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: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.
RESULTS: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.
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.
IMPACT AND IMPLICATIONS: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.