Extracellular Vesicles from Gram-positive and Gram-negative Probiotics Remediate Stress-Induced Depressive Behavior in Mice

Chronic stress causes maladaptive changes in the brain that lead to depressive behavior. In the present study, we investigate whether chronic stress alters gut microbiota and whether specific mediators of probiotics remedies stress-induced maladaptive changes in the brain. Mice treated with daily 2-h restraint for 14 days (CRST) exhibit depressive-like behavior. Sequence readings of 16S rRNA genes prepared from fecal samples taken from CRST-treated mice suggest that chronic stress induces gut microbiota changes that are pronounced 14 days after the last restraint, relative to those that occur in the 14-day stress phase. The genus Lactobacillus is one such microbiota substantially changed following chronic stress. In contrast, post-stress treatment with extracellular vesicles (EVs) derived from the Gram-positive probiotic Lactobacillus plantarum are sufficient to ameliorate stress-induced depressive-like behavior. Interestingly, EVs from the Gram-positive probiotic Bacillus subtilis and EVs from the Gram-negative probiotic Akkermansia muciniphila also produce anti-depressive-like effects. While chronic stress decreases expression of MeCP2, Sirt1, and/or neurotrophic factors in the hippocampus, EVs from the selected probiotics differentially restore stress-induced changes of these factors. These results suggest that chronic stress produces persistent changes in gut microbiota composition, whereas EVs of certain probiotics can be used for treatment of stress-induced maladaptive changes.