Abstract
BackgroundThe brain–gut–microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion.MethodsThe fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined.ResultsThe ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes.ConclusionsThese findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain–gut–microbiota axis participates in the pathogenesis of depression via the vagus nerve.
Highlights
The brain–gut–microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression
We reported that microbiome depletion via antibiotic treatment contributed to resilience to anhedonia in mice subjected to chronic social defeat stress (CSDS) [15], suggesting that the brain–gut– microbiota axis plays a role in resilience versus susceptibility to CSDS
Antibiotic-induced microbiota depletion in the host is essential for the development of fecal microbiota transplantation (FMT)-induced behavioral and biochemical changes in recipient mice. 16S rRNA analysis suggested that among antibiotic-treated mice, L. intestinalis and L. reuteri counts were higher in the FMT group from CSDS-susceptible mice than in the FMT group from control mice, suggesting that these two bacteria may play a role in the anhedonialike phenotype, inflammation, and reduction of synaptic protein expression in the prefrontal cortex (PFC)
Summary
The brain–gut–microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. Instead of germ-free mice, antibiotic cocktail-induced microbiome depletion has been used to investigate the role of the gastrointestinal microbiota in pathological conditions such as Parkinson’s disease and depression [13, 15, 22,23,24,25]. The transplantation of fecal microbes from mice with depression into germ-free mice resulted in depression-like behaviors compared with the effects of the transplantation of fecal microbes obtained from control animals [9]. It appears that the brain–gut–microbiota axis plays a key role in depression- and anhedonia-like phenotypes in rodents. The precise mechanisms underlying fecal microbiota transplantation (FMT)-induced behavioral abnormalities in rodents treated with an antibiotic cocktail remain unknown
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