Longitudinal Gut Microbiota Dysbiosis Underlies Olanzapine-Induced Weight Gain

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.