Abstract
The gut microbiome harbors a ‘silent reservoir’ of antibiotic resistance (AR) genes that is thought to contribute to the emergence of multidrug-resistant pathogens through horizontal gene transfer (HGT). To counteract the spread of AR, it is paramount to know which organisms harbor mobile AR genes and which organisms engage in HGT. Despite methods that characterize the overall abundance of AR genes in the gut, technological limitations of short-read sequencing have precluded linking bacterial taxa to specific mobile genetic elements (MGEs) encoding AR genes. Here, we apply Hi-C, a high-throughput, culture-independent method, to surveil the bacterial carriage of MGEs. We compare two healthy individuals with seven neutropenic patients undergoing hematopoietic stem cell transplantation, who receive multiple courses of antibiotics, and are acutely vulnerable to the threat of multidrug-resistant infections. We find distinct networks of HGT across individuals, though AR and mobile genes are associated with more diverse taxa within the neutropenic patients than the healthy subjects. Our data further suggest that HGT occurs frequently over a several-week period in both cohorts. Whereas most efforts to understand the spread of AR genes have focused on pathogenic species, our findings shed light on the role of the human gut microbiome in this process.
Highlights
The gut microbiome harbors a ‘silent reservoir’ of antibiotic resistance (AR) genes that is thought to contribute to the emergence of multidrug-resistant pathogens through horizontal gene transfer (HGT)
This potentially reduces our ability for overall detection, especially for larger mobile genetic elements (MGEs), since mobile contigs are often fragmented in metagenomic assemblies[14]
The molecular dynamics of HGT in the gut microbiome are not wellunderstood, our data from healthy subjects point to a basal level of transmission, even in the absence of inflammation or antibiotic use
Summary
The gut microbiome harbors a ‘silent reservoir’ of antibiotic resistance (AR) genes that is thought to contribute to the emergence of multidrug-resistant pathogens through horizontal gene transfer (HGT). We develop a modified version of current Hi-C protocols and analytical pipelines (Supplementary Fig. 1) in conjunction with metagenomic shotgun sequencing to surveil the bacterial taxa harboring specific mobile AR genes in the gut microbiomes of two healthy individuals and seven patients undergoing hematopoietic stem cell transplantation. These patients have prolonged hospitalizations during their transplants (21 ± 4 days) and often receive multiple courses of antibiotic therapy, increasing the likelihood of an MDR infection. In a mock community of three organisms, each harboring an identifiable plasmid, we are able to confidently link each plasmid to its nascent genome (Supplementary Fig. 3)
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