The impact of inosine on chronic unpredictable mild stress-induced depressive and anxiety-like behaviors with the alteration of gut microbiota

Current antidepressants do not seem to offer a clear advantage for children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on MDD, and gut microbiomes are significantly associated with MDD through the microbiota-gut-brain axis. However, the possible association between inosine and gut microbiota was rarely explored in MDD. In this study, we investigated the potential antidepressant effects of inosine by male C57BL/6 mice. After 4 weeks chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by the body weight (BW), sucrose preference test (SPT), open field test (OFT) and elevated plus maze (EPM), and the microbiota compositions of feces were determined by using 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors including SPT, OFT and EPM. Meanwhile, we found that the fecal microbial composition was prominently different among CON+Saline, CUMS+Saline and CUMS+Inosine groups, which were characterized by 126 discriminative amplicon sequence variants (ASVs) belonging to Bacteroidetes and Firmicute at the phylum level, and Muribaculaceae and Lachnospiraceae at the family level. Additionally, the family Muribaculaceae appeared to be positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine possibly affected gut microbiota through carbohydrate metabolism and lipid metabolism pathways. Taken together, our study revealed that inosine improved depressive and anxiety-like behaviors with the alteration of microbial composition, which might provide a novel perspective on the antidepressant effects of inosine.