Metformin acts on the gut-brain axis to ameliorate antipsychotic-induced metabolic dysfunction.

Abstract

Antipsychotic-induced metabolic dysfunction (AIMD) is an intractable clinical challenge worldwide. The situation is becoming more critical as second-generation antipsychotics (SGAs), to a great extent, have replaced the role of first-generation antipsychotics in managing major psychiatric disorders. Although the exact mechanisms for developing AIMD is intricate, emerging evidence has indicated the involvement of the microbiota-gut-brain axis in AIMD. SGAs treatment may change the diversity and compositions of intestinal flora (e.g., decreased abundance of Bacteroidetes and Akkermansia muciniphila, and increased Firmicutes). Short-chain fatty acids and other metabolites derived from gut microbiota, on the one hand, can regulate the activity of intestinal endocrine cells and their secretion of satiety hormones (e.g., glucagon-like peptide 1, peptide YY, cholecystokinin and ghrelin); on the other hand, can activate the vagus nerve or transport into the brain to exert a central modulation of foraging behaviors via binding to neuropeptide receptors. Interestingly, metformin, a classical antidiabetic agent, is capable of alleviating AIMD possibly by regulating the microbiota-gut-brain axis. That is, metformin can not only partially reverse the alterations of gut microbial communities due to SGAs treatment, but also play a positive role in rectifying the disturbances of peripheral and central satiety-related neuropeptides. Current evidence has indicated a promising role for metformin on ameliorating AMID, but further verifications in well-designed clinical trials are still warranted.