Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins

Alberto Caminero, Justin L McCarville, Victor F Zevallos, Marc Pigrau, Xuechen B Yu, Jennifer Jury, Heather J Galipeau, Alexandra V Clarizio, Javier Casqueiro, Joseph A Murray, Stephen M Collins, Armin Alaedini, Premysl Bercik, Detlef Schuppan, Elena F Verdu

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

BACKGROUND & AIMS: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.

METHODS: C57BL/6 (control), Myd88-/-, Ticam1-/-, and Il15-/- mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and intestinal transit. Control mice fed ATIs for 1 week were gavaged daily with Lactobacillus strains that had high or low ATI-degrading capacity. Nonobese diabetic/DQ8 mice were sensitized to gluten and fed an ATI diet, a gluten-containing diet or a diet with ATIs and gluten for 2 weeks. Mice were also treated with Lactobacillus strains that had high or low ATI-degrading capacity. Intestinal tissues were collected and IELs, gene expression, gut permeability and intestinal microbiota profiles were measured.

RESULTS: In intestinal tissues from control mice, ATIs induced an innate immune response by activation of Toll-like receptor 4 signaling to MD2 and CD14, and caused barrier dysfunction in the absence of mucosal damage. Administration of ATIs to gluten-sensitized mice expressing HLA-DQ8 increased intestinal inflammation in response to gluten in the diet. We found ATIs to be degraded by Lactobacillus, which reduced the inflammatory effects of ATIs.

CONCLUSIONS: ATIs mediate wheat-induced intestinal dysfunction in wild-type mice and exacerbate inflammation to gluten in susceptible mice. Microbiome-modulating strategies, such as administration of bacteria with ATI-degrading capacity, may be effective in patients with wheat-sensitive disorders.

Original languageEnglish
Pages (from-to)2266-2280
Number of pages15
JournalGastroenterology
Volume156
Issue number8
Early online date22 Feb 2019
DOIs
Publication statusPublished - 1 Jun 2019
Externally publishedYes

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