title: Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease.
abstract: OBJECTIVE
  Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn's Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis.
  
  
  METHODS
  We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI; 0.1 mg/mouse), or high dose indomethacin (HDI; 1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype.
  
  
  RESULTS
  Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% gram + Firmicutes to >95% gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2(-/-), and reduced dysbiosis in ileitis-resistant CCR2(-/-) mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion.
  
  
  CONCLUSIONS
  Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.
authors: Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
authors: Melanie
authors: M
authors: Craven
authors: Charlotte E
authors: CE
authors: Egan
authors: Scot E
authors: SE
authors: Dowd
authors: Sean P
authors: SP
authors: McDonough
authors: Belgin
authors: B
authors: Dogan
authors: Eric Y
authors: EY
authors: Denkers
authors: Dwight
authors: D
authors: Bowman
authors: Ellen J
authors: EJ
authors: Scherl
authors: Kenneth W
authors: KW
authors: Simpson
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000502:physiology*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005872:Giardia / Q000502:physiology; D005873:Giardiasis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007079:Ileitis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D014122:Toxoplasma / Q000502:physiology; D014123:Toxoplasmosis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
chemical_list: C515335:Ccr2 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D054390:Receptors, CCR2