The pathogenesis of NCGS is not yet well understood, but the activation of the innate immune system, the direct cytotoxic effects of<unk> , and probably the cytotoxicity of other wheat molecules are implicated. Besides<unk> , other components in wheat, rye, barley, and their derivatives, including amylasetrypsin inhibitors (ATIs) and FODMAPs, may cause symptoms.<unk>  It was hypothesized that<unk> , as occurs in<unk>  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<unk>  is cytotoxic and causes direct intestinal damage.<unk>  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.<unk>  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 ATIs) present in<unk> -containing cereals that are able to inhibit amylase and trypsin. They have been identified as the possible activator of the innate immune system in<unk>  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<unk> -containing cereals (wheat, rye, barley, and derivatives) and may induce innate immunity in people with<unk>  disease or NCGS. ATIs resist proteolytic digestion. ATIs are about 2%–4% of the total protein in modern wheat and are present in commercial<unk> . 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<unk>  disease and<unk><unk> . 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<unk> -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,<unk> . The amount of fructans in<unk> -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<unk> -containing cereals while continue to eat fruits and vegetables with high FODMAPs content.
Non-celiac gluten sensitivity
Hereditary diffuse gastric cancer
Intestinal neuronal dysplasia
Autoimmune gastrointestinal dysmotility
Tropical sprue
Lysinuric protein intolerance
Exocrine pancreatic insufficiency
Foreign body in alimentary tract