Non-celiac gluten sensitivity

[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.[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][4][6][5][7] These include any of the following: headache, migraine, "foggy mind", fatigue, fibromyalgia,[7][33] joint and muscle pain, leg or arm numbness, tingling of the extremities, dermatitis (eczema or skin rash), atopic disorders such as asthma, rhinitis, other allergies, depression, anxiety, iron-deficiency anemia, folate deficiency, or autoimmune diseases.[1][34][2][3][4][5][6][7][35][36][37] Above 20% of people with NCGS have IgE-mediated allergy to one or more inhalants, foods, or metals, among which most common are mites, graminaceae, parietaria, cat or dog hair, shellfish, and nickel.In addition to its ability to elicit abnormal responses of the immune system, in vitro studies on cell cultures showed that gluten is cytotoxic and causes direct intestinal damage.Gluten alters cellular morphology and motility, cytoskeleton organization, oxidative balance and intercellular contact (tight junction proteins).[21][40] These TLR4-stimulating activities of ATIs are limited to gluten-containing cereals (wheat, rye, barley, and derivatives) and may induce innate immunity in people with celiac disease or NCGS.[21] Modern wheat cultivation, by breeding for high ATI content, may play a role in the onset and course of disorders such as celiac disease and gluten sensitivity.[7] FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) that are present in gluten-containing grains (mainly fructans) have been identified as a possible cause of gastrointestinal symptoms in people with NCGS, in place of,[42] or in addition to, gluten.Many people with NCGS report resolution of their symptoms after removing gluten-containing cereals while continuing to eat fruits and vegetables with high FODMAPs content.[9] Absence of reliable biomarkers and the fact that some people do not have digestive symptoms make the recognition and diagnosis of non-celiac gluten sensitivity (NCGS) difficult.[35] To exclude a placebo effect, a double-blind placebo-controlled gluten challenge is a useful tool, although it is expensive and complicated for routine clinical use, and so is usually performed in research studies.[13] A 2015 systematic review found that 20% of people with NCGS presenting with HLA-DQ2 and/or HLA-DQ8 haplotypes, negative serology, and normal histology or duodenal lymphocytosis had celiac disease.The absence of celiac disease-specific antibodies is more common in patients without villous atrophy who only have duodenal lymphocytosis (Marsh 1 lesions) and who respond to a gluten-free diet with histological and symptomatic improvement.[11] If an allergic reaction can not be clearly identified, the diagnosis should be confirmed by food provocation tests, ideally performed in a double-blinded and placebo-controlled manner.Nevertheless, recent studies have shown that a two-week challenge of 3 g of gluten per day may induce histological and serological abnormalities in most adults with proven celiac disease.[7] After exclusion of celiac disease and wheat allergy,[29] the subsequent step for diagnosis and treatment of NCGS is to start a strict gluten-free diet (GFD) to assess if symptoms improve or resolve completely.[6] The degree of gluten cross contamination tolerated by people with NCGS is not clear but there is some evidence that they can present with symptoms even after consumption of small amounts.[10] A subgroup may not improve when eating commercially available gluten-free products, as these can be rich in preservatives and additives such as sulfites, glutamates, nitrates and benzoates, which can also have a role in triggering functional gastrointestinal symptoms.[57][58] Another reason that contributed to this trend was the publication of several books that demonize gluten and point to it as a cause of type 2 diabetes, weight gain and obesity, and a broad list of conditions ranging from depression and anxiety to arthritis and autism.[3][59][63] Data from a 2015 Nielsen survey of 30,000 adults in 60 countries around the world showed that 21% of people prefer to buy gluten-free foods, with interest highest among younger generations.[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.[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.