An engineered Escherichia coli Nissle strain prevents lethal liver injury in a mouse model of tyrosinemia type 1

Background & Aims: 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. Methods: Eschenchia coli Nissle 1917 (EcN) was engineered to express genes involved in tyrosine metabolism in the anoxic conditions that are characteristic of the intestine (EcN-HT). Bodyweight, survival rate, plasma (tyrosine/liver function), H&E staining and RNA sequencing 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. Results: EcN-HT consumed tyrosine and produced L-DOPA (levodopa) 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 sequencing analysis revealed that EcN-HT rescued the global gene expression pattern in the livers of FahKO mice, particularly of genes involved in metabolic signaling and liver homeostasis. Moreover, EcN-HT treatment was found to be safe and well -tolerated in the mouse intestine. Conclusions: 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.