Gut Microbiome-Origin Enzyme Functions Similarly to Host One Targeted in Diabetes Management

Researchers have uncovered a gut microbiome-derived enzyme that functions similarly to a host enzyme that is itself a drug target for diabetes management. As they report in Science, researchers from Peking University and elsewhere developed an enzyme activity-screening platform to identify gut microbe-derived enzymes that affect host physiology, which they applied to a set of stool samples from three healthy human volunteers. The researchers' analysis in particular focused on 110 enzymes involved in different human diseases to find that dipeptidyl peptidase 4 (DPP4) had the highest effect size in their samples. DPP4 degrades active glucagon-like peptide-1 (GLP-1) but in mice, the researchers found that the microbial-derived DPP4 did not affect GLP-1 levels among chow-fed mice. It did, however, have an effect on mice fed high-fat diets and mice with "leaky guts." Further, sitagliptin, a DPP4 inhibitor used clinically to treat type 2 diabetes, did not affect microbial-derived DPP4, but through high-throughput screening, they found the daurisoline derivate Dau-d4 could inhibit microbial DPP4 and improve blood glucose homeostasis in mice. The researchers note that these variations in microbial DPP4 activity could be reflected in the differing responses patients treated with sitagliptin exhibit. "Our findings highlight the promise of developing therapies that target both host and gut microbial enzymes to achieve greater clinical efficacy," the researchers write in their paper.