DataSheet_8_Antibiotic-Induced Primary Biles Inhibit SARS-CoV-2 Endoribonuclease Nsp15 Activity in Mouse Gut.pdf

The gut microbiome profile of COVID-19 patients was found to correlate with a viral load of SARS-CoV-2, COVID-19 severity, and dysfunctional immune responses, suggesting that gut microbiota may be involved in anti-infection. In order to investigate the role of gut microbiota in anti-infection against SARS-CoV-2, we established a high-throughput in vitro screening system for COVID-19 therapeutics by targeting the endoribonuclease (Nsp15). We also evaluated the activity inhibition of the target by substances of intestinal origin, using a mouse model in an attempt to explore the interactions between gut microbiota and SARS-CoV-2. The results unexpectedly revealed that antibiotic treatment induced the appearance of substances with Nsp15 activity inhibition in the intestine of mice. Comprehensive analysis based on functional profiling of the fecal metagenomes and endoribonuclease assay of antibiotic-enriched bacteria and metabolites demonstrated that the Nsp15 inhibitors were the primary bile acids that accumulated in the gut as a result of antibiotic-induced deficiency of bile acid metabolizing microbes. This study provides a new perspective on the development of COVID-19 therapeutics using primary bile acids.

研究发现，新冠（COVID-19）患者的肠道微生物组（gut microbiome）特征与新型冠状病毒（SARS-CoV-2）载量、新冠病情严重程度以及免疫功能异常显著相关，提示肠道菌群可能参与机体抗感染过程。为探究肠道菌群在抗新型冠状病毒（SARS-CoV-2）感染中的作用，本研究以核糖核酸内切酶（endoribonuclease，Nsp15）为靶点，构建了用于筛选新冠治疗药物的高通量体外筛选体系。同时，本研究借助小鼠模型评估肠道来源物质对该靶点的抑制活性，以探索肠道菌群与新型冠状病毒之间的相互作用。研究结果意外显示，抗生素处理可诱导小鼠肠道内产生具有Nsp15抑制活性的物质。通过粪便宏基因组（fecal metagenomes）功能谱分析以及对抗生素富集菌与代谢物（metabolites）的核糖核酸内切酶活性检测，本研究证实，该Nsp15抑制剂为初级胆汁酸（primary bile acids）；此类胆汁酸因抗生素诱导的胆汁酸代谢微生物（bile acid metabolizing microbes）缺失而在肠道中蓄积。本研究为利用初级胆汁酸开发新冠治疗药物提供了全新视角。