title: Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis.
abstract: Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: D
authors.initials: D
authors.lastname: Corridoni
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez-Palacios
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: G
authors.initials: G
authors.lastname: Di Stefano
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: L
authors.initials: L
authors.lastname: Di Martino
authors.affiliation: Biosciences Division, Argonne National Laboratory, Argonne, Illinois, USA.|Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Antonopoulos
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Chang
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: K O
authors.initials: KO
authors.lastname: Arseneau
authors.affiliation: Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.|Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA.|Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cominelli
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D064806:Dysbiosis; D005243:Feces / Q000382:microbiology; D006801:Humans; D007079:Ileitis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D007413:Intestinal Mucosa / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D064307:Microbiota / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012336:RNA, Ribosomal, 16S / Q000032:analysis; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012336:RNA, Ribosomal, 16S; D051192:Receptors, Pattern Recognition; D050800:STAT6 Transcription Factor; D016264:Dextran Sulfate