The Role of Microbiota Remodeling in the Antidepressant Effects of Fluoxetine

Background:  Bidirectional interaction between gut and brain is associated with the maintenance of host nervous system health. Considerable progress has been made in understanding how microbiota-related gut signals affect central nervous system, however, how nervous diseases leading to dysbiosis is not well recognized. Method:  We investigated changes in gut microbiota in a depression model induced by chronic unpredicted mild stress (CUMS) and a restoration model by applying the classic antidepressant drug fluoxetine. Behavior tests were performed to evaluate the depression and anxiety-like behaviors, 16S rRNA amplicon sequencing was used to analyze the gut microbiota profiles.   Findings:  In CUMS-induced depression model, fluoxetine showed significant antidepressant and mild anti-anxiety effects in mice. Consistent with behavior test, in gut microbiota, CUMS led to low bacterial diversity, simpler bacterial network, and altered microbiota. Most intriguingly, CUMS led to increased abundance of pathogens, such as Escherichia/Shigella, and conditional pathogens, such as Enterococcus, Vagococcus, and Aerococcus. However, these changes were attenuated by fluoxetine directly and indirectly. Furthermore, correlations analysis indicated strong correlations between gut microbiota and anxiety- and depression-like behaviors. Interpretation: This study reveals that fluoxetine leads to restoration of dysbiosis induced by stress stimulation. It suggests that antidepressant effects of fluoxetine in CUMS model may be mediated, in part, by the restoration of the gut microbiota. Altogether, our finding uncover a novel role of nervous disorders on gut microbiota. Funding Statement:  This study was supported by the National Natural Science Foundation of China (grant No. 81730016).   Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All procedures carried out in accordance with the recommendations of 'the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.' The protocol was approved by the Animal Research Ethics Board of The Fourth Military Medical University (Approval number: 20170206).