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

• 成果类型: Article
• 署名作者: Wang, Kai; Zhang, Zhiwei; Hang, Jing; Liu, Jia; Guo, Fusheng; Ding, Yong; Li, Meng; Nie, Qixing; Lin, Jun; Zhuo, Yingying; Sun, Lulu; Luo, Xi; Zhong, Qihang; Ye, Chuan; Yun, Chuyu; Zhang, Yi; Wang, Jue; Bao, Rui; Pang, Yanli; Wang, Guang; Gonzalez, Frank J.; Lei, Xiaoguang; Qiao, Jie; Jiang, Changtao
• 署名单位: Peking University; Peking University; Capital Medical University; Peking University; Peking University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Sichuan University; Peking University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12923
• DOI: 10.1126/science.add5787
• 发表日期: 2023-08-04
• 页码: 501-+
• 关键词: inhibitor sitagliptin; glycemic control; rna; liraglutide; mechanisms; metformin; efficacy; safety; range; iv

摘要

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.