title: The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
abstract: OBJECTIVE
  Alterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice.
  
  
  METHODS
  Specific pathogen-free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Administration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior.
  
  
  CONCLUSIONS
  The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.
authors.affiliation: The Farncombe Family Digestive Health Institute, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. bercikp@mcmaster.ca
authors.forename: Premysl
authors.initials: P
authors.lastname: Bercik
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Denou
authors.forename: Josh
authors.initials: J
authors.lastname: Collins
authors.forename: Wendy
authors.initials: W
authors.lastname: Jackson
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jury
authors.forename: Yikang
authors.initials: Y
authors.lastname: Deng
authors.forename: Patricia
authors.initials: P
authors.lastname: Blennerhassett
authors.forename: Joseph
authors.initials: J
authors.lastname: Macri
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Collins
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D016207:Cytokines / Q000378:metabolism; D005856:Germ-Free Life; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D013562:Sympathectomy; D014628:Vagotomy
chemical_list: D000900:Anti-Bacterial Agents; D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D009195:Peroxidase