title: Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice.
abstract: The preferential localization of some neoplasms, such as serrated polyps (SPs), in specific areas of the intestine suggests that nongenetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB-EGF throughout the intestine but developed SPs only in the cecum. Here we show that a host-specific microbiome was associated with SPs and that alterations of the microbiota induced by antibiotic treatment or by embryo transfer rederivation markedly inhibited the formation of SPs in the cecum. Mechanistically, development of SPs was associated with a local decrease in epithelial barrier function, bacterial invasion, production of antimicrobials, and increased expression of several inflammatory factors such as IL-17, Cxcl2, Tnf-α, and IL-1. Increased numbers of neutrophils were found within the SPs, and their depletion significantly reduced polyp growth. Together these results indicate that nongenetic factors contribute to the development of SPs and suggest that the development of these intestinal neoplasms in the cecum is driven by the interplay between genetic changes in the host, an inflammatory response, and a host-specific microbiota.
authors.affiliation: Mount Sinai, New York, NY 10029.
authors.forename: Gerold
authors.initials: G
authors.lastname: Bongers
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Pacer
authors.forename: Thais H
authors.initials: TH
authors.lastname: Geraldino
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: He
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Glaucia C
authors.initials: GC
authors.lastname: Furtado
authors.forename: Jordi
authors.initials: J
authors.lastname: Ochando
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kelley
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Harm
authors.initials: H
authors.lastname: van Bakel
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002432:Cecum / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007417:Intestinal Polyps / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D064307:Microbiota / Q000502:physiology*; D008958:Models, Molecular; D011487:Protein Conformation; D013045:Species Specificity
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins