摘要
出身背景
抗生素抗性组是个体中存在的所有抗生素抗性基因（ARGs）的集合。一个人对感染的易感性以及由严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的2019年冠状病毒病（新冠肺炎）的最终严重程度是否受其呼吸道抗生素耐药性的影响尚不清楚。此外，呼吸道和肠道抗生素耐药性基因组成之间是否存在关系尚未得到充分探讨。
方法
我们招募了66名处于三个疾病阶段（入院、进展和恢复）的新冠肺炎患者，并对143份痰和97份粪便样本进行了宏基因组测序分析。分析呼吸道、肠道宏基因组和外周血单核细胞（PBMC）转录组，以比较重症监护室（ICU）和非重症监护室患者的肠道和呼吸道ARGs，并确定ARGs与免疫反应之间的关系。
后果
在呼吸道ARGs中，我们发现ICU患者的氨基糖苷类、多药类和万古霉素与nICU患者相比增加。在肠道中，我们发现重症监护室患者的多药、万古霉素和甲胺磷增加。经过进一步研究，发现呼吸道和肠道中ARGs（即氨基糖苷类和四环素类的亚型）的相对丰度之间存在显著的正相关。我们发现多药的相对丰度与临床指标显著相关，ARGs与呼吸道和肠道微生物群之间存在显著正相关。我们发现PBMC中的免疫相关途径增强，并且它们与多药、万古霉素和四环素ARGs的相对丰度显著相关。基于ARG类型的相对丰度，我们构建了一个呼吸道输出型ARG组合随机分类器，以区分ICU新冠肺炎患者和非重症监护病房患者，AUC为0.969。肠道中氨基糖苷和万古霉素的水平被认为是最显著的生物标志物。
结论
累积起来，我们的研究结果首次揭示了呼吸道和肠道抗生素耐药性在新冠肺炎进展和疾病严重程度中的动态变化。他们还可以更好地了解这种疾病如何影响不同的患者群体。因此，这些发现应该有助于更好的诊断和治疗方案。
Abstract
Background

The antibiotic resistome is the collection of all the antibiotic resistance genes (ARGs) present in an individual. Whether an individual’s susceptibility to infection and the eventual severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is influenced by their respiratory tract antibiotic resistome is unknown. Additional, whether a relationship exists between the respiratory tract and gut antibiotic resistance genes composition has not been fully explored.

Method

We recruited 66 patients with COVID-19 at three disease stages (admission, progression and recovery) and conducted a metagenome sequencing analysis of 143 sputum and 97 fecal samples obtained from them. Respiratory tract, gut metagenomes, and peripheral blood mononuclear cell (PBMC) transcriptomes are analyzed to compare the gut and respiratory tract ARGs of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between ARGs and immune response.

Results

Among the respiratory tract ARGs, we found that Aminoglycoside, Multidrugand Vancomycin are increased in ICU patients compared with nICU patients. In the gut, we found that Multidrug, Vancomycin and Fosmidomycinwere increased in ICU patients. Upon further investigation a significantly positive correlation was found between the relative abundance in ARGs (i.e., subtypes of the Aminoglycoside and Tetracyclinetypes) in the respiratory tract and gut. We discovered that the relative abundances of Multidrug were significantly correlated with clinical indices, and there was a significantly positive correlation between ARGs and microbiota in respiratory tract and gut. We found that immune related pathways in PBMC were enhanced, and they were significantly correlated with the relative abundance of Multidrug, Vancomycin and Tetracycline ARGs. Based on the relative abundance of ARG types, we built a respiratory tract-gut ARG combined random-forest classifier to distinguish ICU COVID-19 patients from nICU patients with an AUC of 0.969. The level of Aminoglycoside and Vancomycinin the gut was regarded as the most prominent biomarker.

Conclusions

Cumulatively, our findings provide some of the first insights into the dynamic alterations of respiratory tract and gut antibiotic resistome in the progression of COVID-19 and disease severity. They also provide a better understanding of how this disease affects different cohorts of patients. As such, these findings should contribute to better diagnosis and treatment scenarios.

https://www.researchsquare.com/article/rs-2612412/v1