Wheat sensitivity: Impact of wheat varieties and wheat growing conditions on innate immunity

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Non-celiac wheat sensitivity (NCWS) is defined as an immunological reaction to ingestion of wheat that is not caused by celiac disease or wheat allergy. NCWS affects between 2% and 10% of wheat consuming subjects and is caused by an innate immune response to wheat proteins. Recently, we identified the family of wheat amylase-trypsin inhibitors (ATIs) as triggers of innate immunity. Wheat ATIs activate the toll like receptor 4 (TLR4)-MD2-CD14 complex, lead to the release of proinflammatory cytokines in dendritic cells>macrophages>monocytes and to the maturation of dendritic cells. Relevant TLR4 stimulating activity is confined to ATIs of gluten containing grains like wheat, rye and barley. Notably, we demonstrated that nutritional ATIs exacerbate experimental autoimmune and allergic diseases in a dose-dependent manner. Therefore, determination of ATI content, ATI bioactivity and of ATI-gene regulation in currently used and alternative wheat variants should be of high relevance to human health. To date, only a single wheat variety had been subjected to extensive transcriptome and proteome analysis, showing that ATIs represented 2-4% and gluten proteins >80% of total protein. Moreover, 19 DNA regions encoded potential ATIs. Since the expression of wheat genes and proteins is highly dependent on the wheat variety and growing conditions, studies with larger numbers of wheat varieties grown under different conditions are urgently needed, to better understand the regulation of ATI expression. This should allow the production of healthier wheat products, preventing enhanced morbidity due to wheat sensitivity and worsening of chronic inflammatory diseases.Our proposal combines the expertise of biomedicine, of wheat breeding and wheat growing research, and of genetics and proteomics, to study the role and the regulation of wheat ATIs and their in vitro and in vivo effects on innate and adaptive immunity. 160 wheat varieties comprising modern elite strains and important old varieties will be grown at 3 different field locations in Germany. The harvested samples will be subjected to examination of quality traits regularly selected by wheat breeders, advanced proteomic and genetic analyses focused on ATI expression, and to cell based in vitro TLR4 stimulatory activity. Select samples will be employed for in vivo feeding studies, addressing food matrix effects on intestinal and general ATI-induced innate and adaptive immune activation. Combined with thorough statistical analyses, the data will enable us to characterize ATI expression and bioactivity in a wide variety of wheats, grown under different conditions, to select for variants and conditions with low ATI expression and bioactivity. This will likely promote the growing of less immunogenic and therefore healthier wheat strains.