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.

中文翻译：

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抗精神病药诱导的代谢综合征的潜在益生菌：支持 Akkermansia muciniphila 亚型如何改善奥氮平诱导的小鼠葡萄糖稳态的机制

背景

奥氮平 (OLZ) 是最有效的非典型抗精神病药之一，但与严重的代谢副作用有关，其中肠道微生物群起着重要作用。Akkermansia muciniphila ( A. muciniphila ; Akk) 是肠道中的一种革兰氏阴性厌氧菌，可以潜在地改善代谢综合征。

客观的

本研究调查了A. muciniphila亚型 ( A. muciniphila ^sub ; Akk ^sub ) 对瘦和肥胖小鼠OLZ诱导的代谢功能障碍的影响和潜在机制。

方法

在 OLZ 治疗 16 周之前，C57BL/6 雌性小鼠被喂食高脂肪饮食以诱导肥胖或正常饮食 8 周。治疗期间，各组小鼠口服A. muciniphila ^sub。评估体重增加、葡萄糖和脂质代谢以及炎症。

结果

A. muciniphila ^sub仅在瘦小鼠第 16 周减少OLZ相关的体重增加，并显着减轻 OLZ 诱导的高血糖，而与饮食无关。这伴随着葡萄糖-6-磷酸酶 (G6Pase) 和磷酸烯醇式丙酮酸羧激酶 (PEPCK)（肝糖异生的关键酶）水平的降低以及 OLZ 相关的胰岛素抵抗。此外，OLZ 诱导的血清白细胞介素 (IL)-6 和肿瘤坏死因子 (TNF)-α 水平的增加被A. muciniphila ^sub在肥胖和瘦小鼠中改善。OLZ 不会增加血清脂质水平或肝脏脂肪堆积。

结论

A. muciniphila ^sub通过调节 G6Pase 和 PEPCK 水平以及胰岛素抵抗来改善OLZ相关的高血糖症。此外，A. muciniphila ^sub减轻了由OLZ引起的全身炎症。A. muciniphila ^sub是一种很有前途的益生菌治疗OLZ诱导的代谢功能障碍。