Caffaratti Clément, Plazy Caroline, Cunin Valérie, Toussaint Bertrand, Le Gouellec Audrey
University Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, CHU Grenoble Alpes, TIMC, 38000 Grenoble, France.
Plateforme de Métabolomique GEMELI-GExiM, Service de Biochimie, Biologie Moléculaire et Toxicologie Environnementale, UM Biochimie des Enzymes et des Protéines, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France.
Metabolites. 2022 Nov 2;12(11):1061. doi: 10.3390/metabo12111061.
Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are of interest to increase host spermidine intakes. Here, we show that metabolic engineering can be used to increase spermidine production by the probiotic 1917 (EcN), used in humans. First, we found that increasing the expression of genes involved in polyamine biosynthesis, namely the S-adenosylmethionine synthase and the spermidine synthase , resulted in an increase in spermidine produced and excreted by our engineered bacteria. The major drawback of this first attempt was the production of acetylated forms of spermidine. Next, we propose to solve this problem by increasing the expression of the spermidine exporter system MdtI/MdtJ. This second strategy had a major impact on the spermidine profile found in the culture supernatant. Our results demonstrate, for the first time, the feasibility of rationally engineering bacterial probiotic strains to increase their ability to deliver the microbiota-derived metabolite, spermidine. This work illustrates how metabolomic and synthetic biology can be used to design and improve engineered Live Biotherapeutic Products that have the potential to be used in personalized medicine.
微生物群衍生的代谢产物对其宿主具有生物学重要性。亚精胺是一种因其在与年龄相关疾病中的保护作用而被描述的代谢产物，目前正在研究其在炎症消退和肠道稳态中的作用。调节其在胃肠道中产生的策略对于增加宿主亚精胺摄入量具有重要意义。在此，我们表明代谢工程可用于增加用于人类的益生菌1917（EcN）产生亚精胺的能力。首先，我们发现增加参与多胺生物合成的基因的表达，即S-腺苷甲硫氨酸合酶和亚精胺合酶，会导致我们工程改造的细菌产生和分泌的亚精胺增加。首次尝试的主要缺点是产生了亚精胺的乙酰化形式。接下来，我们建议通过增加亚精胺输出系统MdtI/MdtJ的表达来解决这个问题。这第二种策略对培养上清液中发现的亚精胺谱有重大影响。我们的结果首次证明了合理改造细菌益生菌菌株以提高其递送微生物群衍生代谢产物亚精胺能力的可行性。这项工作说明了代谢组学和合成生物学如何可用于设计和改进有可能用于个性化医疗的工程化活体生物治疗产品。
