Wheat Consumption Aggravates Colitis in Mice via Amylase Trypsin Inhibitor-mediated Dysbiosis.

Abstract

BACKGROUND & AIMS:

Wheat has become the world's major staple and its consumption correlates with prevalence of noncommunicable disorders such as inflammatory bowel diseases. Amylase trypsin inhibitors (ATIs), a component of wheat, activate the intestine's innate immune response via toll-like receptor 4 (TLR4). We investigated the effects of wheat and ATIs on severity of colitis and fecal microbiota in mice.

METHODS:

C57BL/6 wild-type and Tlr4-/- mice were fed wheat- or ATI-containing diets or a wheat-free (control) diet and then given dextran sodium sulfate to induce colitis; we also studied Il10-/- mice, which develop spontaneous colitis. Changes in fecal bacteria were assessed by taxa-specific quantitative polymerase chain reaction and 16S ribosomal RNA metagenomic sequencing. Feces were collected from mice on wheat-containing, ATI-containing, control diets and transplanted to intestines of mice with and without colitis on control or on ATI-containing diets. Intestinal tissues were collected and analyzed by histology, immunohistochemistry, and flow cytometry. Bacteria with reported immunomodulatory effects were incubated with ATIs and analyzed in radial diffusion assays.

RESULTS:

The wheat- or ATI-containing diets equally increased inflammation in intestinal tissues of C57BL/6 mice with colitis, compared with mice on control diets. The ATI-containing diet promoted expansion of taxa associated with development of colitis comparable to the wheat-containing diet. ATIs inhibited proliferation of specific human commensal bacteria in radial diffusion assays. Transplantation of microbiota from feces of mice fed the wheat- or ATI-containing diets to intestines of mice on control diets increased the severity of colitis in these mice. The ATI-containing diet did not increase the severity of colitis in Tlr4-/- mice.

CONCLUSIONS:

Consumption of wheat or wheat ATIs increases intestinal inflammation in mice with colitis, via TLR4, and alters their fecal microbiota. Wheat-based, ATI-containing diets therefore activate TLR4 signaling and promote intestinal dysbiosis.

• Authors: Geethanjali Pickert, Stefan Wirtz, Johannes Matzner, Muhammad Ashfaq-Khan, Rosario Heck, Sebastian Rosigkeit, Dorothe Thies, Rambabu Surabattula, Dirk Ehmann, Jan Wehkamp, Misbah Aslam, Guiwei He, Andreas Weigert, Friedrich Foerster, Luisa Klotz, Julia-Stefanie Frick, Christoph Becker, Ernesto Bockamp, Detlef Schuppan
• Journal: Gastroenterology (Gastroenterology) Vol. 159 Issue 1 Pg. 257-272.e17 (07 2020) ISSN: 1528-0012 [Electronic] United States
• PMID: 32251667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Plant Proteins, Dietary
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Trypsin Inhibitors
• Dextran Sulfate

Topics

• Animal Feed (adverse effects)
• Animals
• Colitis (chemically induced, diagnosis, immunology, microbiology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Dysbiosis (complications, diagnosis, immunology, microbiology)
• Fecal Microbiota Transplantation
• Feces (microbiology)
• Gastrointestinal Microbiome (immunology)
• Humans
• Immunity, Innate
• Inflammatory Bowel Diseases (chemically induced, diagnosis, immunology, microbiology)
• Male
• Mice
• Mice, Knockout
• Plant Proteins, Dietary (adverse effects, immunology)
• Severity of Illness Index
• Signal Transduction (genetics, immunology)
• Toll-Like Receptor 4 (genetics, metabolism)
• Triticum (immunology)
• Trypsin Inhibitors (adverse effects, immunology)