Considerable evidence suggests that insulin resistance is closely linked to Parkinson's disease (PD), leading to agents aiming at treating diabetes can be regarded as new neuroprotective strategies in PD, notably glucagon-like peptide-1 (GLP-1). However, the extremely short half-life of GLP-1 due to degradation by the ubiquitous proteolytic enzyme limits its clinical application. In this study, we engineered the recombinant integrant probiotic strain Escherichia coli Nissle 1917 (EcN) to create a strain EcN-GLP-1 that effectively delivers the heterologous GLP-1 molecule. Subsequently, we assessed its neuroprotective effects on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. We demonstrated that EcN-GLP-1 treatment could improve motor deficits, increase tyrosine hydroxylase-positive neurons, suppress microglia and astrocyte activation, reduce brain and colon inflammation, and ameliorate colonic barrier function damaged by MPTP induction. Meanwhile, we confirmed that the oral administration of EcN-GLP-1 could restore the disturbance of gut microbiota in the MPTP-induced PD mice, by reducing the relative abundances of Akkermansia and Oscillospira, and increasing the level of Prevotella in the gut. These results support further development of an engineered probiotic platform in which production of GLP-1 for gut-brain disorders, such as PD.

中文翻译：

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工程大肠杆菌 Nissle 1917 通过传递 GLP-1 和调节肠道微生物群对小鼠帕金森病产生神经保护作用

大量证据表明，胰岛素抵抗与帕金森病 (PD) 密切相关，因此治疗糖尿病的药物可被视为帕金森病的新神经保护策略，特别是胰高血糖素样肽-1 (GLP-1)。然而，GLP-1由于普遍存在的蛋白水解酶的降解而半衰期极短，限制了其临床应用。在这项研究中，我们对重组整合益生菌菌株Escherichia coli Nissle 1917 (EcN) 进行了工程改造，创建了能够有效递送异源 GLP-1 分子的菌株 EcN-GLP-1。随后，我们评估了其对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的 PD 小鼠的神经保护作用。我们证明 EcN-GLP-1 治疗可以改善运动缺陷，增加酪氨酸羟化酶阳性神经元，抑制小胶质细胞和星形胶质细胞活化，减少大脑和结肠炎症，并改善 MPTP 诱导受损的结肠屏障功能。同时，我们证实口服EcN-GLP-1可以通过降低阿克曼氏菌和颤螺菌的相对丰度并增加肠道中普雷沃氏菌的水平来恢复MPTP诱导的PD小鼠肠道微生物群的紊乱。这些结果支持进一步开发工程益生菌平台，在该平台中生产 GLP-1，用于治疗帕金森病等肠脑疾病。