Akkermansia muciniphila ameliorates olanzapine-induced metabolic-associated fatty liver disease via PGRMC1/SIRT1/FOXO1 signaling pathway

Long-term use of Olanzapine (OLZ), a primary medication for schizophrenia, increases the risk of Metabolic-dysfunction associated fatty liver disease (MAFLD) in patients. MAFLD-driven rapid liver disease progression significantly contributes to reduced quality of life and decreased life expectancy in patients with schizophrenia. While there are several treatments available for MAFLD, their efficacy is limited and some have significant side effects. Consequently, there is an urgent need to develop new strategies to prevent and treat OLZ-induced MAFLD and enhance the prognosis of schizophrenia patients. OLZ may cause dysbiosis of the intestinal flora and disrupt the gutliver axis, potentially exacerbating MAFLD development. However, probiotics and prebiotics have been shown to alleviate gastrointestinal discomfort induced by antipsychotics. Therefore, a thorough understanding of the gut microbiome's function and targeted interventions are crucial for improving outcomes in OLZ-induced MAFLD. Our preliminary findings suggest that supplementation with the probiotic B- GOS increased levels of Akkermansia muciniphila (AKK) and partially alleviated OLZ-induced lipid metabolism disorders. AKK is potentially lipid-lowering, anti-inflammatory, and insulin resistance-improving; however, their effectiveness in alleviating OLZ-induced MAFLD has not been fully validated. Additionally, the PGRMC1/SIRT1/FOXO1 pathway is crucial in regulating glucose homeostasis, insulin sensitivity, and lipid metabolism, with notable interactions between this pathway and the gut microbiome. To date, no study has clarified the potential association between the AKK-PGRMC1/SIRT1/FOXO1 pathway and the OLZinduced MAFLD triad.