First Exposure to Second-Generation Antipsychotics Alters Gut Microbiota and Metabolic Profiles in Patients with Glucose-Lipid Metabolism Disorders

Yuexia Wu^1*Sai Zang^2,3Zhiming Wu¹JIngsong Huang¹

• ¹Dalian Seventh People's Hospital and Dalian Psychological Hospital, Dalian, China
• ²Xi'an Jiaotong University Affiliated Children's Hospital, Xi'an, China
• ³Dalian Medical University, Dalian, China

Backgroud: Second-generation antipsychotics (SGAs) are widely used in the treatment of schizophrenia, however, growing concerns have emerged regarding theire adverse effects on glucose and lipid metabolism. This study aimed to investigate the potential mechanisms underlying SGA-induced disturbances in glucose and lipid metabolism by integrating gut microbiota profiling with metabolomic analysis, thereby providing a scientific basis for future clinical interventions. Methods: A self-controlled before-after study was conducted on subjects who were initially medication-free (pre-medication group) and subsequently initiated on second-generation antipsychotics for 3 months (post-medication group). Anthropometric measurements—including waist circumference, hip circumference, body weight—as well as fasting blood samples (for assessment of glucose, insulin, C peptide, blood lipid) and stool samples were collected at baseline and after three months of treatment. Gut microbiota composition and fecal metabolomic profiles were analyzed using high-throughput sequencing and mass spectrometry–based approaches, respectively. Results: Firstly, Gut microbial diversity differed significantly between groups. At genus level, the abundances of Escherichia and Bifidobacterium were increased significantly in the post-medication patients, while the abundances of Faecalibacterium and Blautia were decreased. Metabolomic analysis revealed decreased levels of oleamide and stearamide in the post-medication group, which exhibited a negative correlation with the abundance of Faecalibacterium. Additionally, the arginine and proline metabolic pathway, D-amino acid metabolic pathway, and arginine biosynthesis pathway were also altered in this group. Ornithine was identified as a key player in these three differential metabolic pathways. Conclusion: In summary, first-time exposure to second-generation antipsychotics in patients with schizophrenia is associated with disturbances in glucose and lipid metabolism, which appear to be closely linked to SGA-induced perturbations in gut microbiota composition and their associated metabolic profiles.