Akkermansia muciniphila gavage alleviates depression-like behaviors in female A53T α-synuclein transgenic mice

Parkinson's disease (PD) is characterized not only by progressive motor deficits but also by non-motor symptoms, such as depression, which often emerge during the prodromal stage and significantly impair quality of life. While Akkermansia muciniphila (AKK) has shown potential in modulating neuroinflammation, its specific role and underlying mechanisms in alleviating PD-associated non-motor symptoms remain unclear. In this study, we investigated the effects of AKK intervention in 16-month-old female A53T α-synuclein (α-syn) transgenic mice. Behavioral assessments revealed that oral administration of AKK significantly ameliorated depression-like behaviors, evidenced by reduced immobility in the forced swim test and increased sucrose preference, without affecting motor function, spatial memory, or gastrointestinal motility. Mechanistically, the intervention exhibited genotype-specific effects: AKK significantly increased plasma 5-HT levels in C57 mice. This increase was associated with an enrichment of Lactobacillus taiwanensis and metabolic pathways favoring peripheral tryptophan conversion. Conversely, in A53T mice, the treatment specifically elevated hippocampal 5-HT levels without altering plasma concentrations. This central effect correlated with distinct microbial remodeling, characterized by the enrichment of butyrate/propionate-producing Lachnospiraceae and the activation of purine degradation. Collectively, these findings provide novel mechanistic insights into the therapeutic potential of AKK for managing non-motor symptoms in PD. While limited to a female cohort, our results suggest that AKK ameliorates depression-like behaviors in PD through sex-specific remodeling of the gut microbiome and serotonergic signaling.