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

doi:10.1053/j.gastro.2019.02.028

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 journal › Article › peer-review

110 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 language	English
Pages (from-to)	2266-2280
Number of pages	15
Journal	Gastroenterology
Volume	156
Issue number	8
Early online date	22 Feb 2019
DOIs	https://doi.org/10.1053/j.gastro.2019.02.028
Publication status	Published - 1 Jun 2019
Externally published	Yes

Keywords

Amylases/antagonists & inhibitors
Animals
Celiac Disease/diet therapy
Diet, Gluten-Free/methods
Disease Models, Animal
Gastrointestinal Microbiome/immunology
Gliadin/adverse effects
Humans
Immunity, Innate/drug effects
Lactobacillus/immunology
Mice
Mice, Inbred C57BL
Random Allocation
Reference Values
Sensitivity and Specificity
Triticum/adverse effects
Trypsin Inhibitors/immunology

Access to Document

10.1053/j.gastro.2019.02.028

Cite this

Caminero, A., McCarville, J. L., Zevallos, V. F., Pigrau, M., Yu, X. B., Jury, J., Galipeau, H. J., Clarizio, A. V., Casqueiro, J., Murray, J. A., Collins, S. M., Alaedini, A., Bercik, P., Schuppan, D., & Verdu, E. F. (2019). Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins. Gastroenterology, 156(8), 2266-2280. https://doi.org/10.1053/j.gastro.2019.02.028

@article{ddd30094596c4dbc826151249024560e,

title = "Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins",

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.",

keywords = "Amylases/antagonists & inhibitors, Animals, Celiac Disease/diet therapy, Diet, Gluten-Free/methods, Disease Models, Animal, Gastrointestinal Microbiome/immunology, Gliadin/adverse effects, Humans, Immunity, Innate/drug effects, Lactobacillus/immunology, Mice, Mice, Inbred C57BL, Random Allocation, Reference Values, Sensitivity and Specificity, Triticum/adverse effects, Trypsin Inhibitors/immunology",

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

year = "2019",

month = jun,

day = "1",

doi = "10.1053/j.gastro.2019.02.028",

language = "English",

volume = "156",

pages = "2266--2280",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "8",

}

Caminero, A, McCarville, JL, Zevallos, VF, Pigrau, M, Yu, XB, Jury, J, Galipeau, HJ, Clarizio, AV, Casqueiro, J, Murray, JA, Collins, SM, Alaedini, A, Bercik, P, Schuppan, D & Verdu, EF 2019, 'Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins', Gastroenterology, vol. 156, no. 8, pp. 2266-2280. https://doi.org/10.1053/j.gastro.2019.02.028

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

SN - 0016-5085

VL - 156

SP - 2266

EP - 2280

JO - Gastroenterology

JF - Gastroenterology

IS - 8

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this