Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing, China.
Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
J Med Virol. 2024 Jan;96(1):e29336. doi: 10.1002/jmv.29336.
Based on the forefront of clinical research, there is a growing recognition that the gut microbiota, which plays a pivotal role in shaping both the innate and adaptive immune systems, may significantly contribute to the pathogenesis of coronavirus disease 2019 (COVID-19). Although an association between altered gut microbiota and COVID-19 pathogenesis has been established, the causative mechanisms remain incompletely understood. Additionally, the validation of the precise functional alterations within the gut microbiota relevant to COVID-19 pathogenesis has been limited by a scarcity of suitable animal experimental models. In the present investigation, we employed a newly developed humanized ACE2 knock-in (hACE2-KI) mouse model, capable of recapitulating critical aspects of pulmonary and intestinal infection, to explore the modifications in the gut microbiota following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Examination of fecal samples using 16S rRNA gene profiling unveiled a notable reduction in species richness and conspicuous alterations in microbiota composition at 6 days postinfection (dpi). These alterations were primarily characterized by a decline in beneficial bacterial species and an escalation in certain opportunistic pathogens. Moreover, our analysis entailed a correlation study between the gut microbiota and plasma cytokine concentrations, revealing the potential involvement of the Lachnospiraceae_NK4A136_group and unclassified_f_Lachnospiraceae genera in attenuating hyperinflammatory responses triggered by the infection. Furthermore, integration of gut microbiota data with RNA-seq analysis results suggested that the increased presence of Staphylococcus in fecal samples may signify the potential for bacterial coinfection in lung tissues via gut translocation. In summary, our hACE2-KI mouse model effectively recapitulated the observed alterations in the gut microbiota during SARS-CoV-2 infection. This model presents a valuable tool for elucidating gut microbiota-targeted strategies aimed at mitigating COVID-19.
基于临床研究的前沿，越来越多的人认识到，肠道微生物群在塑造先天和适应性免疫系统方面发挥着关键作用，可能对 2019 年冠状病毒病（COVID-19）的发病机制有重大贡献。虽然已经确定了肠道微生物群的改变与 COVID-19 发病机制之间存在关联，但因果机制仍不完全清楚。此外，由于缺乏合适的动物实验模型，验证与 COVID-19 发病机制相关的肠道微生物群的确切功能改变受到限制。在本研究中，我们使用了一种新开发的人源化 ACE2 敲入（hACE2-KI）小鼠模型，该模型能够模拟肺部和肠道感染的关键方面，以探索严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染后肠道微生物群的变化。使用 16S rRNA 基因谱分析粪便样本发现，感染后 6 天（dpi）时，物种丰富度明显降低，微生物群落组成发生显著改变。这些改变的主要特征是有益细菌种类减少和某些机会性病原体增加。此外，我们还进行了肠道微生物群与血浆细胞因子浓度之间的相关性研究，揭示了 Lachnospiraceae_NK4A136_group 和未分类_f_Lachnospiraceae 属可能参与减轻感染引发的过度炎症反应。此外，将肠道微生物群数据与 RNA-seq 分析结果整合表明，粪便样本中葡萄球菌的增加可能表明通过肠道易位在肺部组织中存在细菌合并感染的潜力。总之，我们的 hACE2-KI 小鼠模型有效地再现了 SARS-CoV-2 感染期间观察到的肠道微生物群改变。该模型为阐明针对肠道微生物群的 COVID-19 缓解策略提供了有价值的工具。
