Gut microbiota can produce enzymes that are homologous in function to host enzymes that alter the host physiology. These microbial isozymes may not exhibit sequence homology with their related host enzymes, which necessitates alternative means for discovery. To enhance the identification of these gut-derived enzymes, Wang et al. developed an enzyme-activity-based screening platform by using protein extracts from stool-derived ex vivo communities and testing their effects on 110 enzymes. In particular, a microbial version of DPP4 that was produced mainly by Bacteroides spp. exhibited the highest activity in control feces relative to that in germ-free conditions. Host DPP4 (hDPP4) mediates the degradation of GLP-1, a hormone that regulates glucose homeostasis.
Microbiota-derived DPP4 (mDPP4) degraded host GLP-1 mainly in mouse models of intestinal barrier damage, including mice fed a high-fat diet. The effects of mDPP4 resulted in a corresponding decrease in intestinal and plasma levels of GLP-1, accompanied by impaired glucose tolerance. However, mDPP4 was resistant to the effects of clinical DPP4 inhibitors. Aiming to identify a specific mDPP4 inhibitor, Wang et al. performed a high-throughput small-molecule screen that identified daurisoline (Dau), an alkaloid natural product, as having the greatest inhibition of mDPP4 activity. A derivative of Dau, Dau-d4, directly interacted with and inhibited mDPP4 while sparing hDPP4. A crystal structure confirmed that Dau-d4 interacted with residues that were not conserved in human DPP4. Dau-d4 rescued glucose metabolism in diabetic mice by restoring GLP-1 levels and exhibited synergism with the human DPP4 inhibitor, revealing a potential therapeutic for gut-mediated disruptions in glucose homeostasis. This study highlights the potential of microbe–host isozymes in precision treatments for metabolic diseases.
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