Evaluation of the substrate profile of microbial-host-isozyme reveals the role of BvDPP4 in inflammatory bowel disease.

Gut microbiota is known to interact with the host to modulate homeostasis and disease. Recent studies have shown that gut microbiota can produce enzymes, such as dipeptidyl peptidase 4 (DPP4), that perform functions similar to host enzymes, thus acting as "microbial-host-isozyme" within the host. However, the strain specificity and substrate adaptability of microbiota-derived DPP4 both remain poorly characterized, and the potential implications of microbiota-derived DPP4 on the host remain unclear. Here, we screened different microbiota-derived DPP4s for their enzymatic activities and substrate adaptability, and characterized a specific regulatory effect of Bacteroides vulgatus-derived DPP4 (BvDPP4) on GLP-2. We found that BvDPP4 could disrupt the intestinal barrier and aggravate colitis by inactivating GLP-2. Moreover, we conducted a screen of natural products and identified theaflavin as an inhibitor of BvDPP4, which also regulates levels of GLP-2. Notably, treatment with theaflavin could ameliorate BvDPP4-induced worsening of colitis in a preclinical model. Taken together, our results demonstrate that gut microbial enzymes are therapeutic targets that can be modulated by treatment with natural products, such as theaflavin, to improve gut health. Moreover, our activity-based screening strategy represents an innovative new approach for characterizing microbial enzymes in host disease.