Abstract
Current antidepressants do not confer a clear advantage in children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on adult MDD, and gut microbiomes are significantly associated with MDD via the microbiota-gut-brain axis. However, few studies have investigated possible associations between inosine and gut microbiota in adolescents with MDD. The current study investigated the potential antidepressant effects of inosine in adolescent male C57BL/6 mice. After 4 weeks of chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by body weight, the sucrose preference test (SPT), open field test, and the elevated plus maze (EPM). The microbiota compositions of feces were determined by 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors in adolescent mice including SPT and EPM results. Fecal microbial composition differed in the CON+saline, CUMS+saline, and CUMS+inosine groups, which were characterized by 126 discriminative amplicon sequence variants belonging to Bacteroidetes and Firmicute at the phylum level and Muribaculaceae and Lachnospiraceae at the family level. Muribaculaceae was positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine might affect gut microbiota through carbohydrate metabolism and lipid metabolism pathways. The results of the study indicated that inosine improved depressive and anxiety-like behaviors in adolescent mice, in conjunction with the alteration of fecal microbial composition. Our findings may provide a novel perspective on the antidepressant effects of inosine in children and adolescents.
Highlights
Major depressive disorder (MDD) is becoming a common mental health problem in young people, especially those aged 10–24 years (Mokdad et al, 2016)
In the chronic unpredictable mild stress (CUMS)+inosine group, inosine ameliorated the reductions in sucrose preference (p = 0.04) and time spent in the open arm (p = 0.029) and increased time spent in the closed arm (p = 0.038) compared with the CUMS+saline group
Inosine could significantly ameliorate depressive and anxiety-like behaviors and was associated with partial restoration of gut microbiota dysbiosis induced by CUMS stimulations
Summary
Major depressive disorder (MDD) is becoming a common mental health problem in young people, especially those aged 10–24 years (Mokdad et al, 2016). Inosine is an endogenous purine nucleoside generated by adenosine deaminase (Junqueira et al, 2017) that showed antidepressant effects in adult depressive rodent models (Kaster et al, 2013; Muto et al, 2014). It reduced immobility time in normal adolescent animals without stress stimuli, which activated extracellular signal-regulated kinases and cyclic AMP response element binding protein signaling pathways (Yuan et al, 2018). Collective studies have demonstrated that inosine has marked antidepressant-like effects in adult animals, but no corresponding evidence has been generated in depressive adolescent animals
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