title: Microbiota-Independent Ameliorative Effects of Antibiotics on Spontaneous Th2-Associated Pathology of the Small Intestine.
abstract: We have previously generated a mouse model of spontaneous Th2-associated disease of the small intestine called TRAF6ΔDC, in which dendritic cell (DC)-intrinsic expression of the signaling mediator TRAF6 is ablated. Interestingly, broad-spectrum antibiotic treatment ameliorates TRAF6ΔDC disease, implying a role for commensal microbiota in disease development. However, the relationship between the drug effects and commensal microbiota status remains to be formally demonstrated. To directly assess this relationship, we have now generated TRAF6ΔDC bone marrow chimera mice under germ-free (GF) conditions lacking commensal microbiota, and found, unexpectedly, that Th2-associated disease is actually exacerbated in GF TRAF6ΔDC mice compared to specific pathogen-free (SPF) TRAF6ΔDC mice. At the same time, broad-spectrum antibiotic treatment of GF TRAF6ΔDC mice has an ameliorative effect similar to that observed in antibiotics-treated SPF TRAF6ΔDC mice, implying a commensal microbiota-independent effect of broad-spectrum antibiotic treatment. We further found that treatment of GF TRAF6ΔDC mice with broad-spectrum antibiotics increases Foxp3+ Treg populations in lymphoid organs and the small intestine, pointing to a possible mechanism by which treatment may directly exert an immunomodulatory effect. To investigate links between the exacerbated phenotype of the small intestines of GF TRAF6ΔDC mice and local microbiota, we performed microbiotic profiling of the luminal contents specifically within the small intestines of diseased TRAF6ΔDC mice, and, when compared to co-housed control mice, found significantly increased total bacterial content characterized by specific increases in Firmicutes Lactobacillus species. These data suggest a protective effect of Firmicutes Lactobacillus against the spontaneous Th2-related inflammation of the small intestine of the TRAF6ΔDC model, and may represent a potential mechanism for related disease phenotypes.
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walsh
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Kwang Soon
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Sung-Wook
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Junyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea.
authors.forename: Jaeu
authors.initials: J
authors.lastname: Yi
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Gloriany
authors.initials: G
authors.lastname: Rivas
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, 790-784, Republic of Korea; Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea; Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California, 92037, United States of America.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Surh
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005856:Germ-Free Life; D006706:Homeostasis / Q000187:drug effects; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007421:Intestine, Small / Q000187:drug effects* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D064307:Microbiota; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D048029:TNF Receptor-Associated Factor 6