Development of an engineered probiotic for the treatment of branched chain amino acid related metabolic diseases

Abstract Metabolic dysfunction arising from missing or impaired enzymes comprising the branched chain amino acid (BCAA) degradation pathway, especially those involving leucine, can result in the accumulation of toxic metabolic intermediates and cause severe metabolic disease. Removal of dietary BCAAs via their degradation by engineered microbes could be a viable approach to prevent BCAA-mediated disease sequelae. In this article, we describe the design and construction of an engineered leucine degrading strain of E. coli Nissle, the improvement of the degradation pathway through high throughput screening, and the demonstration of strain activity in animal models monitored by disease and strain-specific biomarkers. This work provides a path for the development of engineered probiotic bacterial strains as a treatment for BCAA-related metabolic disorders in humans.