The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice

The Farncombe Family Digestive Health Institute, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
Gastroenterology (Impact Factor: 16.72). 04/2011; 141(2):599-609. DOI: 10.1053/j.gastro.2011.04.052


Background & AimsAlterations 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.ResultsAdministration 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.

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    • "Experimentally , FMT allows for prospective evaluation of the effects of complex microbial populations on a model system. When performed using axenic mice, there is little difficulty in constitution of recipients with the microbes of interest, and such methods have been applied in seminal studies on the influence of the microbiota on the gut–brain axis (Bercik et al. 2011; Collins et al. 2013), metabolic rate and adiposity (Backhed et al. 2004; Turnbaugh et al. 2006), and determinants of host fitness (Rawls et al. 2006; Seedorf et al. 2014). The use of FMT in GF mice also allows for a period of life in which mice are lacking the microbial stimulation necessary for normal ontogeny of the immune system . "
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    • "This could yield true insights into the real relationships among gut microbiota, brain development and behavior. In addition, long-term high-dose antibiotic administration might impair the gut mucosal barrier and disturb normal gut homeostasis, resulting in a decline in body weight, diarrhea and anxiety-like behavior (Bercik et al., 2011; Ling et al., 2015). However, potential changes in the gut mucosa and behavior were not evaluated. "
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    • "By treating only the intestine, it is possible to treat central nervous system pathology. More direct evidence of this derives from two independent studies where transplantation of gut contents from one animal to another was able to induce behavioral changes repeatedly (Bercik et al. 2011; Hsiao et al. 2013). Such results involving behavior and gut status hold for mouse models even in strict germ-free environments where commensal bacteria can be more tightly controlled (Nishino et al. 2013). "
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