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

Article (PDF Available)inGastroenterology 141(2):599-609 · April 2011with876 Reads
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.


    • "Interestingly, BDNF shows a close relationship to microbiota. Experimental studies demonstrated that hippocampal expression of BDNF was reduced by modulating the balance of microbiota [30, 32]. Furthermore, BDNF expression in mucosal epithelial and lamina propria cells was reported to be lower in slow-transit constipation patients [33]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Late defecation was recently reported to be associated with worse clinical outcomes in critically ill patients. However, more research is needed to examine the causes and clinical significance of late defecation. The objectives of this study were to investigate the risk factors for late defecation and its association with the outcomes of intensive care unit (ICU) patients. Methods: Patients in an ICU for ≥7 days between January and December 2011 were retrospectively assessed. Based on the time between admission and the first defecation, they were assigned to early (<6 days; n = 186) or late (≥6 days; n = 96) defecation groups. Changes in clinical variables between admission and ICU day 7 were assessed to investigate the effects of late defecation. The clinical outcomes were ICU mortality, length of ICU stay, and length of mechanical ventilation. Results: Late enteral nutrition (odds ratio (OR) 3.42; 95 % confidence interval (CI) 1.88-6.22; P < 0.001), sedatives (OR 3.07; 95 % CI 1.71-5.52; P < 0.001), and surgery (OR 1.86; 95 % CI 1.01-3.42; P = 0.047) were the independent risk factors for late defecation. The median (interquartile) changes in body temperature (0.3 [-0.4 to 1.0] vs 0.7 [0.1 to 1.5] °C; P = 0.004), serum C-reactive protein concentration (1.6 [-0.5 to 6.6] vs 3.5 [0.7 to 8.5] mg/dL; P = 0.035), and Sequential Organ Failure Assessment score (-1 [-2 to 1] vs 0 [-1 to 2]; P = 0.008) between admission and ICU day 7 were significantly greater in the late defecation group than in the early defecation group. ICU stay was significantly longer in the late defecation group (12 [9 to 19] vs 16 [10 to 23] days; P = 0.021), whereas ICU mortality and the length of mechanical ventilation were similar in both groups. Conclusions: Late enteral nutrition, sedatives, and surgery were independent the risk factors for late defecation in critically ill patients. Late defecation was associated with prolonged ICU stay.
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    • "Notwithstanding the caveats of antibiotic use described above, antibiotic depletion when combined with fecal transfer a useful tool for exploring the effect of distinct gut microbiota compositions on the gut brain axis. The use of gut microbiota transfer into germ-free animals has been used previously to suggest that distinct behavioral traits of mouse strains may be transferred to germ free mice by the fecal microbiota [32] . However, the experimental use of germ-free mice has limitations. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction The microbiota-gut-brain axis is a term that is commonly used and covers a broad set of functions and interactions between the gut microbiome, endocrine, immune and nervous systems and the brain. The field is not much more than a decade old and so large holes exist in our knowledge. Discussion At first sight it appears gut microbes are largely responsible for the development, maturation and adult function of the enteric nervous system as well as the blood brain barrier, microglia and many aspects of the central nervous system structure and function. Given the state of the art in this exploding field and the hopes, as well as the skepticism, which have been engendered by its popular appeal, we explore recent examples of evidence in rodents and data derived from studies in humans, which offer insights as to pathways involved. Communication between gut and brain depends on both humoral and nervous connections. Since these are bi-directional and occur through complex communication pathways, it is perhaps not surprising that while striking observations have been reported, they have often either not yet been reproduced or their replication by others has not been successful. Conclusions We offer critical and cautionary commentary on the available evidence, and identify gaps in our knowledge that need to be filled so as to achieve translation, where possible, into beneficial application in the clinical setting.
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    • "Gut microbiota transplantation to GF or antibiotictreated animals is a powerful approach to verify causality of gut microbiota in a broad range of diseases (Bercik et al., 2011; Goodrich et al., 2014; Natividad et al., 2015). However, due to the need for strict containment of each human donor microbiota in separate isolators, it is a challenge for many studies to reach a representative amount of donors. "
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