摘要
      由可逆启动子调节的抗生素抗性基因（ARGs）可以降低在没有抗生素的情况下维持ARGs的适应度成本，并可能延长ARGs在细菌种群中的持久性。然而，这些由可逆启动子调控的ARG的起源、流行和分布仍知之甚少。在这里，我们试图通过系统地搜索人类肠道微生物组中由可逆启动子调节的ARGs，并检查其起源、流行和分布，来评估由可逆启动基因调节的ARG所构成的威胁。通过2227个人类肠道宏基因组的宏基因组组装和统一人类胃肠道基因组（UHGG）集合的基因组分析，我们鉴定了由可逆启动子调控的ARG，并根据转化酶调控期的变化将其分为三类。在人类肠道微生物组中，由可逆启动子调节的ARGs仅在拟杆菌门物种中发现。通过基因组分析，我们观察到由可逆启动子调节的ARG已经从ARG插入到聚糖合成基因座中汇聚而来，这些基因座被可逆启动子至少调节了三次。此外，调节ARGs的所有三类可逆启动子都位于整合偶联元件（ICEs）内。因此，通过ICEs的水平转移可以解释由可逆启动子调节的ARGs的广泛分类分布。总的来说，这些发现表明，在拟杆菌门物种中，由可逆启动子调控的聚糖合成基因座是出现由可逆启动基因调控的临床相关ARG的重要热点。
Abstract
Antibiotic-resistance genes (ARGs) regulated by invertible promoters 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 these ARGs regulated by invertible promoters remains poorly understood. Here, we sought to assess the threat posed by ARGs regulated by invertible promoters by systematically searching for ARGs regulated by invertible promoters 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 ARGs regulated by invertible promoters and categorized them into three classes based on the invertase-regulating phase variation. In the human gut microbiome, ARGs regulated by invertible promoters are exclusively found in Bacteroidales species. Through genomic analysis, we observed that ARGs regulated by invertible promoters have convergently originated from ARG insertions into glycan-synthesis loci that were regulated by invertible promoters at least three times. Moreover, all three classes of invertible promoters regulating ARGs are located within integrative conjugative elements (ICEs). Therefore, horizontal transfer via ICEs could explain the wide taxonomic distribution of ARGs regulated by invertible promoters. Overall, these findings reveal that glycan-synthesis loci regulated by invertible promoters in Bacteroidales species are an important hotspot for the emergence of clinically-relevant ARGs regulated by invertible promoters.

https://www.nature.com/articles/s41522-021-00260-1