Microbial dipeptidyl peptidase 4 (mDPP4)

Microbial dipeptidyl peptidase 4 (mDPP4) is a serine protease produced by specific members of the gut microbiota, particularly within the Bacteroides genus, that mimics the activity of human DPP4. This enzyme plays a critical role in the degradation of host-produced incretin hormones, such as glucagon-like peptide-1 (GLP-1), before they can enter systemic circulation or activate local signaling pathways (Wang et al., Science, 2023). By cleaving the N-terminal dipeptides of GLP-1, mDPP4 reduces the hormone's ability to stimulate insulin secretion and regulate blood glucose levels, thereby contributing to the pathogenesis of type 2 diabetes and metabolic syndrome (Zhong et al., Cell Host & Microbe, 2022). Unlike human DPP4, which is primarily membrane-bound or circulating, mDPP4 operates within the intestinal lumen, making it less accessible to conventional systemic DPP4 inhibitors like sitagliptin. Consequently, mDPP4 has emerged as a novel therapeutic target for gut-restricted inhibitors designed to enhance the incretin effect and improve metabolic health through microbiome modulation (Deacon, Reviews in Endocrine and Metabolic Disorders, 2019). Research indicates that targeting mDPP4 can synergize with existing diabetes treatments and may explain individual variability in patient responses to standard DPP4 inhibitor therapies.

Other names

Bacterial dipeptidyl peptidase 4Gut microbial DPP4X-prolyl dipeptidyl aminopeptidaseBacterial DPP-IV

Inhibition of microbial-derived DPP4 enzymes in the intestinal lumen to prevent the premature degradation of host glucagon-like peptide-1 (GLP-1), thereby enhancing the incretin effect and improving systemic insulin secretion and glucose regulation.