Microbiota-based probiotics to treat inborn errors in metabolism

Project Summary/Abstract The human gut is a metabolic organ where anaerobic microbial pathways run at high capacity, expanding the biochemical landscape of the human body. Exploiting members of the gut microbiota and the metabolic pathways they encode represents an exciting new strategy to treat genetically encoded biochemical defects in humans such as Phenylketonuria. There are three reasons why identifying new microbiota probiotics should be a priority: 1) Gut microbes represent an important yet untapped resource for new metabolic pathways that influence human biochemistry. 2) Microbiota pathways are present in healthy individuals, and their metabolic end products are unlikely to be toxic to humans. 3) Native, non-genetically modified strains are likely to have a straightforward regulatory pathway for use in humans. While this proposal is focused on identifying microbes and pathways to reduce blood phenylalanine levels to treat phenylketonuria, our long-term goal is to lay the foundation for an entirely new approach to treat inborn errors in metabolism: controlling metabolic circuits via the gut microbiota. Our proposal is organized into the following two aims: In Aim 1, we will use gene cluster searches, transcriptomics, genetics, and metabolomics to identify and characterize anaerobic pathways for phenylalanine metabolism by gut bacteria. In Aim 2, we will assess the ability of microbial pathways to reduce plasma Phe levels in a gnotobiotic mouse model of phenylketonuria (PKU). Our results will not only provide new insights into how the microbiome expands the biochemical landscape of the host but will also lay the groundwork for a new approach to treating inborn errors in metabolism.