title: Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment.
abstract: Chronic inflammation and composition of the colon microbiota have been associated with colorectal cancer in humans. The human commensal enterotoxigenic Bacteroides fragilis (ETBF) is linked to both inflammatory bowel disease and colorectal cancer and, in our murine model, causes interleukin 17A (IL-17A)-dependent colon tumors. In these studies, we hypothesized that persistent colonization by ETBF is required for tumorigenesis.
  
  
  
  We established a method for clearing ETBF in mice, using the antibiotic cefoxitin. Multiple intestinal neoplasia mice were colonized with ETBF for the experiment duration or were cleared of infection after 5 or 14 days. Gross tumors and/or microadenomas were then evaluated. In parallel, IL-17A expression was evaluated in wild-type littermates.
  
  
  
  Cefoxitin treatment resulted in complete and durable clearance of ETBF colonization. We observed a stepwise increase in median colon tumor numbers as the duration of ETBF colonization increased before cefoxitin treatment. ETBF eradication also significantly decreased mucosal IL-17A expression.
  
  
  
  The timing of ETBF clearance profoundly influences colon adenoma formation, defining a period during which the colon is susceptible to IL-17A-dependent tumorigenesis in this murine model. This model system can be used to study the microbiota-dependent and molecular mechanisms contributing to IL-17A-dependent colon tumor initiation.
authors.affiliation: Department of Oncology.
authors.forename: Christina E
authors.initials: CE
authors.lastname: DeStefano Shields
authors.affiliation: Department of Medicine.
authors.forename: Sara W
authors.initials: SW
authors.lastname: Van Meerbeke
authors.affiliation: Department of Oncology.
authors.forename: Franck
authors.initials: F
authors.lastname: Housseau
authors.affiliation: Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Department of Oncology.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.
authors.forename: Heather M
authors.initials: HM
authors.lastname: O'Hagan
authors.affiliation: Department of Oncology Department of Medicine.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sears
mesh_terms: D000818:Animals; D001441:Bacteroides fragilis / Q000737:chemistry; D063646:Carcinogenesis / Q000187:drug effects*; D002440:Cefoxitin / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003106:Colon / Q000382:microbiology; D003110:Colonic Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000382:microbiology; D004768:Enterotoxins / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice
chemical_list: D004768:Enterotoxins; D002440:Cefoxitin
keywords: colitis; colon cancer; enterotoxigenic Bacteroides fragilis; microbiota