Extracellular Vesicles Derived from Lactobacillus plantarum Increase BDNF Expression in Cultured Hippocampal Neurons and Produce Antidepressant-like Effects in Mice.

Gut microbiota play a role in regulating mental disorders, but the mechanism by which gut microbiota regulate brain function remains unclear. Gram negative and positive gut bacteria release membrane-derived extracellular vesicles (EVs), which function in microbiota-host intercellular communication. In the present study, we investigated whether Lactobacillus plantarum derived EVs (L-EVs) could have a role in regulating neuronal function and stress-induced depressive-like behaviors. HT22 cells treated with the stress hormone glucocorticoid (GC; corticosterone) had reduced expression of Bdnf and Sirt1, whereas L-EV treatment reversed GC-induced decreased expression of Bdnf and Sirt1. The siRNA-mediated knockdown of Sirt1 in HT22 cells decreased Bdnf4, a splicing variant of Bdnf, and Creb expression, suggesting that Sirt1 plays a role in L-EV-induced increase of BDNF and CREB expression. Mice exposed to restraint for 2-h daily for 14 days (CRST) exhibited depressive-like behaviors, and these CRST-treated mice had reduced expression of Bdnf and Nt4/5 in the hippocampus. In contrast, L-EV injection prior to each restraint treatment blocked the reduced expression of Bdnf and Nt4/5, and stress-induced depressive-like behaviors. Furthermore, L-EV treatment in CRST-treated mice also rescued the reduced expression of Bdnf, and blocked stress-induced depressive-like behaviors. These results suggest that Lactobacillus derived EVs can change the expression of neurotropic factors in the hippocampus and afford antidepressant-like effects in mice with stress-induced depression.