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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2023-08-04 DOI:10.1126/science.add5787

Kai Wang, Zhiwei Zhang, Jing Hang, Jia Liu, Fusheng Guo, Yong Ding, Meng Li, Qixing Nie, Jun Lin, Yingying Zhuo, Lulu Sun, Xi Luo, Qihang Zhong, Chuan Ye, Chuyu Yun, Yi Zhang, Jue Wang, Rui Bao, Yanli Pang, Guang Wang, Frank J. Gonzalez, Xiaoguang Lei, Jie Qiao, Changtao Jiang

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引用次数: 11

Abstract

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.

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微生物宿主同工酶分析显示微生物DPP4是一个潜在的抗糖尿病靶点。

对微生物蛋白质如何影响宿主的机制理解可以更深入地了解肠道微生物群与宿主的相互作用。我们开发了一个酶活性筛选平台，以研究肠道微生物群衍生的酶如何影响宿主生理。我们发现二肽基肽酶4（DPP4）由微生物群的特定细菌类群表达。微生物DPP4能够降低肠道渗漏小鼠的活性胰高血糖素样肽-1（GLP-1）并破坏葡萄糖代谢。此外，目前靶向人类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，我们确定道豆醇-d4（Dau-d4）是一种选择性微生物DPP4抑制剂，可改善糖尿病小鼠的糖耐量。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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