遗传性酪氨酸血症 1 型 (HT1) 是由延胡索酰乙酰乙酸水解酶 (FAH) 活性丧失引起的，可导致致命的肝损伤。 HT1 的治疗选择仍然有限。在这项研究中，我们的目的是构建一种能够重编程宿主代谢的工程细菌，从而为治疗 HT1 提供一种潜在的替代方法。大肠杆菌 Nissle 1917 (EcN) 被设计为表达酪氨酸代谢基因并响应缺氧条件在肠道中（EcN-HT）。使用体重、存活率、血浆（酪氨酸/肝功能）、HE 染色和 RNA-seq 来评估其在 Fah 敲除 (KO) 小鼠（一种广为接受的 HT1 模型）中降解酪氨酸和防止致命性肝损伤的能力.EcN-HT 在体外系统中消耗酪氨酸并产生 L-DOPA。重要的是，在 Fah-KO 小鼠中，口服 EcN-HT 可以增强酪氨酸降解，减少有毒代谢物的积累，并防止致命性肝损伤。 RNA-seq 分析显示，EcN-HT 挽救了模型小鼠肝脏中的整体基因表达模式，特别是与代谢信号和肝脏稳态相关的基因。此外，EcN-HT 治疗被发现在小鼠肠道中是安全且耐受性良好的。这是第一份关于工程化活细菌可以降解酪氨酸并减轻 HT1 小鼠致命性肝损伤的报告。 EcN-HT 是一种新型工程益生菌，具有治疗这种疾病的潜力。 1 型遗传性酪氨酸血症 (HT1) 患者的特点是无法正常代谢酪氨酸，并患有肝衰竭、肾功能障碍、神经功能障碍和癌症。鉴于宿主和微生物代谢途径之间的重叠和互补性，肠道微生物组提供了通过酪氨酸降解和减少可能有毒的副产物来调节宿主代谢的潜在机会。在这里，我们证明了一种工程活细菌 EcN-HT 可以增强酪氨酸分解，减少有毒酪氨酸副产物的积累，并防止 Fah 基因敲除小鼠的致命性肝损伤。这些发现表明，可以降解肠道酪氨酸的工程活生物治疗药物可能是预防 HT1 致命性肝损伤以及减轻其相关病理的可行且安全的策略。版权所有 © 2023 欧洲研究协会肝。由 Elsevier B.V. 出版。保留所有权利。

Hereditary tyrosinemia type 1 (HT1) results from the loss of fumarylacetoacetate hydrolase (FAH) activity and can lead to lethal liver injury. Therapeutic options for HT1 remain limited. In this study, we aimed to construct an engineered bacterium capable of reprogramming host metabolism and thereby provide a potential alternative approach for the treatment of HT1.Escherichia coli Nissle 1917 (EcN) was engineered to express genes for tyrosine-metabolizing and respond to anoxic conditions in the intestine (EcN-HT). Bodyweight, survival rate, plasma (tyrosine/liver function), HE staining and RNA-seq were used to assess its ability to degrade tyrosine and protect against lethal liver injury in Fah-knockout (KO) mice, a well-accepted model of HT1.EcN-HT consumed tyrosine and produced L-DOPA in an in vitro system. Importantly, in Fah-KO mice, the oral administration of EcN-HT enhanced tyrosine degradation, reduced the accumulation of toxic metabolites, and protected against lethal liver injury. RNA-seq analysis revealed that EcN-HT rescued the global gene expression pattern in the liver of the model mice, particularly which relating to genes involved in metabolic signaling and liver homeostasis. Moreover, EcN-HT treatment was found to be safe and well-tolerated in the mouse intestine.This is the first report of an engineered live bacterium that can degrade tyrosine and alleviate lethal liver injury in mice with HT1. EcN-HT represents a novel engineered probiotic with the potential to treat this condition.Patients with hereditary tyrosinemia type 1 (HT1) is characterized by an inability to metabolize tyrosine normally and suffer from liver failure, renal dysfunction, neurological impairments, and cancer. Given the overlap and complementarity between the host and microbial metabolic pathways, the gut microbiome provides a potential chance to regulate host metabolism through degradation of tyrosine and reduction of byproducts that might be toxic. Here, we demonstrated that an engineered live bacterium, EcN-HT, could enhance tyrosine breakdown, reduce the accumulation of toxic tyrosine byproducts, and protect against lethal liver injury in Fah-knockout mice. These findings suggested that engineered live biotherapeutics that can degrade tyrosine in the gut may represent a viable and secure strategy for the prevention of lethal liver injury in HT1 as well as the mitigation of its associated pathologies.Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.