• What Causes Wheat Sensitivity in People Without Celiac Disease?

What Causes Wheat Sensitivity in People Without Celiac Disease?

Gluten-containing cereals have high concentrations of amylase-trypsin inhibitors (ATIs), which activate innate immunity via the toll-like receptor 4 (TLR4), researchers report in the April issue of Gastroenterology. These ATIs are resistant to proteases and heat, and increase intestinal inflammation by activating intestinal and mesenteric lymph node myeloid cells.

Wheat is the most widely consumed food staple worldwide. Its widespread use in breads, cakes, pastas, and related products is believed to have increased hypersensitivities to wheat. These hypersensitivities include asthma and immunologic reactions to ingestion of wheat, such as nutritional wheat allergy, celiac disease, and non-celiac/non-allergy wheat sensitivity (prevalence of 3%–10% in most wheat-consuming populations).

Wheat proteins can be classified into albumins, globulins, gliadins, and glutenins, based on their structural properties and solubility. Commercial wheat contains approximately 10%–20% albumins or globulins and 80%–90% gluten—a complex mixture of monomeric gliadins and polymeric glutenins that are partly resistant to gastrointestinal enzymatic proteolysis.

ATIs are found in the endosperm of plant seeds, where they support the natural defense against parasites and insects and may regulate starch metabolism during seed development and germination. They bind to TLR4 on myeloid cells to activate production of inflammatory innate cytokines in cells and intestinal tissues.

Victor F. Zevallos et al characterized the TLR4 stimulatory activity of ATIs from 38 different gluten-containing and gluten-free products, either unprocessed (such as wheat, rye, barley, quinoa, amaranth, soya, lentils, and rice) or processed (such as pizza, pasta, bread, and biscuits).

ATIs extracted from wheat stimulated secretion of interleukin 8 (IL8) by myeloid cells, in a dose-dependent manner, followed by expression of IL6 and IL1B and release of TNF and CCL2 (also called MCP1).

The authors found that modern gluten-containing staples had levels of TLR4-activating ATIs that were as much as 100-fold higher than in most gluten-free foods. Processed or baked foods retained ATI bioactivity.

Zevallos et al explained that the primary and secondary structures of ATIs in gluten-free food differ from those in wheat (rye, barley) in that ATIs in gluten-free foods contain only 1–3, instead of 5, intrachain disulfides and a different arrangement of α helices. Accordingly, only low (below 20% of modern wheat) or no TLR4 stimulatory activity was found in extracts from gluten-free products.

High ATI bioactivity was found in modern hexaploid wheat, rye, and barley. ATI bioactivity was lower in older wheat variants, including spelt (an ancient hexaploid wheat), emmer (tetraploid), and Einkorn (diploid).

ATI species CM3 and 0.19 were the activators of TLR4 most frequently found in modern wheat. These were highly resistant to intestinal proteolysis.

Mice fed an ATI-free and gluten-free diet for 4 weeks that then received a single gavage (about 12 mg/mouse) of commercial gluten (containing approximately 0.2 mg ATIs) developed modest intestinal myeloid cell infiltration and activation. This was characterized by release of inflammatory mediators (IL8, MCP1, TNF, and IL15)—mostly in the colon, then in the ileum, and then in the duodenum.

This activation was insignificant when mice were gavaged with the same dose of gluten from which approximately 70% of ATIs were extracted. This indicates that pure gluten itself does not have inflammatory activity in normal mice.

The bioactivity of gluten-free staples was low and could be subdivided into those with <20% (soya, buckwheat, millet, and teff), <10% (lentils, quinoa, and oats), and <2% (amaranth, rice, corn, and potatoes) of the activity of a modern standard off-the-shelf wheat flour, as measured per gram of extracted flour.

Adjuvant effect of repetitive gavage of ATIs in mice with low-level intestinal inflammation. Figure shows CD68-positive sections of the terminal ileum (green) and nuclei (blue).

Zevallos et al investigated the effects of feeding ATIs to mice with pre-existing low-level intestinal inflammation (given low-level polyinosinic:polycytidylic acid or dextran sodium sulfate). Ileum tissues from mice fed ATIs contained significantly higher numbers of CD68+ macrophages than mice that were fed a control protein (BSA, see figure).

The authors found higher numbers of CD68+ monocytes/macrophages and F4/80+ macrophages with ATI feeding in all areas of the intestine (duodenum, terminal ileum, and mid colon)—most prominently in mice with low baseline inflammation.

The authors propose that ATIs in food promote intestinal and extra-intestinal inflammatory disorders. Studies of non-celiac wheat sensitivity have focused on abdominal symptoms associated with gluten-containing diets. Challenge studies have indicated that either (ATI-containing) gluten or FODMAPs (fermentable oligo- and disaccharides) contribute to abdominal symptoms such as bloating and pain after wheat consumption.

Further studies are needed to determine the effect of an ATI-free diet on intestinal and extra-intestinal, chronic inflammatory diseases. Zevallos et al propose that it might be possible to determine a safe threshold of ATI consumption, because its effects are dose-dependent, unlike the effect of even small doses of gluten for patients with celiac disease.

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