Pathology of NCGS

  1. Dr. Schär Institute
  2. Pathology of NCGS
Aerztin mit Brille schaut durchs Mikroskop

The exact pathogenetic causes of non-eliac gluten sensitivity (NCGS) are still not fully understood. What is certain is that it is not an auto-immune reaction or allergic reaction.

The exact pathogenesis of NCGS is still unclear. It is now known that it is neither an auto-immune reaction like celiac disease nor an allergic reaction like wheat allergy. In contrast to celiac disease, autoimmune antibodies are not evident in  NCGS. However, immunological mechanisms may still be involved. The high expression of Toll-like-4 receptors (TLR4s), typical of innate immunity, points towards a disorder of the innate immune response [1]. Once these are activated, an inflammatory response is triggered. However, unlike celiac disease, it is not possible to establish any change in the typical cytokines involved in the adaptive immune response associated with NCGS. Furthermore, in contrast to celiac disease patients, it’s possible to establish a substantial reduction in levels of the FoxP3 molecule in patients with NCGS. This is an important regulatory T-cell marker. In contrast to celiac disease patients, patients with NCGS also exhibit normal intestinal permeability and over-regulation of Claudin-4 [2].

Unlike celiac disease it is not clear if gluten is crucial in the pathogenic mechanism of NCGS. For example there is ongoing research into whether amylase-trypsin inhibitors (ATIs), which are also found in wheat, could trigger the innate immune reaction seen in NCGS [3]. Furthermore FODMAPs, in particular fructans, found in wheat, could also cause gastrointestinal symptoms described in the case of NCGS [4].

The genetic predisposition markers HLA-DQ2 and DQ8, which are present in nearly all individuals with celiac disease, are positive in only around 50% of patients with NCGS [5]. Because the pathogenesis is unclear, the process used for diagnosis is one of exclusion by means of positive response to avoiding gluten for 2-3 weeks. The diagnosis is then confirmed by a return of symptoms and deterioration upon re-exposure to gluten.

  • What are ATIs?

    Amylase-trypsin inhibitors (ATIs) are proteins in cereals that make them more resistant to pests and are contained mainly in cultivated wheat varieties. ATIs are contained in particular in cereals that contain gluten.

  • What are claudins?

    Claudins are integral membrane proteins that are involved in the function of cell junctions ("tight junctions"). These tight junctions block the passage of fluid between the cells, creating a kind of belt around the cell perimeter (zonula). They occur in the intestinal epithelium, for example, in order to prevent leakage of substances between the different environments.

  • What is the FoxP3 factor?

    Regulatory T-cells are instrumental in keeping the immune system in balance and protecting against autoimmune diseases and excessive inflammatory responses. They contain the FoxP3 protein. This transcription factor acts as both activator and repressor. Mutations of this protein causes the development of  autoimmune diseases.




  1. Sapone, A. et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 9, 23 (2011).
  2. Sapone, A. et al. Differential mucosal IL 17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int. Arch. Allergy Immunol. 152, 75–80 (2010).
  3. Junker, Y. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 209, 2395–2408 (2012).
  4. Biesiekierski, J. R. et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 145, 320–328 (2013).
  5. Carroccio, A. et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am. J. Gastroenterol. 107, 1898–1906 (2012).