind placebo cross-over trial, small amounts of purified wheat gluten triggered gastrointestinal symptoms (such as abdominal bloating and pain) and extra-intestinal manifestations (such as foggy mind, depression and aphthous stomatitis) in self-reported NCGS. Nevertheless, it remains elusive whether these findings specifically implicate gluten or proteins present in gluten-containing cereals.[7] In a 2018 double-blind, crossover research study on 59 persons on a gluten-free diet with challenges of gluten, fructans or placebo, intestinal symptoms (specifically bloating) were borderline significantly higher after challenge with fructans, in comparison with gluten proteins (P = 0.049).[21][9] Although the differences between the three interventions was very small, the authors concluded that fructans (the specific type of FODMAP found in wheat) are more likely to be the cause of NCGS gastrointestinal symptoms, rather than gluten.[21] In addition, fructans used in the study were extracted from chicory root, so it remains to be seen whether the wheat fructans produce the same effect.[9]