Synthetic bacterial therapies for intestinal diseases based on quorum-sensing circuits.

ABSTRACT

Bacterial therapy has become a key strategy against intestinal infectious diseases in recent years. Moreover, regulating the gut microbiota through traditional fecal microbiota transplantation and supplementation of probiotics faces controllability, efficacy, and safety challenges. The infiltration and emergence of synthetic biology and microbiome provide an operational and safe treatment platform for live bacterial biotherapies. Synthetic bacterial therapy can artificially manipulate bacteria to produce and deliver therapeutic drug molecules. This method has the advantages of solid controllability, low toxicity, strong therapeutic effects, and easy operation. As an essential tool for dynamic regulation in synthetic biology, quorum sensing (QS) has been widely used for designing complex genetic circuits to control the behavior of bacterial populations and achieve predefined goals. Therefore, QS-based synthetic bacterial therapy might become a new direction for the treatment of diseases. The pre-programmed QS genetic circuit can achieve a controllable production of therapeutic drugs on particular ecological niches by sensing specific signals released from the digestive system in pathological conditions, thereby realizing the integration of diagnosis and treatment. Based on this as well as the modular idea of synthetic biology, QS-based synthetic bacterial therapies are divided into an environmental signal sensing module (senses gut disease physiological signals), a therapeutic molecule producing module (plays a therapeutic role against diseases), and a population behavior regulating module (QS system). This review article summarized the structure and function of these three modules and discussed the rational design of QS gene circuits as a novel intervention strategy for intestinal diseases. Moreover, the application prospects of QS-based synthetic bacterial therapy were summarized. Finally, the challenges faced by these methods were analyzed to make the targeted recommendations for developing a successful therapeutic strategy for intestinal diseases.