Therapeutic effects of pasteurized Akkermansia muciniphila on metabolic and behavioral dysregulation in a zebrafish model of type 2 diabetes mellitus comorbid with depression

Type 2 diabetes mellitus (T2DM) and depression (DEP) frequently co-occur, with growing evidence implicating the gut microbiota in both conditions. In this study, we investigated the therapeutic potential of pasteurized Akkermansia muciniphila (AKK) in a zebrafish model of T2DM comorbid with DEP, established through a high-sugar, high-fat diet and reserpine exposure. Zebrafish treated with pasteurized AKK exhibited significant improvements in metabolic parameters, including reduced fasting blood glucose, body mass index, and improved lipid profiles. AKK also restored gut microbial diversity, increasing beneficial bacteria such as Cetobacterium and reducing harmful bacteria like Aerococcus . Importantly, AKK treatment alleviated anxiety-like behaviors, improved social interactions, and enhanced monoamine neurotransmitter levels (5-HT and NE), likely through modulation of the BDNF-TrkB signaling pathway and reduction of pro-inflammatory cytokines (IL-6, TNF-α). These findings suggest that pasteurized AKK offers a novel microbiota-based intervention for managing the metabolic and neuropsychiatric dysfunctions associated with T2DM and DEP comorbidity. • Pasteurized AKK improves metabolic health in zebrafish with T2DM + DEP • Restores gut microbiota diversity and increases beneficial bacteria like Cetobacterium • Alleviates anxiety-like behavior and social deficits via the gut-brain axis • Activates BDNF-TrkB signaling, reduces inflammation, and enhances neuroprotection