title: Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
abstract: OBJECTIVE
  Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms.
  
  
  METHODS
  AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain.
  
  
  RESULTS
  T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy.
  
  
  CONCLUSIONS
  Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.
authors.affiliation: Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. bercikp@mcmaster.ca
authors.forename: Premysl
authors.initials: P
authors.lastname: Bercik
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.forename: Jane A
authors.initials: JA
authors.lastname: Foster
authors.forename: Joseph
authors.initials: J
authors.lastname: Macri
authors.forename: Murray
authors.initials: M
authors.lastname: Potter
authors.forename: Xiaxing
authors.initials: X
authors.lastname: Huang
authors.forename: Paul
authors.initials: P
authors.lastname: Malinowski
authors.forename: Wendy
authors.initials: W
authors.lastname: Jackson
authors.forename: Patricia
authors.initials: P
authors.lastname: Blennerhassett
authors.forename: Karen A
authors.initials: KA
authors.lastname: Neufeld
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
authors.forename: Irene
authors.initials: I
authors.lastname: Corthesy-Theulaz
authors.forename: Christine
authors.initials: C
authors.lastname: Cherbut
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Bergonzelli
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Collins
mesh_terms: D000818:Animals; D001007:Anxiety / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood; D006624:Hippocampus / Q000502:physiology*; D007737:Kynurenine / Q000097:blood; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D014257:Trichuriasis / Q000276:immunology / Q000503:physiopathology*; D014258:Trichuris; D014364:Tryptophan / Q000097:blood; D014628:Vagotomy; D014630:Vagus Nerve / Q000276:immunology / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D012333:RNA, Messenger; D007737:Kynurenine; D014364:Tryptophan