Gut microbiota-SCFAs-brain axis associated with the antidepressant activity of berberine in CUMS rats

The anti-depressant effect of berberine (BBR) has been widely reported. However, the underlying mechanism remains unclear. The microbiota-gut-brain (MGB) axis plays a key role in the pathogenesis of depression. Therefore, we aimed to explore the anti-depressant mechanisms of BBR involving the association of the gut microbiota, neurotransmitters, BDNF, and SCFAs in chronic unpredictable mild stress (CUMS)-induced depressive rats.The antidepressant effects of BBR were detected by open-field test, 1 % sucrose preference test and body weight test in CUMS-induced depressive rats. 16S rDNA sequencing was performed to identify the change of gut microbiota. The concentrations of fecal SCFAs were analyzed by GC-MS targeted metabolomics. At the same time, neurotransmitters and BDNF expression were measured by enzyme linked immunosorbent assay (ELISA).BBR improved depression-like behaviors in CUMS rats by increasing the expression of serotonin (5-HT), norepinephrine (NE), dopamine (DA), and BDNF in the hippocampus. BBR regulates Firmicutes, Bacteroidetes, and Lachnospiraceae in depressive rats, resulting in the alteration of the synthesis and metabolism of SCFAs, including acetic, propanoic, and isovaleric acids.Direct evidence that BBR improves depressive behaviors via gut microbiota-SCFAs-brain axis is lacking, and only male rats were investigated in the present study.The anti-depressant mechanism of BBR is related to the regulation of the MGB axis via modulating the gut microbiota-SCFAs-monoamine neurotransmitters/BDNF.