Altering the gut microbiome may be a useful long-term therapeutic strategy for treating metabolic disorders. One approach is to genetically modify intestinal bacteria to secrete therapeutic compounds that mitigate against metabolic diseases and thereby provide continuous treatment without requiring continuous drug administration. To test the feasibility of this concept, we genetically modified the intestinal bacteria E. coli Nissle 1917 (EcN) to secrete N-acyl-phosphatidylethanolamines (NAPEs) by expressing NAPE acyltransferase (pNAPE-EcN). NAPEs are normally synthesized by the small intestine and then rapidly hydrolyzed to the highly anorexigenic N-acyl-ethanolamines (NAEs) by NAPE-specific phospholipase D (NAPE-PLD) in the intestine. We found that administration of pNAPE-EcN bacteria to mice in their drinking water markedly inhibited body weight and body fat gain of mice fed a high-fat diet compared to mice administered control bacteria or vehicle only. Hepatic levels of NAEs and of fatty acid gene expression were markedly increased by pNAPE-EcN administration, demonstrating that bacterially synthesized therapeutic compounds can be delivered to extra-intestinal tissues. Viable pNAPE-EcN was detected in fecal samples for at least four weeks after ending their administration in drinking water and body weight and body fat remained significantly lower than for control treated mice even 12 weeks post-administration, demonstrating that sufficient pNAPE-EcN persisted after administration to exert pharmacological effects. To test whether the anorexigenic effects of pNAPE-EcN required hydrolysis of NAPE to NAE, we coexpressed both NAPE-PLD and NAPE acyltransferase to generate bacteria that secrete NAEs (pNAE-EcN) but not NAPEs. In wild-type mice, administration of pNAE-EcN exerted similar effects as pNAPE-EcN. In NAPE-PLD null mice, administration of pNAE-EcN but not pNAPE-EcN significantly inhibited body weight and body fat gain on the high-fat diet. Thus hydrolysis of NAPE to NAE by NAPE-PLD is absolutely required for the anorexigenic effect of NAPE. In summary, our studies provide proof-of-concept that incorporating bacteria engineered to secrete NAPE into the gut microbiota can be an effective long-term strategy for inhibiting development of obesity and provide insight into the mechanisms of action of these therapeutic bacteria.

Incorporation of therapeutic bacteria into the gut microbiome for treatment of obesity

249th National Meeting (2015)

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