title: ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice.
abstract: OBJECTIVE
  The spondyloarthritides share genetic susceptibility, interleukin-23 (IL-23) dependence, and the involvement of microbiota. The aim of the current study was to elucidate how host genetics influence gut microbiota and the relationship between microbiota and organ inflammation in spondyloarthritides.
  
  
  METHODS
  BALB/c ZAP-70(W163C) -mutant (SKG) mice, Toll-like receptor 4 (TLR-4)-deficient SKG mice, and wild-type BALB/c mice were housed under specific pathogen-free conditions. SKG and wild-type BALB/c mice were maintained under germ-free conditions, and some of these mice were recolonized with altered Schaedler flora. All of the mice were injected intraperitoneally with microbial β-1,3-glucan (curdlan). Arthritis, spondylitis, and ileitis were assessed histologically. Microbiome composition was analyzed in serial fecal samples obtained from mice that were co-housed beginning at the time of weaning, using 454 pyrosequencing. Infiltrating cells and cytokines in the peritoneal cavity were measured by flow cytometry and enzyme-linked immunosorbent assay. Cytokine, endoplasmic reticulum (ER) stress marker, and tight junction protein transcription was measured by quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  Microbiota content and response to curdlan varied according to whether T cell receptor signal strength was normal or was impaired due to the ZAP-70(W163C) mutation. Curdlan triggered acute inflammation regardless of the presence of the SKG allele or microbiota. However, no or limited microbiota content attenuated the severity of arthritis. In contrast, ileal IL-23 expression, ER stress, lymph node IL-17A production, goblet cell loss, and ileitis development were microbiota-dependent. Ileitis but not arthritis was suppressed by microbiota transfer upon co-housing SKG mice with wild-type BALB/c mice, as well as by TLR-4 deficiency.
  
  
  CONCLUSIONS
  The interaction between immunogenetic background and host microbiota leads to an IL-23-dependent loss of mucosal function, triggering ileitis in response to curdlan.
authors.affiliation: University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rehaume
authors.forename: Stanislas
authors.initials: S
authors.lastname: Mondot
authors.forename: Daniel
authors.initials: D
authors.lastname: Aguirre de Cárcer
authors.forename: Jared
authors.initials: J
authors.lastname: Velasco
authors.forename: Helen
authors.initials: H
authors.lastname: Benham
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bowman
authors.forename: Merja
authors.initials: M
authors.lastname: Ruutu
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Mark
authors.initials: M
authors.lastname: Morrison
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D000818:Animals; D020022:Genetic Predisposition to Disease; D005838:Genotype; D007079:Ileitis / Q000235:genetics* / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D064307:Microbiota; D012720:Severity of Illness Index; D025241:Spondylarthritis / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D053759:Interleukin-23; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051746:ZAP-70 Protein-Tyrosine Kinase