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The article is a recent publication that looks at the interconnectedness of several topics about horizontal gene transfer, antibiotic resistance, and the human microbiome. Please read this attached article and do annotations (highlight any parts of interest or confusion in the article you would like, then write a question and/or a comment in 4-6 sentences for each of these parts). Require 6-8 questions and comments in total. Here are some starting points for the discussion:Why is the accumulation and sharing of antibiotic resistance genes in the human microbiome a health concern?What is the difference between commensal and pathogenic bacteria? Does it matter which ones have antibiotic resistance genes?Are antibiotic resistance genes shared between closely related species? What about distantly related species?How are these genes being transferred: transformation, transduction, and/or conjugation?How were antibiotic resistance genes and transfer events detected?How do they confirm that these genes can actually confer antibiotic resistance?Note: Please focus on the major conclusions of the data and the implications of this data on human health. You don’t need to have a deep understanding of how each sequencing technique works nor do you need to detailed understanding of the statistics.
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ARTICLE
https://doi.org/10.1038/s41467-022-29096-9
OPEN
Strain-level characterization of broad host range
mobile genetic elements transferring antibiotic
resistance from the human microbiome
1234567890():,;
Samuel C. Forster 1,2,3,4 ✉, Junyan Liu1,4, Nitin Kumar 1, Emily L. Gulliver 2,3, Jodee A. Gould2,3,
Alejandra Escobar-Zepeda1, Tapoka Mkandawire 1, Lindsay J. Pike1, Yan Shao1, Mark D. Stares1,
Hilary P. Browne 1, B. Anne Neville1 & Trevor D. Lawley 1 ✉
Mobile genetic elements (MGEs) carrying antibiotic resistance genes (ARGs) disseminate
ARGs when they mobilise into new bacterial hosts. The nature of such horizontal gene
transfer (HGT) events between human gut commensals and pathogens remain poorly
characterised. Here, we compare 1354 cultured commensal strains (540 species) to 45,403
pathogen strains (12 species) and find 64,188 MGE-mediated ARG transfer events between
the two groups using established methods. Among the 5931 MGEs, we find 15 broad host
range elements predicted to have crossed different bacterial phyla while also occurring in
animal and environmental microbiomes. We experimentally demonstrate that predicted
broad host range MGEs can mobilise from commensals Dorea longicatena and Hungatella
hathewayi to pathogen Klebsiella oxytoca, crossing phyla simultaneously. Our work establishes
the MGE-mediated ARG dissemination network between human gut commensals and
pathogens and highlights broad host range MGEs as targets for future ARG dissemination
management.
1 Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton CB10 1SA, UK. 2 Centre for Innate Immunity and Infectious Diseases, Hudson
Institute of Medical Research, Clayton, Vic 3168, Australia. 3 Department of Molecular and Translational Science, Monash University, Clayton, Vic 3800,
Australia. 4These authors contributed equally: Samuel C. Forster, Junyan Liu. ✉email: [email protected]; [email protected]
NATURE COMMUNICATIONS | (2022)13:1445 | https://doi.org/10.1038/s41467-022-29096-9 | www.nature.com/naturecommunications
1
ARTICLE
NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29096-9
H
umans are colonized by microbial communities dominated by bacteria from the Firmicutes, Bacteroidetes,
Actinobacteria, and Proteobacteria phyla that play an
essential role regulating immune response1, aiding sustenance2,
and providing pathogen colonization resistance3. Antibiotic
treatment, though intended to eliminate pathogens, simultaneously eradicates indigenous commensal bacteria that are sensitive to the antibiotic. This can result in a microbiome with a
vastly altered community structure and function; however,
commensal species with intrinsic or acquired antibiotic resistance
are protected from elimination. Antibiotic selection likely results
in antibiotic resistance genes (ARGs) accumulation among
commensal bacteria4 that may also act as a reservoir from which
ARGs are transferred on mobile genetic elements (MGEs) or by
bacteriophage transduction to other species, including pathogens,
via horizontal gene transfer (HGT)5–12.
The extent of HGT in human gut microbiome and the types of
MGEs involved, especially those associated with ARGs, have been
the focus of continued research interest in the last decade. Several
key metagenomic studies showed that HGT between gut bacteria
is more frequent than HGT with bacteria from other body sites or
environments because intestinal bacteria occupy the same
habitat5. Most MGEs involved mobilise within the same phylum
or lower taxonomic groups9 and the transfer of ARGs between
pathogens and commensals is considered limited5,13. A recent
bioinformatic study utilising two separate genome collections has
demonstrated a capacity to accurately predict compatible HGT
host-recipient pairs12. However, experimental validation of HGT
has largely relied on high-throughput chromatin conformation
capture (Hi-C) which has uncovered extensive HGT in situ
including between pathogenic and commensal species10,11. Many
studies using animal models have also demonstrated individual
cases of increased HGT between pathogens and commensals
during infections14,15. Despite these advances, the majority of
large-scale studies still do not experimentally validate MGE
mobility at the isolate level. It is therefore imperative to understand the true scale of HGT between pathogenic and commensal
species coexisting in the human gut, to identify MGEs posing
high risks in order to better inform future interventions to curb
spread of ARGs. We and others have recently demonstrated that
the vast majority of the human gastrointestinal bacteria can be
cultured16–21.
In this work, we apply this resource to systematically investigate the extent of HGT between pathogens and commensals, with
a focus on ARG-associated MGEs. We are able to confirm host
range of MGEs with high confidence, strain-level resolution and
validate in vitro putative past HGT events to demonstrate that
these MGEs retain the ability to mobilise and can potentially
spread associated ARG to numerous bacteria species.
Results
MGEs are shared extensively between commensals and pathogens. To map the extent of horizontally shared MGEs that carry
ARGs between pathogenic and commensal bacteria of the human
gastrointestinal tract, we first compared 1354 commensal genomes (530 species) from the Human Gastrointestinal Microbiota
Genome Collection (HGG)22 (Supplementary Data 1) to 45,403
publicly available genomes (Supplementary Data 2) selected to
capture representatives of 12 gastrointestinal pathogenic and
opportunistic pathogenic species which will be referred to as
pathogens in this work, including 8 Proteobacteria; Klebsiella
oxytoca (n = 139), K. pneumoniae (n = 7712), Escherichia coli
(n = 17,142), Salmonella enterica (n = 10,394), Shigella sonnei
(n = 1290), S. flexneri (n = 453), Campylobacter coli (n = 919)
and C. jejuni (n = 1554) and 4 Firmicutes; Enterococcus faecalis
2
(n = 1364), E. faecium (n = 1706), Clostridioides difficile
(n = 2016) and Clostridium perfringens (n = 138) (Fig. 1a). Some
of the 12 species are among the most prevalent gastrointestinal
pathogens globally23–25, some are posing great risk to the public
as they become increasingly resistant to antibiotics26.
We reasoned that genes originating either directly or indirectly
through recent horizontal transfer events would exhibit high
nucleotide homology between isolates incongruent with phylogenetic distance. Pairwise gene comparisons were performed
between the 1354 commensal genomes and 45,403 pathogen
genomes to identify those genes sharing significant nucleotide
identity (>99% identity across over 500 bp in organisms
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