An activity-based enzyme activity screening system identified gut microbial DPP4 isozymes that can decrease active GLP-1 but cannot be inhibited by sitagliptin. Gut microbial DPP4 isozyme can impair host glucose homeostasis, and variations in microbial DPP4 activities could possibly contribute to the heterogeneous responses to sitagliptin observed among patients with T2D. INTRODUCTION: Gut microbiota can regulate the physiology and pathophysiology of the host by producing enzymes with functions similar to those of the host. [Extracted from the article]