We propose the development and feasibility assessment, in-vivo, of a "synthetic living medicine" where we engineer bacteria to sense the intestinal environment, detect inflammatory signals associated with gut inflammation, and deliver localized, natural, treatment at the optimal dosage. This synthetic living medicine consists of live biotherapeutics composed of bacterial cells capable of detecting specific inflammatory biomarkers and producing natural therapeutic molecules. The bacterial engineering is based on the design of advanced logic gates (or switches) to increase sensitivity and accuracy. We hypothesize that targeted, localized treatment for gut inflammation, (including ulcerative colitis and Crohn’s disease)—released at the right place, time, and dosage—will be essential for improving efficacy while significantly reducing systemic side effects.
We aim to convert commensal gut bacteria, residents of the natural gut microbiota, into living medicine which can detect inflammatory signals such as excess of blood (typical in inflammatory conditions), and as a consequence produce butyrate, a natural molecule known for its ability to reduce gut inflammation. Our design entails the engineered bacteria to produce butyrate directly in the inflamed regions of the gut, only when inflammation is detected ̶ “at the right place and time”. Our results indicate the feasibility of the engineered butyrate production, in vitro and in a limited number of Germ-Free mouse models, where gut inflammation was introduced by the chemical Dextran-Sodium-Sulphate (DSS). We propose to finalize the design of the blood sensors, to combine both engineered entities (“sensing” and “producing”) and to validate the model in inflamed mice models.