title: Commensal Gram-positive bacteria initiates colitis by inducing monocyte/macrophage mobilization.
abstract: Breakdown of the intestinal epithelial layer's barrier function results in the inflow of commensal flora and improper immune responses against the commensal flora, leading to inflammatory bowel disease (IBD) development. Using a mouse dextran sodium sulfate (DSS)-induced colitis model, we show here that commensal Gram-positive bacteria trigger the mobilization of inflammatory monocytes and macrophages into the colon. Monocytes/macrophages are major producers of tumor necrosis factor-α (TNF-α), a representative cytokine that aggravates colitis. Notably, pretreating mice with vancomycin, which eliminated Gram-positive bacteria, particularly the Lachnospiraceae family, significantly reduced the severity of the colitis by selectively blocking the recruitment of monocytes/macrophages, but not of other cells. Importantly, vancomycin treatment specifically downregulated the colonic epithelial cell (cEC) expression of C-C chemokine receptor type-2 (CCR2) ligands, which are critical chemokines for monocyte/macrophage mobilization into the inflamed colon. Collectively, these results provide previously undiscovered evidence that Gram-positive commensal bacteria induce colitis by recruiting colitogenic monocytes and macrophages. Our findings may lead to new avenues of treatment for IBD.
authors.affiliation: 1] Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: 1] Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan [2] Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: 1] Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohteki
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology; D003106:Colon / Q000276:immunology*; D016264:Dextran Sulfate / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014640:Vancomycin / Q000008:administration & dosage
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D014640:Vancomycin; D016264:Dextran Sulfate