Raspberry Ketone Prevents LPS‐Induced Depression‐Like Behaviors in Mice by Inhibiting TLR‐4/NF‐κB Signaling Pathway via the Gut‐Brain Axis

Scope Depression, a prevalent mental disorder, has significantly impacted the lives of 350 million people, yet it holds promise for amelioration through food‐derived phenolics. Raspberries, renowned globally for their delectable flavor, harbor a phenolic compound known as raspberry ketone (RK). However, the impact of RK on depressive symptoms remains ambiguous. This study aims to investigate the impact of RK on lipopolysaccharide (LPS)‐induced depressed mice and elucidates its potential mechanisms, focusing on the gut‐brain axis. Methods and results Through behavioral tests, RK exerts a notable preventive effect on LPS‐induced depression‐like behaviors in mice. RK proves capable of attenuating gut inflammation, repairing gut barrier impairment, modulating the composition of the gut microbiome ( Muribaculaceae , Streptococcus , Lachnospiraceae , and Akkermansia ), and promoting the production of short‐chain fatty acids. Furthermore, RK alleviates neuroinflammation by suppressing the TLR‐4/NF‐κB pathway and bolsters synaptic function by elevating levels of neurotrophic factors and synapse‐associated proteins. Conclusion The current study provides compelling evidence that RK effectively inhibits the TLR‐4/NF‐κB pathway via the gut‐brain axis, leading to the improvement of LPS‐induced depression‐like behaviors in mice. This study addresses the research gap in understanding the antidepressant effects of RK and illuminates the potential of utilizing RK as a functional food for preventing depression.