Geethanjali Pickert1, Stefan Wirtz2, Johannes Matzner1, Muhammad Ashfaq-Khan1, Rosario Heck1, Sebastian Rosigkeit1, Dorothe Thies1, Rambabu Surabattula1, Dirk Ehmann3, Jan Wehkamp3, Misbah Aslam1, Guiwei He2, Andreas Weigert4, Friedrich Foerster5, Luisa Klotz6, Julia-Stefanie Frick7, Christoph Becker2, Ernesto Bockamp1, Detlef Schuppan8. 1. Institute of Translational Immunology, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany; Research Center for Immunotherapy, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany. 2. Department of Medicine 1, Friedrich-Alexander-University, Erlangen, Germany. 3. Department of Internal Medicine 1, University Hospital Tübingen, Germany. 4. Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany. 5. Institute of Translational Immunology, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany; Research Center for Immunotherapy, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Internal Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Germany. 6. Department of Neurology, University Hospital Muenster, Muenster, Germany. 7. Department for Medical Microbiology and Hygiene, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, Germany. 8. Institute of Translational Immunology, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany; Research Center for Immunotherapy, Univ. Medical Center, Johannes Gutenberg University Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: detlef.schuppan@unimedizin-mainz.de.
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.
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.
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