Bacteroidales species in the human gut are a reservoir of antibiotic resistance genes regulated by invertible promoters

Wei Yan,Xiaofang Jiang,A Brantley Hall

doi:10.1038/s41522-021-00260-1

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.

Highlights

The proliferation of Antibiotic-resistance genes (ARGs) has compromised antibiotic treatment for bacteria infections[1]
Genomic analysis showed that ARGs regulated by invertible promoters have been convergently derived from ARG insertions into glycan-synthesis loci regulated by invertible promoters
We scanned the operons downstream of the invertible promoters to find those containing ARGs. This search uncovered 62 contigs, from samples collected from 47 individuals, containing invertible promoters regulating ARGs (IP-ARG)

Summary

Introduction

The proliferation of ARGs has compromised antibiotic treatment for bacteria infections[1]. The human gut microbiome is an important reservoir of ARGs2–4 and the spread of ARGs from gut microbes to pathogens has been documented[5]. ARGs in the human gut microbiome pose a growing threat to human health. Bacteria-carrying ARGs are outcompeted by susceptible strains due to the costs associated with the maintenance and expression of the ARGs6–8. Though it is costly, bacteria can ameliorate the fitness costs of maintaining ARGs through different strategies[9], such as no-cost, low-cost or gain-of-fitness mutations[10,11], compensatory mutations at a second site[12,13,14], or genetic coselection of resistance genes in genetic linkage[15,16].

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Results

Conclusion