Akkermansia muciniphila-derived SCFAs improve the depression-like behaviors of mice by inhibiting neuroinflammation

This study was conducted to explore the effects of Akkermansia muciniphila (A. muciniphila) on depression and its underlying molecular mechanisms. Using data from our previous work, we found that the relative abundance of A. muciniphila might be lower in depressed subjects compared to control subjects. Then, using chronic restraint stress (CRS) depression model, we found that mice with depression-like behaviors had significantly disordered gut microbiota, lower short-chain fatty acids (SCFAs) levels (in both feces and serum) and higher inflammation levels in the hippocampus. After A. muciniphila intervention, depression-like behaviors were significantly improved, along with the improved gut microbiota compositions in mice with depression-like behaviors. Meanwhile, the increased SCFAs levels (in both feces and serum), increased free fatty acid receptors 2 (FFAR2) in hippocampus and decreased inflammation levels (in hippocampus) were observed in mice with depression-like behaviors receiving A. muciniphila. We also found that FFAR2 antagonist could counteract the antidepressant effects of A. muciniphila. Our results suggested that A. muciniphila could improve depression-like behaviors by regulating inflammation levels via gut microbiota-derived SCFAs, and SCFAs-FFAR2-NF-κB-NLRP3-IL-6/IL-1β pathway might be a potential pathway in this process.