Engineering Diagnostic and Therapeutic Gut Bacteria

ABSTRACT Genetically engineered bacteria have the potential to diagnose and treat a wide range of diseases linked to the gastrointestinal tract, or gut. Such engineered microbes will be less expensive and invasive than current diagnostics and more effective and safe than current therapeutics. Recent advances in synthetic biology have dramatically improved the reliability with which bacteria can be engineered with the sensors, genetic circuits, and output (actuator) genes necessary for diagnostic and therapeutic functions. However, to deploy such bacteria in vivo , researchers must identify appropriate gut-adapted strains and consider performance metrics such as sensor detection thresholds, circuit computation speed, growth rate effects, and the evolutionary stability of engineered genetic systems. Other recent reviews have focused on engineering bacteria to target cancer or genetically modifying the endogenous gut microbiota in situ . Here, we develop a standard approach for engineering “smart probiotics,” which both diagnose and treat disease, as well as “diagnostic gut bacteria” and “drug factory probiotics,” which perform only the former and latter function, respectively. We focus on the use of cutting-edge synthetic biology tools, gut-specific design considerations, and current and future engineering challenges.