non-celiac gluten sensitivity non-celiac gluten sensitivity non-celiac gluten sensitivity (ncgs) or gluten sensitivity is "a clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that improve once the gluten-containing foodstuff is removed from the diet, and celiac disease and wheat allergy have been excluded". non-celiac gluten sensitivityother namesgluten sensitivityspecialtygastroenterology, internal medicine, neurologysymptomsirritable bowel syndrome-like symptoms, fatigue, headache, fibromyalgia, atopic disorders, neurological diseases, psychiatric problemsusual onsetany agedurationlifelongcausesreaction to gluten, other proteins and fodmaps from gluten-containing cerealsdiagnostic methodexclusion of celiac disease and wheat allergy, improvement with gluten withdrawal and worsening after gluten consumptiontreatmentgluten-free dietfrequency0.5%–13% ncgs is included in the spectrum of gluten-related disorders. the definition and diagnostic criteria of non-celiac gluten sensitivity were debated and established by three consensus conferences. however, as of 2019, there remained much debate in the scientific community as to whether ncgs was a distinct clinical disorder. 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. 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. 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. 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. for these reasons, ncgs is a controversial clinical condition and some authors still question it. 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. ncgs is the most common syndrome of gluten-related disorders with prevalence rates between 0.5%–13% in the general population. 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. 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. people with ncgs are often unrecognized by specialists and lack adequate medical care and treatment. 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. signs and symptoms reported symptoms of ncgs are similar to those of celiac disease, with most patients reporting both gastrointestinal and non-gastrointestinal symptoms. in the "classical" presentation of ncgs, gastrointestinal symptoms are similar to those of irritable bowel syndrome, and are also not distinguishable from those of wheat allergy, but there is a different interval between exposure to wheat and onset of symptoms. wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and can be anaphylaxic. gastrointestinal gastrointestinal symptoms may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), nausea, aerophagia, flatulence, gastroesophageal reflux disease, and aphthous stomatitis. extraintestinal ncgs can cause a wide range of extraintestinal symptoms, which can be the only manifestation of ncgs in absence of gastrointestinal symptoms. these include any of the following: headache, migraine, "foggy mind", fatigue, fibromyalgia, 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. ncgs is also linked to a wide spectrum of neurological and psychiatric disorders, including ataxia, schizophrenia, epilepsy, peripheral neuropathy, encephalopathy, vascular dementia, eating disorders, autism, attention deficit hyperactivity disorder (adhd), hallucinations (so-called "gluten psychosis"), and various movement disorders (restless legs syndrome, chorea, parkinsonism, tourette syndrome, palatal tremor, myoclonus, dystonia, opsoclonus myoclonus syndrome, paroxysms, dyskinesia, myorhythmia, myokymia). 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. approximately 35% of patients suffer other food intolerances, mainly lactose intolerance. causes the pathogenesis of ncgs is not yet well understood, but the activation of the innate immune system, the direct cytotoxic effects of gluten, and probably the cytotoxicity of other wheat molecules are implicated. besides gluten, other components in wheat, rye, barley, and their derivatives, including amylasetrypsin inhibitors (atis) and fodmaps, may cause symptoms. gluten it was hypothesized that gluten, as occurs in celiac disease, is the cause of ncgs. 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 and gliadin promote cell apoptosis (a form of programmed cell death) and reduce the synthesis of nucleic acids (dna and rna) and proteins, leading to a reduction in the viability of cells. gluten alters cellular morphology and motility, cytoskeleton organization, oxidative balance and intercellular contact (tight junction proteins). other proteins some people may have a reaction to other proteins (α-amylase/trypsin inhibitors ) present in gluten-containing cereals that are able to inhibit amylase and trypsin. they have been identified as the possible activator of the innate immune system in celiac disease and ncgs. atis are part of the plant's natural defence against insects and may cause toll-like receptor 4 (tlr4)-mediated intestinal inflammation in humans. 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. atis resist proteolytic digestion. atis are about 2%–4% of the total protein in modern wheat and are present in commercial gluten. a 2017 study in mice demonstrated that atis exacerbate preexisting inflammation and may also worsen it at extraintestinal sites. this may explain why there is an increase of inflammation in people with preexisting diseases upon ingestion of ati-containing grains. 