Psychopharmacology · 2026
The gut microbiota mediates the antidepressant effects of imipramine: Evidence from fecal microbiota transplantation and prebiotic inulin intervention.
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Chen Yonglan, Lan Yuxin, Yi Jingyan, Qi Xiaoyi, Liu Li, Liu Sha, Xu Xinxin, Liu Huan, He Yufeng, He Bing, Ma Xiaochi, Lü Muhan, Liang Sicheng
Аннотация
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.
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.