Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

Abstract

AbstractBackgroundThe gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigated whether microbiota DPP4-like counterparts perform the same function.ResultsWe identified novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations betweenParabacteroidesandPorphyromonasDPP4-like genes and type 2 diabetes (T2D). We also found that the DPP4-like enzyme from the gut symbiontParabacteroides merdaemimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) hormonesin vitro.Importantly, administration ofE. colioverexpressing theP. merdaeDPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduced active GIP and GLP-1 levels, which was attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observed that linagliptin, saxagliptin, sitagliptin and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme fromP. merdae.ConclusionsOur findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.