Gut microbiota of patients insusceptible to olanzapine-induced fatty liver disease relieves hepatic steatosis in rats.

Olanzapine-induced fatty liver disease continues to pose vital therapeutic challenges in the treatment of psychiatric disorders. In addition, we observed that some patients were less prone to hepatic steatosis induced by olanzapine. Therefore, we aimed to investigate the role and the underlying mechanism of the intestinal flora in olanzapine-mediated hepatic side effects and explore the possible countermeasures. Our results showed that patients with different susceptibilities to olanzapine-induced fatty liver disease had different gut microbial diversity and composition. Furthermore, we performed fecal microbiota treatment (FMT), and confirmed that the gut microbiome of patients less prone to the fatty liver caused by olanzapine exhibited an alleviation against fatty liver disease in rats. In terms of mechanism, we revealed that the cross talk of leptin with the gut-short-chain fatty acid (SCFA)-liver axis play a critical role in olanzapine-related fatty degeneration in liver. These findings propose a promising strategy for overcoming the issues associated with olanzapine application and will hopefully inspire future in-depth research of fecal microbiota-based therapy in olanzapine-induced fatty liver disease.NEW & NOTEWORTHY Patients who were less inclined to have olanzapine-induced fatty liver had different gut microbiota profiles than did those in the susceptible cohort. Lachnospiraceae, Ruminococcaceae, Oscillospiraceae, Butyricicoccaceae, and Christensenellaceae were enriched in patients who were less prone to fatty liver disease caused by olanzapine. Fecal microbiota treatment (FMT) with these fecal samples promoted short-chain fatty acid (SCFA) production, which attenuated the circulating leptin and inhibited FASN and ACC1, thereby suppressing lipid synthesis in the liver, ultimately leading to alleviation of hepatic steatosis.