Genistein improves depression-like behavior in rats by regulating intestinal flora and altering glutamate gene expression.

Depression is a mental disorder, and genistein is known to have antidepressant effects, but its mechanism of action is still unclear. Here, the mechanism of genistein improving depression based on gut microbiota was explored using classic behavioral indicators of depression combined with genomic technology. The behavioral evaluation showed that rats gavaged with 20-40 mg/kg genistein showed an increase in body weight, glucose preference, absenteeism score, body temperature, and 5-hydroxytryptamine (5-HT) content, while a decrease in adrenocorticotropic hormone (ACTH) and corticosterone (CORT) content compared to the depression rat model group, but there was no significant difference compared to the positive control (fluoxetine). The results of high-throughput sequencing showed that genistein increased the relative abundance of Firmicutes and Actinobacteriota and decreased the relative abundance of Bacteroidota at the phylum level. At the genus level, the abundance of , a short-chain fatty acid producing bacterium, was increased. Furthermore, metagenome results revealed that the antidepressant effect of genistein can be achieved by promoting glutamate metabolism, increasing glutamic acid decarboxylase (GAD) expression levels, promoting γ-aminobutyric acid (GABA) synthesis, and indirectly increasing 5-HT levels.