Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target

A mechanistic understanding of how microbial proteins affect the host
could yield deeper insights into gut microbiota–host cross-talk. We
developed an enzyme activity-screening platform to investigate how gut
microbiota-derived enzymes might influence host physiology. We discovered
that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa
of the microbiota. Microbial DPP4 was able to decrease the active glucagon
like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky
gut. Furthermore, the current drugs targeting human DPP4, including
sitagliptin, had little effect on microbial DPP4. Using high-throughput
screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial
DPP4 inhibitor that improves glucose tolerance in diabetic mice.