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.

Download full-text


Available from: Premysl Bercík, Jun 24, 2014
  • Source
    • "The body of work demonstrating the systemic role of the microbiome, especially in neural development and function, is extensive. Disruption or absence of the microbiome impairs behavior and its development, leading to increased exploration, decreased apprehension, and impaired social behavior (Bercik et al., 2011; Desbonnet et al., 2014). Conversely, chronic administration of Lactobacillus rhamnosus (JB-1) alters GABAR expression in the brain, and reduces anxiety-like and depressive behavior (Bravo et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Given the lasting impact of psychological distress on behavior, along with the role of the microbiome in neurobehavioral development, we sought to examine the relationship between the microbiota and stress-induced behavioral deficits. Methods: Male C57BL/6 mice exposed to chronic social defeat were subjected to behavioral analysis and profiling of the intestinal microbiome. Mice were also analyzed for phenotypic and functional immune changes. A computational approach on 16S rRNA marker gene sequences was used to predict functional changes in the metagenome as a consequence of structural shifts in the microbiota. Results: Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community, along with distinct shifts at the level of operational taxonomic units (OTU) across phyla. The degree of deficits in social, but not exploratory behavior was correlated with group differences between the microbial community profile. In silico analysis predicted a shift in the functional profile of the microbiome: defeated mice exhibited reduced functional diversity and a lower prevalence of pathways involved in the synthesis and metabolism of neurotransmitter precursors and short-chain fatty acids. Defeated mice also exhibited sustained alterations in dendritic cell activation, and transiently elevated levels of IL-10+ T regulatory cells that were suppressed over time. Conclusions: This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses and complex OTU-level shifts in the microbiota. It is thus suggested that a dysbiotic state, along with specific changes in microbial markers, may predict the onset of adverse neurocognitive deficits commonly observed following exposure to severe stressors. The data also predict novel pathways that might underlie microbiota-mediated effects on brain and behavior, thus presenting targets for investigations into mechanisms and potential therapy.
    Psychoneuroendocrinology 10/2015; 63:217-227. DOI:10.1016/j.psyneuen.2015.10.001 · 4.94 Impact Factor
  • Source
    • "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 . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eukaryotic organisms are colonized by rich and dynamic communities of microbes, both internally (e.g., in the gastrointestinal and respiratory tracts) and externally (e.g., on skin and external mucosal surfaces). The vast majority of bacterial microbes reside in the lower gastrointestinal (GI) tract, and it is estimated that the gut of a healthy human is home to some 100 trillion bacteria, roughly an order of magnitude greater than the number of host somatic cells. The development of culture-independent methods to characterize the gut microbiota (GM) has spurred a renewed interest in its role in host health and disease. Indeed, associations have been identified between various changes in the composition of the GM and an extensive list of diseases, both enteric and systemic. Animal models provide a means whereby causal relationships between characteristic differences in the GM and diseases or conditions can be formally tested using genetically identical animals in highly controlled environments. Clearly, the GM and its interactions with the host and myriad environmental factors are exceedingly complex, and it is rare that a single microbial taxon associates with, much less causes, a phenotype with perfect sensitivity and specificity. Moreover, while the exact numbers are the subject of debate, it is well recognized that only a minority of gut bacteria can be successfully cultured ex vivo. Thus, to perform studies investigating causal roles of the GM in animal model phenotypes, researchers need clever techniques to experimentally manipulate the GM of animals, and several ingenious methods of doing so have been developed, each providing its own type of information and with its own set of advantages and drawbacks. The current review will focus on the various means of experimentally manipulating the GM of research animals, drawing attention to the factors that would aid a researcher in selecting an experimental approach, and with an emphasis on mice and rats, the primary model species used to evaluate the contribution of the GM to a disease phenotype. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email:
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 08/2015; 56(2). DOI:10.1093/ilar/ilv021 · 2.39 Impact Factor
  • Source
    • "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. "

    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.07.013 · 5.89 Impact Factor
Show more