Abstract
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.
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Acknowledgments
We thank Dr. Matthew B. Scholz, the director of the VANTAGE Microbiome Services core, for helpful advice in regard to microbial composition studies. EcN was a gift from ArdeyPharm.
Funding
This work was supported in part by the National Institutes of Health grants R01 AT007830 (SSD) and U24 DK059637 (Vanderbilt MMPC). VANTAGE is supported by the National Institutes of Health grants P30 CA68485, P30 EY08126, and G20 RR030956.
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Author 2 (ZC) and Author 6 (SSD) have a patent pending for the use of engineered bacteria expressing NAPE or NAE for treating obesity. Authors 1, 3, 4, and 5 declare that they have no conflict of interest.
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All applicable international, national, and institutional guidelines for care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Dosoky, N.S., Chen, Z., Guo, Y. et al. Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment. Appl Microbiol Biotechnol 103, 6711–6723 (2019). https://doi.org/10.1007/s00253-019-09958-x
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DOI: https://doi.org/10.1007/s00253-019-09958-x
Keywords
- Gut microbiota
- Engineered bacteria
- N-acyl-phosphatidylethanolamines
- N-acyl-ethanolamides
- N-acyltransferases
- Antibiotics