title: Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.
abstract: OBJECTIVE
  Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement.
  
  
  METHODS
  Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis.
  
  
  RESULTS
  GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis.
  
  
  CONCLUSIONS
  We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.
authors.affiliation: Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Monika
authors.identifier: http://orcid.org/0000-0003-3054-7608
authors.initials: M
authors.lastname: Schaubeck
authors.affiliation: ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavel
authors.affiliation: Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Calasan
authors.affiliation: ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Ilias
authors.initials: I
authors.lastname: Lagkouvardos
authors.affiliation: Department of Proteomics, Helmholtz-Centre for Environmental Research-UFZ, Leipzig, Germany.
authors.forename: Sven Bastiaan
authors.initials: SB
authors.lastname: Haange
authors.affiliation: Department of Proteomics, Helmholtz-Centre for Environmental Research-UFZ, Leipzig, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Jehmlich
authors.affiliation: Institut for Medical Microbiology, RWTH University, Aachen, Germany.
authors.forename: Marijana
authors.initials: M
authors.lastname: Basic
authors.affiliation: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Dupont
authors.affiliation: Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hornef
authors.affiliation: Department of Proteomics, Helmholtz-Centre for Environmental Research-UFZ, Leipzig, Germany UFZ, Department of Metabolomics, Helmholtz-Centre for Environmental Research, Leipzig, Germany Department of Biotechnology, Chemistry and Environmental Engineering, University of Aalborg, Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Bleich
authors.affiliation: Chair of Nutrition and Immunology, Technische Universität München, Freising-Weihenstephan, Germany ZIEL-Institute for Food and Health, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003092:Colitis; D003424:Crohn Disease / Q000209:etiology*; D064806:Dysbiosis / Q000150:complications*; D015200:Fluoroimmunoassay; D005856:Germ-Free Life; D007079:Ileitis / Q000209:etiology* / Q000382:microbiology; D007249:Inflammation / Q000503:physiopathology; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D064307:Microbiota / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000900:Anti-Bacterial Agents; D014409:Tumor Necrosis Factor-alpha
keywords: CROHN'S DISEASE; IBD BASIC RESEARCH; INTESTINAL MICROBIOLOGY; SMALL BOWEL DISEASE; TNF