摘要

    相变抗生素抗药性基因（ARGs）可以减轻缺乏抗生素时维持ARGs的适应性成本，并有可能延长ARGs在细菌种群中的持久性。但是，相位可变ARGs的起源，患病率和分布仍然知之甚少。在这里，我们试图通过系统地搜索人类肠道微生物组中的相变ARG并检查其起源，流行和分布，来评估相变ARG所构成的威胁。通过2227个人类肠道元基因组的宏基因组组装和统一人类胃肠基因组（UHGG）的基因组分析，我们确定了相变ARGs，并根据转化酶调节相变将其分为三类。在人类肠道微生物组中，相变ARGs通常且仅分布在拟杆菌属物种中。通过基因组分析，我们观察到相变ARG至少三次收敛于ARG插入相变胶囊多糖生物合成（CPS）基因座中。此外，所有识别出的相位可变ARG均位于整合共轭元件（ICE）中。因此，通过ICE的水平转移可以解释相变ARG的广泛分类学分布。总体而言，这些发现表明，在细菌科物种中，相变CPS位点是临床相关相变ARGs出现的重要热点。

    Phase-variable antibiotic resistance genes (ARGs) can mitigate the fitness cost of maintaining ARGs in the absence of antibiotics and could potentially prolong the persistence of ARGs in bacterial populations. However, the origin, prevalence, and distribution of phase-variable ARGs remains poorly understood. Here, we sought to assess the threat posed by phase-variable ARGs by systematically searching for phase-variable ARGs in the human gut microbiome and examining their origin, prevalence, and distribution. Through metagenomic assembly of 2227 human gut metagenomes and genomic analysis of the Unified Human Gastrointestinal Genome (UHGG) collection, we identified phase-variable ARGs and categorized them into three classes based on the invertase regulating phase variation. In the human gut microbiome, phase-variable ARGs are commonly and exclusively distributed in Bacteroidales species. Through genomic analysis, we observed that phase-variable ARGs have convergently originated from ARG insertions into phase-variable capsule polysaccharide biosynthesis (CPS) loci at least three times. Moreover, all identified phase-variable ARGs are located within integrative conjugative elements (ICEs). Therefore, horizontal transfer via ICEs could explain the wide taxonomic distribution of phase-variable ARGs. Overall, these findings reveal that phase-variable CPS loci in Bacteroidales species are an important hotspot for the emergence of clinically-relevant phase-variable ARGs.

    https://www.biorxiv.org/content/10.1101/2021.04.26.441444v1.abstract