Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
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.
Bercik
Premysl
P
Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. bercikp@mcmaster.ca
Verdu
Elena F
EF
Foster
Jane A
JA
Macri
Joseph
J
Potter
Murray
M
Huang
Xiaxing
X
Malinowski
Paul
P
Jackson
Wendy
W
Blennerhassett
Patricia
P
Neufeld
Karen A
KA
Lu
Jun
J
Khan
Waliul I
WI
Corthesy-Theulaz
Irene
I
Cherbut
Christine
C
Bergonzelli
Gabriela E
GE
Collins
Stephen M
SM
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
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D012333:RNA, Messenger; D007737:Kynurenine; D014364:Tryptophan