- Olanzapine and fecal microbiota transplantation from antipsychotic-naïve schizophrenia patients alter metabolic profiles differentially in male and female mice.

Emerging evidence suggests the role of gut microbiome (GMB) in the pathogenesis of schizophrenia (SCZ) and antipsychotic-induced metabolic perturbations. In the present study, we investigated the role of GMB in metabolic alterations associated with SCZ and olanzapine (a prototype antipsychotic) treatment using human fecal microbiota transplantation (FMT) in mice. FMT from antipsychotic-naïve SCZ patients (SCZ-FMT) and sex-BMI matched healthy controls (HC-FMT) were performed in 5-6 weeks old male and female germ-free C57BL/6 mice. At 10-12 weeks of age, mice were given an irradiated high-fat diet (HFD) with or without olanzapine for six weeks. Weekly food intake and body weight were monitored and an intraperitoneal glucose tolerance test (IPGTT) was performed in the last week. Circulating concentrations of glucose, insulin and free fatty acids (FFA) were measured. Homeostatic model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) were calculated to assess insulin sensitivity. Female SCZ-FMT recipient mice showed significantly decreased area under the curve in IPGTT compared to HC-FMT recipient female mice (p=0.0159), irrespective of olanzapine treatment. This was associated with a significantly increased fasting insulin levels (p=0.0003), increased HOMA-IR (p=0.0005), and decreased QUICKI (p=0.0004) in female SCZ-FMT recipient mice, regardless of olanzapine treatment. Furthermore, SCZ-FMT recipient mice, regardless of sex or olanzapine treatment, showed significantly decreased serum FFA levels, which could indicate reduced lipolysis. These preliminary findings suggest that GMB could be a predisposing factor contributing to the intrinsic risk of developing type 2 diabetes associated with SCZ in females.