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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1550015
This article is part of the Research Topic Harnessing the Medicinal Potential of Gut Microbiota for Human Health View all 3 articles
Akkermansia muciniphila ameliorates olanzapine-induced metabolic dysfunction-associated steatotic liver disease via PGRMC1/SIRT1/FOXO1 signaling pathway
Provisionally accepted
Hui Chen 
Ting Cao 
Chenquan Lin Shimeng Jiao Yifang He Zhenyu Zhu Qiujin Guo 
Renrong Wu 
HuaLin Cai *
Bi-kui ZHANG *- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
Akkermansia muciniphila (AKK), classified as "lean bacteria," has emerged as a promising candidate for ameliorating metabolic disorders, including obesity, diabetes, and liver disease. In this study, we investigated the therapeutic potential of AKK to counteract metabolic dysfunctions induced by Olanzapine (OLZ), a first-class antipsychotic known for its high therapeutic efficacy but also its association with metabolic disturbances, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Previous studies have implicated progesterone receptor membrane component 1 (PGRMC1) as a key player in antipsychotic-induced metabolic side effects. Using male C57BL/6J mice fed a high-fat diet, we assessed the effects of AKK supplementation on OLZ-induced metabolic disturbances. Key parameters such as body weight, hepatic injury markers, glucose tolerance, insulin resistance, and lipid metabolism were analyzed. The study revealed that AKK supplementation reduced hepatic lipid accumulation, oxidative stress, and insulin resistance, while normalizing lipid and glucose metabolism. These effects are likely mediated through the restoration of PGRMC1/SIRT1/FOXO1 signaling pathway by AKK. Additionally, changes in gut microbiota composition, including a reduction in pathogenic bacteria such as Lactococcus and enrichment of beneficial bacteria, were observed. Overall, the study suggests that AKK has therapeutic potential to counteract OLZ-induced MASLD by modulating gut microbiota and key metabolic pathways, making it a promising strategy for managing metabolic side effects in patients receiving antipsychotic treatment.
Keywords: AKK, OLZ, MASLD, Lipid accumulation, Insulin Resistance, PGRMC1
Received: 22 Dec 2024; Accepted: 26 Feb 2025.
Copyright: © 2025 Chen, Cao, Lin, Jiao, He, Zhu, Guo, Wu, Cai and ZHANG. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
HuaLin Cai, Department of Pharmacy, The Second Xiangya Hospital of Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
Bi-kui ZHANG, Department of Pharmacy, The Second Xiangya Hospital of Central South University, Institute of Clinical Pharmacy, Central South University, Changsha, China
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