Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Peking University, Beijing, China.
Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
Science. 2023 Aug 4;381(6657):eadd5787. doi: 10.1126/science.add5787.
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.
对微生物蛋白如何影响宿主的机制的理解，可以深入了解肠道微生物群与宿主的相互作用。我们开发了一种酶活性筛选平台，以研究肠道微生物衍生的酶如何影响宿主生理学。我们发现二肽基肽酶 4（DPP4）是由微生物群中特定的细菌分类群表达的。微生物 DPP4 能够降低肠道通透性增加的小鼠中的活性胰高血糖素样肽 1（GLP-1）并破坏葡萄糖代谢。此外，目前针对人类 DPP4 的药物，包括西他列汀，对微生物 DPP4 几乎没有影响。通过高通量筛选，我们确定了达芦那韦-d4（Dau-d4）作为一种选择性微生物 DPP4 抑制剂，可改善糖尿病小鼠的葡萄糖耐量。
