The gut microbiota mediates the antidepressant effects of imipramine: Evidence from fecal microbiota transplantation and prebiotic inulin intervention

Background Many antidepressants exert their effects by modulating the gut microbiota, but it is unknown if this mechanism extends to the tricyclic antidepressant imipramine. Objective We probed the extent to which specific gut bacterial taxa mediate the antidepressant effects of imipramine. Material and methods Using a chronic unpredictable mild stress (CUMS) mouse model, we administered imipramine, the prebiotic inulin, or their combination, and systematically evaluated depressive-like phenotypes. Gut microbial dynamics were profiled by 16S rRNA sequencing, and fecal microbiota transplantation (FMT) was performed to determine the transmissibility of microbiota-derived antidepressant effects. Immunofluorescence staining was used to quantify brain-derived neurotrophic factor (BDNF) expression and to assess intestinal barrier integrity via ZO-1 and occludin. Results Imipramine treatment significantly increased the relative abundances of putative A. muciniphila and L. reuteri , both of which showed strong correlations with behavioral improvements. Furthermore, FMT from imipramine-treated donors effectively alleviated CUMS-induced depressive-like behaviors, upregulated BDNF expression and restored gut barrier integrity in recipient mice. Co-administration of imipramine and inulin produced synergistic antidepressant effects. Conclusions Imipramine partially exerts its antidepressant activity through microbiota modulation, with putative A. muciniphila and L. reuteri emerging as important mediators. The superior efficacy of the imipramine-inulin combination highlights a promising microbiota-targeted strategy for advancing antidepressant therapy.