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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Available from: Premysl Bercík, Jun 24, 2014
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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). "

    Full-text · Dataset · Feb 2016
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    • "Pregnant C57BL/6J mice received a solution of non-absorbable AB, comprising 5 mg/ml neomycin trisulfate salt hydrate (Sigma–Aldrich, St. Louis, MO, USA; N6386-25G), 5 mg/ml bacitracin (Sigma–Aldrich; B0125-1250KU), 1.25 μg/ml pimaricin (Sigma–Aldrich; P9703-25MG; 5 mg/ml solution in acetic acid used as a stock), and 0.075% (v/v) acetic acid (Nacalai Tesque, Kyoto, Japan; 08885–45) dissolved in drinking water, which was administered by voluntary drinking on E9–E16[5]. Intraperitoneal administration of the non-absorbable AB solution to SPF mice or oral administration of the non-absorbable AB solution to germ-free mice did not induce any apparent effects[5], implying that the non-absorbable AB solution used in this study had minimal collateral effects. Control mice received normal drinking water. "
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    Full-text · Article · Jan 2016 · PLoS ONE
    • "A study using nonabsorbable antimicrobials to deliberately perturb a stable microbiota in mice led to changes in exploratory behavior and brain-derived neurotrophic factor (BDNF) levels in the hippocampus and amygdala. Moreover, behavioral traits of donor mice can be adoptively transferred into adult germ-free mice of a different strain, via the intestinal microbiota (Bercik et al., 2011), suggesting that the intestinal microbiota represents a component input to the brain, influencing behavior and providing an explanation for the frequent coexistence of psychiatric illness in patients with chronic gastrointestinal disorders. Moreover, changes in behavior and brain neurochemistry associated with chronic inflammation can be modulated by administration of the probiotic Bifidobacterium longum str. "
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