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. however, it has been questioned whether there is sufficient empirical evidence to support this claim, because as of 2018 we lack studies that directly compare modern wheat versus ancient cultivars with low ati content (such as einkorn wheat) in people with ncgs. wheat germ agglutinin is also considered to be a possible trigger of ncgs-like symptoms. fodmaps 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, or in addition to, gluten. the amount of fructans in gluten-containing cereals is relatively small and their role has been controversial. in rye they account for 3.6%–6.6% of dry matter, 0.7%–2.9% in wheat, and barley contains only trace amounts. they are only minor sources of fodmaps when eaten in the usual standard amounts in the daily diet. wheat and rye may comprise a major source of fructans when consumed in large amounts. they may cause mild wheat intolerance at most, limited to certain gastrointestinal symptoms, such as bloating, but do not justify the ncgs extradigestive symptoms. a 2018 review concluded that although fructan intolerance may play a role in ncgs, it only explains some gastrointestinal symptoms, but not the extradigestive symptoms that people with ncgs may develop, such as neurological disorders, fibromyalgia, psychological disturbances, and dermatitis. fodmaps cause digestive symptoms when the person is hypersensitive to luminal distension. a 2019 review concluded that wheat fructans can cause certain ibs-like symptoms, such as bloating, but are unlikely to cause immune activation or extra-digestive symptoms. many people with ncgs report resolution of their symptoms after removing gluten-containing cereals while continue to eat fruits and vegetables with high fodmaps content. diagnosis 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. diagnosis is generally performed only by exclusion criteria. ncgs diagnostic recommendations have been established by several consensus conferences. exclusion of celiac disease and wheat allergy is important because these two conditions also appear in people who experience symptoms similar to those of ncgs, which improve with a gluten withdrawal and worsen after gluten consumption. the onset of ncgs symptoms may be delayed hours to a few days after gluten ingestion, whereas in celiac disease it can take days to weeks. wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and can lead to anaphylaxis. the presence of related extraintestinal manifestations has been suggested to be a feature of ncgs. when symptoms are limited to gastrointestinal effects, there may be an overlap with wheat allergy, irritable bowel syndrome (ibs), and (less likely) intolerance to fodmaps. proposed criteria for a diagnosis of ncgs suggest an improvement of gastrointestinal symptoms and extra-intestinal manifestations higher than 30% with a gluten-free diet (gfd), assessed through a rating scale, is needed to make a clinical diagnosis of ncgs. 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. these suggestions were incorporated in the salerno expert consensus on diagnostic criteria for ncgs. these recommend assessment of the response to a 6-week trial of a gluten-free diet using a defined rating scale (step 1), followed by a double-blind, placebo-controlled challenge of gluten (or placebo) for a week of each (step 2). a variation of greater than 30% in the main symptoms when challenged by gluten or placebo is needed for a positive result. further research on possible biomarkers was also identified. differential diagnosis examinations evaluating celiac disease and wheat allergy should be performed before patients remove gluten from their diet. it is critical to make a clear distinction between celiac disease and ncgs. celiac disease the main goal in diagnosing ncgs is to exclude celiac disease. ncgs and celiac disease cannot be separated in diagnosis because many gastrointestinal and non-gastrointestinal symptoms are similar in both diseases, and there are people with celiac disease having negative serology (absence of specific celiac disease antibodies in serum) or without villus atrophy. there is no test capable of eliminating a diagnosis of a celiac disease, but such a diagnosis is unlikely without confirming hla-dq2 and/or hla-dq8 haplotypes. the prevalence of undiagnosed celiac disease has increased fourfold during the past half-century, with most cases remaining unrecognized, undiagnosed and untreated, leaving celiac patients with the risk of long-term complications. some people with ncgs may indeed have celiac disease. 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 presence of autoimmune symptoms in people with ncgs suggests the possibility of undiagnosed celiac disease. autoimmune diseases typically associated with celiac disease are diabetes mellitus type 1, thyroiditis, gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and others. to evaluate the possible presence of celiac disease, specific serology and duodenal biopsies are required while the person is still on a diet that includes gluten. serological markers serological cd markers (iga tissue transglutaminase , iga endomysial and igg deamidated gliadin peptide antibodies) are always negative in those with ncgs; in addition to specific iga autoantibody levels, it is necessary to determine total iga levels. igg ttga antibodies should be checked in selective iga deficiency, which can be associated with celiac disease and occurs in as many as one in 40 celiac patients. nevertheless, the absence of serological markers does not certainly exclude celiac disease. in those with celiac disease before diagnosis (on a gluten-containing diet), celiac disease serological markers are not always present. as the age of diagnosis increases, these antibody titers decrease, and may be low or even negative in older children and adults. the absence of