title: Functional Characterization of Inflammatory Bowel Disease-Associated Gut Dysbiosis in Gnotobiotic Mice.
abstract: OBJECTIVE
  Gut dysbiosis is closely involved in the pathogenesis of inflammatory bowel disease (IBD). However, it remains unclear whether IBD-associated gut dysbiosis contributes to disease pathogenesis or is merely secondary to intestinal inflammation. We established a humanized gnotobiotic (hGB) mouse system to assess the functional role of gut dysbiosis associated with 2 types of IBD: Crohn's disease (CD) and ulcerative colitis (UC).
  
  
  METHODS
  Germ-free mice were colonized by the gut microbiota isolated from patients with CD and UC, and healthy controls. Microbiome analysis, bacterial functional gene analysis, luminal metabolome analysis, and host gene expression analysis were performed in hGB mice. Moreover, the colitogenic capacity of IBD-associated microbiota was evaluated by colonizing germ-free colitis-prone interleukin 10-deficient mice with dysbiotic patients' microbiota.
  
  
  RESULTS
  Although the microbial composition seen in donor patients' microbiota was not completely reproduced in hGB mice, some dysbiotic features of the CD and UC microbiota (eg, decreased diversity, alteration of bacterial metabolic functions) were recapitulated in hGB mice, suggesting that microbial community alterations, characteristic for IBD, can be reproduced in hGB mice. In addition, colonization by the IBD-associated microbiota induced a proinflammatory gene expression profile in the gut that resembles the immunologic signatures found in CD patients. Furthermore, CD microbiota triggered more severe colitis than healthy control microbiota when colonized in germ-free interleukin 10-deficient mice.
  
  
  CONCLUSIONS
  Dysbiosis potentially contributes to the pathogenesis of IBD by augmenting host proinflammatory immune responses. Transcript profiling: GSE73882.
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Hiroko
authors: H
authors: Nagao-Kitamoto
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Andrew B
authors: AB
authors: Shreiner
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Merritt G
authors: MG
authors: Gillilland
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Sho
authors: S
authors: Kitamoto
authors: Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
authors: Chiharu
authors: C
authors: Ishii
authors: Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
authors: Akiyoshi
authors: A
authors: Hirayama
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Peter
authors: P
authors: Kuffa
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Mohamad
authors: M
authors: El-Zaatari
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Helmut
authors: H
authors: Grasberger
authors: Division of Infectious Disease, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Anna M
authors: AM
authors: Seekatz
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Peter D R
authors: PD
authors: Higgins
authors: Division of Infectious Disease, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Vincent B
authors: VB
authors: Young
authors: Institute for Advanced Biosciences, Keio University, Yamagata, Japan.
authors: Shinji
authors: S
authors: Fukuda
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: John Y
authors: JY
authors: Kao
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors: Nobuhiko
authors: N
authors: Kamada
keywords: CD, Crohn's disease; CE-TOFMS, capillary electrophoresis time-of-flight mass spectrometry; Crohn's Disease; Dysbiosis; GB, gnotobiotic; GF, germ-free; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; IVC, individual ventilated cage; Microbiota; NK, natural killer; OTU, operational taxonomic unit; SCFA, short-chain fatty acid; Th, T helper; UC, ulcerative colitis; Ulcerative Colitis; WT, wild type; hGB, humanized gnotobiotic; rRNA, ribosomal RNA