期刊
GASTROENTEROLOGY
卷 156, 期 8, 页码 2266-2280出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2019.02.028
关键词
Microbiome; Bacterial Metabolism; Food Allergy; HLA
资金
- Canadian Institutes of Health Research (CIHR)
- Boris Family award [142773]
- German Research Foundation [DFG Schu 646/17-1, DFG Pic/Sch SPP 1656]
- Leibniz Foundation [SAW-2016-DFA-2]
- Mayo Foundation
- National Institutes of Health
- Crohn Colitis America (CCA)
- DBV Technologies
- Evelo
- Vibrant Technologies
- Actobiotics
- CIHR Foundation [143253]
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000040]
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.
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