• Can Altering the Intestinal Microbiome Reduce Wheat Sensitivity?

Can Altering the Intestinal Microbiome Reduce Wheat Sensitivity?

Amylase trypsin inhibitors (ATIs), which are enzymes in wheat, promote intestinal dysfunction and exacerbate inflammation in response to gluten, researchers show in study of mice published in the June issue of Gastroenterology. Strategies to alter the intestinal microbiome, such as administration of bacteria with ATI-degrading capacity, might be effective for patients with wheat sensitivity.

Gluten-containing grains such as wheat contain proteins and carbohydrates that induce inflammation and gastrointestinal symptoms. Disorders caused by gluten and other molecules in wheat include celiac disease and non-celiac gluten and wheat sensitivity. The prevalence of these disorders is increasing.

Proteins contained in wheat grain are generally classified into non-gluten fractions, including albumins and globulins, and the gluten fraction. Within the non-gluten fraction, amylase-trypsin inhibitors (ATIs) can induce an innate immune response via the  toll like receptor 4 (TLR4) on myeloid cells. Gluten-containing cereals have the highest concentrations of ATIs that activate TLR4. Orally ingested ATIs are resistant to proteases and heat, and increase intestinal inflammation by activating gut and mesenteric lymph node myeloid cells.

Alberto Caminero et al investigated the contributions of ATIs and gluten to intestinal inflammation and the changes they induce in the immune response and microbiomes of NOD/DQ8 mice. They found that ATIs induce intestinal barrier dysfunction and intraepithelial lymphocytes via IL15, and TLR4 signaling via MYD88, and TICAM1. Furthermore, ATIs and gluten had a combined effect in reducing barrier dysfunction.

Caminero et al measured levels of 254 mRNAs in small intestinal sections of gluten-sensitized mice fed different diets, and found that diets with ATIs, with or without gluten, increased the expression of genes that promote inflammation, including Hif1aCxcr2, and Cd40lgFeeding mice a combination of gluten and ATIs increased expression of Il15 mRNA in mouse intestine.

Mice fed ATIs had altered intestinal microbiomes, characterized by reduced abundance of Lactobacillus and a lower ratio of Firmicutes:Bacteroidetes than mice fed control diets. Lactobacillus from human intestinal microbiota were able to degrade ATIs.  C57BL/6 mice were fed an ATI diet for 1 week, along with either Lactobacillus strains with high or low ATI-degrading capacity. The mice fed the Lactobacillus strains with high ATI-degrading ability had lower tissue conductance and lower intra-epithelial cell counts (these cells are a feature of celiac disease) than mice fed the Lactobacillus strains with low ATI-degrading capacity.

Caminero et al found that undigested ATIs and ATIs incubated with Lactobacillus strains with low ATI-degrading capacity stimulated higher production of TNF from mouse splenocytes than ATI incubated with Lactobacillus strains with high ATI-degrading capacity. Administration of a single intragastric dose of ATIs increased levels of the inflammatory cytokine IL6 in serum from mice. Mice that received ATIs that had been incubated with Lactobacillus strains with high ATI-degrading capacity had lower levels of IL6 in serum compared with mice that received ATIs that had been incubated with Lactobacillus strains with low ATI-degrading capacity.

The authors conlcude that  dietary ATIs induce barrier dysfunction and immune activation in the absence of mucosal damage and of celiac risk genes, and might contribute to wheat-related disorders. Lactobacilli that efficiently metabolize ATIs can prevent activation of the inflammatory response by ATIs and reduce many aspects of gut dysfunction induced by wheat immunogenic proteins.

Microbiome-modulating strategies based on the use of strains with specific ATI-degrading capacity could be developed and support or replace dietary restrictions for patients with wheat-sensitive disorders.