Akkermansia muciniphila Alleviates Olanzapine-Induced Hepatic Steatosis via the Gut Microbiota-IGFBP2/APOA1-Liver Axis.

Olanzapine is associated with a high risk of hepatic steatosis as a commonly used atypical antipsychotic. In this study, we observed differential susceptibility to olanzapine-induced fatty liver disease in both rats and patients. Notably, patients with olanzapine-induced liver damage exhibited an altered gut microbiota composition, with Akkermansia muciniphila showing the most pronounced alteration. To explore its therapeutic potential, we administered A. muciniphila to olanzapine-treated rats, which significantly reduced hepatic lipid accumulation and liver injury. Gut microbiome analysis revealed significant alterations in microbial diversity and composition following A. muciniphila treatment. Transcriptomic analysis further identified differentially expressed genes in the liver, highlighting the involvement of IGFBP2 and APOA1 in the protective effects of A. muciniphila . Functional validation demonstrated that overexpression of IGFBP2 and APOA1 alleviated olanzapine-induced hepatic steatosis in both cellular and animal models. These findings suggest that A. muciniphila exerts hepatoprotective effects via the gut microbiota-IGFBP2/APOA1-liver axis, offering a potential microbiota-targeted strategy to mitigate olanzapine-induced metabolic dysfunction.