摘要

肠道微生物群组成的不利变化与肥胖症和各种慢性疾病的发展有关。重新设计肠道微生物群以产生有益的代谢物是治疗这些慢性疾病的潜在策略。 N-酰基 - 磷脂酰乙醇胺（NAPEs）是具有已知抗肥胖特性的生物活性脂质家族。先前的研究表明，用拟南芥NAPE合成酶工程改造大肠杆菌Nissle 1917（EcN）以产生NAPE，从而在结束给药后持续存在的高脂肪饮食诱导对肥胖的抗性。在先前的研究中，在给予工程化的EcN在饮用水中8周之前，用氨苄青霉素预处理小鼠。如果需要使用抗生素和长期施用以获得有益效果，则在人类中实施该策略可能是有问题的。因此，进行研究以确定较少繁重的方案是否仍能赋予持久抗性和持续的NAPE生物合成。在没有用抗生素预处理的情况下施用工程化EcN仅2周就足以建立持久的抗性。在施用工程化的EcN后，需要通过EcN持续NAPE生物合成作为抗生素治疗显着减弱其作用。最后，人类磷脂酶A /酰基转移酶-2（PLAAT2）在EcN中的异源表达提供了与拟南芥NAPE合酶的异源表达相似的对肥胖的抗性，证实NAPEs是该抗性的生物活性介质。

Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.

https://www.ncbi.nlm.nih.gov/pubmed/31203417