TY - JOUR
T1 - Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins
AU - Caminero, Alberto
AU - McCarville, Justin L
AU - Zevallos, Victor F
AU - Pigrau, Marc
AU - Yu, Xuechen B
AU - Jury, Jennifer
AU - Galipeau, Heather J
AU - Clarizio, Alexandra V
AU - Casqueiro, Javier
AU - Murray, Joseph A
AU - Collins, Stephen M
AU - Alaedini, Armin
AU - Bercik, Premysl
AU - Schuppan, Detlef
AU - Verdu, Elena F
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - Amylases/antagonists & inhibitors
KW - Animals
KW - Celiac Disease/diet therapy
KW - Diet, Gluten-Free/methods
KW - Disease Models, Animal
KW - Gastrointestinal Microbiome/immunology
KW - Gliadin/adverse effects
KW - Humans
KW - Immunity, Innate/drug effects
KW - Lactobacillus/immunology
KW - Mice
KW - Mice, Inbred C57BL
KW - Random Allocation
KW - Reference Values
KW - Sensitivity and Specificity
KW - Triticum/adverse effects
KW - Trypsin Inhibitors/immunology
U2 - 10.1053/j.gastro.2019.02.028
DO - 10.1053/j.gastro.2019.02.028
M3 - Article
C2 - 30802444
VL - 156
SP - 2266
EP - 2280
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 8
ER -