Diet-induced programmable GLP-1 delivery by synthetic bacteria enhances anti-obesity efficacy with reduced gut bacterial taxa harboring GLP-1 inactivation potential

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that controls energy homeostasis, and impaired GLP-1 secretion or responsiveness is associated with metabolic diseases. Much effort has been made to develop long-lasting GLP-1-based therapeutics, whereas frequently associated with drug resistance and side effects. GLP-1 is predominantly released postprandially by enteroendocrine cells, while programmable GLP-1 delivery is rarely explored. Herein, genetically engineered probiotic bacteria for diet-induced programmable GLP-1 delivery were developed. The therapeutic efficacy of diet-induced and constitutive GLP-1 delivery was compared in a murine model of obesity, followed by microbiome profiling and functional characterization of gut bacterial GLP-1-degrading enzymes. In murine model of obesity, the anti-adiposity and anti-steatosis effects of diet-induced programmable GLP-1 delivery by synthetic bacteria were greater than that of microbial persistent GLP-1 delivery. Notably, genes encoding microbe-derived GLP-1 peptidase isoenzymes were discovered in gut bacteria specifically enriched by persistent GLP-1 delivery in murine and clinical studies, while diet-induced GLP-1 delivery minimized the abundance of these gut bacteria with GLP-1 inactivation potential. Our findings provide insights into host-microbiome-therapeutic interactions, and highlight programmable delivery strategies for peptide-based therapeutics.