Glucose-responsive probiotics for glycaemic modulation in mice and monkeys

Sustained and controlled delivery of glucose-lowering agents using engineered designer cells is recognized as an effective strategy for diabetes therapy. However, current technologies rely on external signal control or have been programmed into mammalian cells using synthetic gene networks, which pose safety concerns arising from transplantation. Here, we developed an engineered oral-deliverable glucose-sensing and functional response probiotic living drug for 'sense-and-respond'-based control of diabetic blood glucose. We created a glucose sensor based on a synthetic gene circuit that incorporates the glucose-responsive transcriptional regulator HexR, coupled with a synthetic promoter. Upon oral administration of the engineered probiotics carrying the sensor, the cells reside temporarily in the intestine and regulate the expression of therapeutic transgenes in response to glucose levels that exceed the normal threshold. The authors demonstrate efficacy from the engineered probiotics for glycaemic control in multiple diabetic mouse and non-human primate models, showing improvements in lipid profiles and attenuation of diabetic complications. This probiotics-based living drug enables therapeutic dosing in response to real-time blood glucose levels, providing a programmable, orally deliverable sense-and-respond platform for metabolic therapy without transplantation. The use of probiotics as a living drug offers a novel approach to diabetes management, with potential benefits including reduced side effects and improved patient compliance. However, further research is needed to fully understand the mechanisms and long-term effects of this technology. For research use only, this product is not intended for human consumption or therapeutic use.