Department of Biotechnology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Department of Scientific Research, KMHD, Shenzhen, China.
Front Cell Infect Microbiol. 2022 Jul 28;12:896504. doi: 10.3389/fcimb.2022.896504. eCollection 2022.
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 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.
COVID-19 患者的肠道微生物组谱被发现与 SARS-CoV-2 的病毒载量、COVID-19 的严重程度和功能失调的免疫反应相关，这表明肠道微生物组可能参与了抗感染。为了研究肠道微生物组在抗 SARS-CoV-2 感染中的作用，我们建立了一个针对内切核糖核酸酶（Nsp15）的高通量 COVID-19 治疗药物筛选系统。我们还评估了肠道来源的物质对目标的活性抑制作用，使用小鼠模型试图探索肠道微生物组和 SARS-CoV-2 之间的相互作用。结果出人意料地表明，抗生素治疗会诱导小鼠肠道中出现具有 Nsp15 活性抑制的物质。基于粪便宏基因组的功能分析以及抗生素富集细菌和代谢物的内切核糖核酸酶测定的综合分析表明，Nsp15 抑制剂是主要的胆酸，由于抗生素诱导的胆汁酸代谢微生物缺乏，这些胆酸在肠道中积累。本研究为使用初级胆酸开发 COVID-19 治疗药物提供了新的视角。
