Therapeutic engineering of the gut microbiome using synthetic biology and metabolic tools: a comprehensive review with E. coli Nissle 1917 as a model case study.

The human gut microbiome significantly influences host physiology, metabolism, and immune function. The engineering of microbial communities represents a significant advancement in contemporary biotechnology. Conventional methods, including Fecal Microbiota Transplantation (FMT) and probiotic administration, exhibit limitations in efficacy and raise safety and reproducibility concerns; however, they have shown potential therapeutic benefits. Recent progress in biocatalysis and metabolic engineering has led to the development of genetically tractable gut bacteria for targeted therapeutic purposes, particularly in the last five years. This chapter offers an overview of the development of microbiota-based interventions, from early recombinant probiotics to advanced synthetic biology platforms that can detect and respond to host and environmental signals. This analysis examines the mechanistic aspects of enzyme engineering, including improvements in metabolic pathways for the production of short-chain fatty acids, the breakdown of harmful metabolites, and the biosynthesis of immunomodulatory compounds. This review also examines conditions including inflammatory bowel disease, metabolic dysfunction, and colorectal cancer, highlighting microbial production systems pertinent to gut health. The engineering of Escherichia coli Nissle 1917 to produce phenylalanine ammonia-lyase (PAL) and L-amino acid deaminase (LAAD) represents a significant advancement in gut-based metabolic intervention for patients with phenylketonuria (PKU) by degrading excess phenylalanine. Recent studies offer peer-reviewed evidence supporting the translational potential of these inventions, as demonstrated through figures and tables highlighting engineered metabolic circuits, therapeutic outputs, and strain performance metrics. This combination of developments demonstrates the potential of synthetic microbiome engineering to provide precision biotherapeutics for various gut-related conditions.