Kerstin Gronbach1, Isabell Flade1, Otto Holst2, Buko Lindner3, Hans Joachim Ruscheweyh4, Alexandra Wittmann1, Sarah Menz1, Andreas Schwiertz5, Patrick Adam6, Bärbel Stecher7, Christine Josenhans8, Sebastian Suerbaum8, Achim D Gruber9, Andreas Kulik10, Daniel Huson4, Ingo B Autenrieth1, Julia-Stefanie Frick11. 1. Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; German Centre for Infection Research (DZIF), Germany. 2. Division of Structural Biochemistry, Research Center Borstel, Airway Research Center North (ARCN) and German Center for Lung Research (DZL), Borstel, Germany. 3. Division of Immunochemistry, Research Center Borstel, Airway Research Center North (ARCN) and German Center for Lung Research (DZL), Borstel, Germany. 4. Algorithms in Bioinformatics, ZBIT Center for Bioinformatics, University of Tübingen, Tübingen, Germany. 5. Institute of Microoecology, Herborn, Germany. 6. Institute of Pathology, University of Tübingen, Tübingen, Germany. 7. German Centre for Infection Research (DZIF), Germany; Max von Pettenkofer-Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University, Munich, Germany. 8. German Centre for Infection Research (DZIF), Germany; Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. 9. Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany. 10. Institute for Microbiology, University of Tübingen, Tübingen, Germany. 11. Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; German Centre for Infection Research (DZIF), Germany. Electronic address: julia-stefanie.frick@med.uni-tuebingen.de.
Abstract
BACKGROUND & AIMS: The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice. METHODS: Germ-free C57BL/6J-Rag(1tm1Mom) (Rag1(-/-)) mice were colonized with 2 different types of complex intestinal microbiota. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+)CD62L(+) T cells from C57BL/6J mice. Colonic tissues were collected and used for histologic analysis and cell isolation. Activation of lamina propria dendritic cells and T cells was analyzed by flow cytometry. RESULTS: After transfer of CD4(+)CD62L(+) T cells, mice with intestinal Endo(lo) microbiota (a low proportion of Enterobacteriaceae, high proportion of Bacteroidetes, and low endotoxicity) maintained mucosal immune homeostasis, and mice with highly endotoxic Endo(hi) microbiota (a high proportion of Enterobacteriaceae and low proportion of Bacteroidetes) developed colitis. To determine whether the effects of Endo(hi) microbiota were related to the higher endotoxic activity of lipopolysaccharide (LPS), we compared LPS from Enterobacteriaceae with that of Bacteroidetes. Administration of Escherichia coli JM83 (wild-type LPS) to the mice exacerbated colitis, and Escherichia coli JM83 + htrBPG (mutated LPS, with lower endotoxicity, similar to that of Bacteroidetes) prevented development of colitis after transfer of the T cells to mice. CONCLUSIONS: The endotoxicity of LPS produced by the intestinal microbiota is a determinant of whether mice develop colitis after transfer of CD4(+)CD62L(+) T cells. This finding might aid the design of novel biologics or probiotics to treat inflammatory bowel disease.
BACKGROUND & AIMS: The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice. METHODS: Germ-free C57BL/6J-Rag(1tm1Mom) (Rag1(-/-)) mice were colonized with 2 different types of complex intestinal microbiota. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+)CD62L(+) T cells from C57BL/6J mice. Colonic tissues were collected and used for histologic analysis and cell isolation. Activation of lamina propria dendritic cells and T cells was analyzed by flow cytometry. RESULTS: After transfer of CD4(+)CD62L(+) T cells, mice with intestinal Endo(lo) microbiota (a low proportion of Enterobacteriaceae, high proportion of Bacteroidetes, and low endotoxicity) maintained mucosal immune homeostasis, and mice with highly endotoxic Endo(hi) microbiota (a high proportion of Enterobacteriaceae and low proportion of Bacteroidetes) developed colitis. To determine whether the effects of Endo(hi) microbiota were related to the higher endotoxic activity of lipopolysaccharide (LPS), we compared LPS from Enterobacteriaceae with that of Bacteroidetes. Administration of Escherichia coli JM83 (wild-type LPS) to the mice exacerbated colitis, and Escherichia coli JM83 + htrBPG (mutated LPS, with lower endotoxicity, similar to that of Bacteroidetes) prevented development of colitis after transfer of the T cells to mice. CONCLUSIONS: The endotoxicity of LPS produced by the intestinal microbiota is a determinant of whether mice develop colitis after transfer of CD4(+)CD62L(+) T cells. This finding might aid the design of novel biologics or probiotics to treat inflammatory bowel disease.
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