Non-celiac gluten sensitivity (NCGS) or gluten sensitivity is a disorder which can cause both gastrointestinal and other problems. Non-celiac gluten sensitivity is included in the spectrum of gluten-related disorders. The definition and diagnostic criteria of NCGS 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 called amylase-trypsin inhibitors (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 both functional disease and celiac disease specialists, leading to a lack of 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 anaphylactic.
Gastrointestinal Gastrointestinal symptoms may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), nausea, aerophagia, and flatulence.
Extraintestinal NCGS can cause a wide range of extraintestinal symptoms, which can be the only manifestation of NCGS in the 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 the 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. 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 amylase-trypsin 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).
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