Aetiology/pathology

  1. Dr. Schär Institute
  2. Aetiology/pathology
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The exact pathogenetic causes of non-coeliac 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 coeliac disease nor an allergic reaction like wheat allergy. In contrast to coeliac disease, autoimmune antibodies are not evident in cases of NCGS. However, immunological mechanisms may still be involved.

ATIs, have been identified to trigger the innate immune system in intestinal myeloid cells via the stimulation of Toll-like-4 receptors (TLR4s) [1]. Once these are activated, an inflammatory response is triggered, pointing towards a disorder of the innate immune system.

However, unlike coeliac 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 coeliac 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 coeliac disease patients, patients with NCGS have been demonstrated to exhibit normal intestinal permeability and over-regulation of Claudin-4 [2]. Recently there has been a lack of consensus on intestinal permeability in NCGS, with conflicting studies suggesting either reduced or increased intestinal permeability [3]. Further research is required to elucidate this further. Changes in the gut microbiota induced by gluten consumption may also influence NCGS [4].

Unlike coeliac disease it is not clear if gluten is crucial in the pathogenic mechanism of NCGS. Several components of wheat are potentially harmful for NCGS, including gluten proteins, amylase/trypsin inhibitors (ATIs), wheat germ aggluteninins (WGA) and fermentable oligo-, di- and monosaccharides and polyols (FODMAPs) [3].

The genetic predisposition markers HLA-DQ2 and DQ8, which are present in nearly all persons with coeliac 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 renewed 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.

     

     

Reference

  1. Junker Y, Zeissig S, Kim S.J, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 2012, 209, 2395–2408
  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. Catassi C, Alaedini A, Bojarski et al. The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update. Nutrients 2017, 9, 1268
  4. Volta U, Caio G, Karunaratne TB, Alaedini A, De Giorgio R. Non-coeliac gluten/wheat sensitivity: advances in knowledge and relevant questions. Expert Rev Gastroenterol Hepatol 2017; 11: 9-18
  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).