title: Nod2 Deficiency Leads to a Specific and Transmissible Mucosa-associated Microbial Dysbiosis Which Is Independent of the Mucosal Barrier Defect.
abstract: OBJECTIVE
  Crohn's disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [NOD2] are CD risk factors. Increase of intestinal permeability, CD4+T cell infiltration, and bacterial dysbiosis are also seen in Nod2-knockout [Nod2KO] mice. However, the specificity and relationship between these Nod2-associated abnormalities remain largely unexplored.
  
  
  METHODS
  Wild-type [WT], Nod1-knockout [Nod1KO] and Nod2KOmice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer's patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother's microbiota at birth, analyses were also performed in Nod2KOand WT mice born from WT surrogate mothers after embryo transfer.
  
  
  RESULTS
  Nod2KOmice exhibited colonic bacterial dysbiosis different from WT and Nod1KOmice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2KOand WT mice obtained by embryo transfer was similar to that observed in Nod2KOmice, arguing for a dominant effect of Nod2KO-associated dysbiosis. In contrast, increased levels of CD4+T cells and gut barrier defects across Peyer's patches were specific to Nod2 deficiency and independent of Microbial dysbiosis.
  
  
  CONCLUSIONS
  Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.
authors.affiliation: Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.|INSERM, UMR 1149, F-75018 Paris, France.|INRA, MICALIS-UMR1319, Jouy-en-Josas, France.|AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Al Nabhani
authors.affiliation: INRA, MICALIS-UMR1319, Jouy-en-Josas, France.|AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: CNRS, TAAM, Orléans, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mauny
authors.affiliation: INSERM, UMR 989, F-75015 Paris, France.|Université Paris Descartes - Sorbonne Paris Cité, Institut IMAGINE, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montcuquet
authors.affiliation: Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.|INSERM, UMR 1149, F-75018 Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Roy
authors.affiliation: INRA, MICALIS-UMR1319, Jouy-en-Josas, France.|AgroParisTech, MICALIS-UMR1319, Jouy-en-Josas, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Le Roux
authors.affiliation: Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.|INSERM, UMR 1149, F-75018 Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Dussaillant
authors.affiliation: Services d'anatomie et de cytologie pathologiques, Hôpital Robert Debré, Université Paris-Diderot Sorbonne Paris-Cité, Paris, France.|UMR996, Cytokines, chimiokines et immunopathologie, Clamart, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.affiliation: Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France.|INSERM, UMR 1149, F-75018 Paris, France.|Services des maladies digestives et respiratoires de l'enfant et service d'anatomie pathologique, Hôpital Robert Debré, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.affiliation: Laboratoire d'excellence Inflamex, Université Paris-Diderot Sorbonne Paris-Cité, France frederick.barreau@inserm.fr.|INSERM, UMR 1149, F-75018 Paris, France.|Institut de Recherche en Santé Digestive, Université de Toulouse, Toulouse, France.
authors.forename: Frédérick
authors.initials: F
authors.lastname: Barreau
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D064806:Dysbiosis / Q000503:physiopathology*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency* / Q000502:physiology; D010581:Peyer's Patches / Q000503:physiopathology; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D023181:Antimicrobial Cationic Peptides; D009077:Mucins; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012336:RNA, Ribosomal, 16S
keywords: Crohn’s disease; Nod-like; gut barrier dysfunction; intestinal microbiota