Akkermansia Muciniphila vs. Fluoxetine: Amelioration of Depression-like Behaviors and Cognitive Dysfunction Through Distinct Neurobiological Mechanisms

To date, no research has directly compared the potential of Akkermansia muciniphila (AKK) and the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) in alleviating depression-like behaviors and thier neural mechanisms. This study addressed this gap by examining the effects of chronic mild stress (CMS) on depression-like behavior and recognition memory deficits in rats. The results showed that both AKK and FLX reduced CMS-induced depression-like behaviors and restored recognition memory in a rat model. Both AKK and FLX increased serum 5-HT levels; however, only AKK reduced corticosterone (CORT) levels. Notably, AKK increased c-Fos expression in cognition-related regions of the medial prefrontal cortex (mPFC, such as the Cg1, PrL, and IL), emotion-related regions of the amygdala (BLA and CeA), and spatial learning-associated regions of the hippocampus (CA1, CA2, CA3, and DG). In contrast, FLX increased c-Fos expression only in the Cg1 and PrL. AKK significantly reduced IL-1β expression across all target brain regions, whereas FLX only reduced IL-1β in the CeA. Regarding apoptotic and neuroplasticity-related markers, AKK decreased p-ERK expression in all examined regions, while FLX increased p-ERK expression in the Cg1, PrL, IL, BLA, CA1, and DG. Both AKK and FLX reduced Caspase-3 expression in all target regions. Overall, AKK demonstrated a broader and more effective impact on CORT and 5-HT regulation, c-Fos activation, and IL-1β and p-ERK modulation. This study highlights the therapeutic potential of live A. muciniphila (administered for 28 days at 5.10 × 108 CFU/day) for treating depression-like behaviors and cognitive dysfunction in the neural mechanisms. These findings provide valuable insights for future clinical applications.