Lactobacillus reuteri ATG-F4 alleviates chronic stress-induced anhedonia through modulating prefrontal serotonergic system

초록

Mental health is influenced by the gut-brain axis. For example, gut dysbiosis is observed in patients with major depressive disorder (MDD). It has also been reported that gut microbial changes by fecal microbiota transplantation or probiotics treatment modulated depressive symptoms. However, it is still unclear how gut dysbiosis induces mental dysfunction and how the correction of gut microbiota recovers neuropsychiatric disorders. Our previous study identified that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induces neurometabolic alterations in healthy mice. However, it remains unexplored whether F4 can exert its therapeutic effects on depressive-like behaviors by influencing the central nervous system. In this study, we employed chronic unpredictable stress (CUS) to bring about anhedonia, one of main MDD symptoms which is the inability to feel pleasure to verify the therapeutic effect of F4. We found that chronic F4 consumption relieves CUS-induced anhedonic behaviors accompanied by biochemical changes within the gut, serum, and brain. Notably, 5-HT level in the brain was elevated in the CUS group, and the elevation was significantly relieved by F4 consumption. Further, the expression level of Htr1a, one of the 5-HT receptor subtypes, from stressed mice was increased in the medial prefrontal cortex (mPFC); and it was restored to the level of stress-naïve by supplementation of F4. Lastly, we employed the AAV-shRNA system to recapitulate the anti-anhedonic effect of Htr1a downregulation in the mPFC in CUS mice. As a result, Htr1a knockdown in the mPFC reversed CUS-induced anhedonic behaviors. Together, these results shed light on the F4 as a potential therapeutic method to treat at least partial depressive symptoms and show the serotonergic contribution involved in relieving CUS-induced depressive-like behaviors by this bacterium.