title: Nucleotide-oligomerization-domain-2 affects commensal gut microbiota composition and intracerebral immunopathology in acute Toxoplasma gondii induced murine ileitis.
abstract: BACKGROUND
  Within one week following peroral high dose infection with Toxoplasma (T.) gondii, susceptible mice develop non-selflimiting acute ileitis due to an underlying Th1-type immunopathology. The role of the innate immune receptor nucleotide-oligomerization-domain-2 (NOD2) in mediating potential extra-intestinal inflammatory sequelae including the brain, however, has not been investigated so far.
  
  
  RESULTS
  Following peroral infection with 100 cysts of T. gondii strain ME49, NOD2-/- mice displayed more severe ileitis and higher small intestinal parasitic loads as compared to wildtype (WT) mice. However, systemic (i.e. splenic) levels of pro-inflammatory cytokines such as TNF-α and IFN-γ were lower in NOD2-/- mice versus WT controls at day 7 p.i. Given that the immunopathological outcome might be influenced by the intestinal microbiota composition, which is shaped by NOD2, we performed a quantitative survey of main intestinal bacterial groups by 16S rRNA analysis. Interestingly, Bifidobacteria were virtually absent in NOD2-/- but not WT mice, whereas differences in remaining bacterial species were rather subtle. Interestingly, more distinct intestinal inflammation was accompanied by higher bacterial translocation rates to extra-intestinal tissue sites such as liver, spleen, and kidneys in T. gondii infected NOD2-/- mice. Strikingly, intracerebral inflammatory foci could be observed as early as seven days following T. gondii infection irrespective of the genotype of animals, whereas NOD2-/- mice exhibited higher intracerebral parasitic loads, higher F4/80 positive macrophage and microglia numbers as well as higher IFN-γ mRNA expression levels as compared to WT control animals.
  
  
  CONCLUSIONS
  NOD2 signaling is involved in protection of mice from T. gondii induced acute ileitis. The parasite-induced Th1-type immunopathology at intestinal as well as extra-intestinal sites including the brain is modulated in a NOD2-dependent manner.
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.affiliation: Department of Microbiology and Hygiene, University of Magdeburg, Magdeburg, Germany.
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Alutis
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Microbiology and Hygiene, University of Magdeburg, Magdeburg, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Möhle
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Ulf B
authors.initials: UB
authors.lastname: Göbel
authors.affiliation: Department of Internal Medicine, Rheumatology and Clinical Immunology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000469:parasitology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D007079:Ileitis / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000469:parasitology; D007371:Interferon-gamma / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology / Q000382:microbiology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D059208:Parasite Load; D012336:RNA, Ribosomal, 16S / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology* / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012336:RNA, Ribosomal, 16S; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma