A potential probiotic bacterium for antipsychotic-induced metabolic syndrome: mechanisms underpinning how Akkermansia muciniphila subtype improves olanzapine-induced glucose homeostasis in mice

Background Olanzapine (OLZ) is one of the most effective atypical antipsychotics but is associated with severe metabolic side effects, in which the gut microbiota plays an important role. Akkermansia muciniphila ( A. muciniphila ; Akk), a Gram-negative anaerobic bacterium in the intestine, can potentially improve metabolic syndrome. Objective This study investigated the effect and underlying mechanisms of an A. muciniphila subtype ( A. muciniphila sub ; Akk sub ) on OLZ-induced metabolic dysfunction in lean and obese mice. Methods C57BL/6 female mice were fed a high-fat diet to induce obesity or normal chow for 8 weeks before OLZ treatment for 16 weeks. During the treatment period, mice in each group were orally administrated A. muciniphila sub . Weight gain, glucose and lipid metabolism, and inflammation were evaluated. Results A. muciniphila sub decreased OLZ-related weight gain only at week 16 in lean mice and significantly alleviated OLZ-induced hyperglycemia irrespective of diet. This was accompanied by reduced levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)—key enzymes in hepatic gluconeogenesis—and OLZ-associated insulin resistance. Moreover, OLZ-induced increases in serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels were improved by A. muciniphila sub in both obese and lean mice. OLZ did not increase serum lipid levels or hepatic fat accumulation. Conclusions A. muciniphila sub improves OLZ-related hyperglycemia via regulation of G6Pase and PEPCK levels and insulin resistance. Moreover, A. muciniphila sub alleviates systemic inflammation caused by OLZ. A. muciniphila sub is a promising probiotic treatment for OLZ-induced metabolic dysfunction.