Sub-MIC antibiotics influence the microbiome, resistome and structure of riverine biofilm communities
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The effects of sub-minimum inhibitory concentrations (sub-MICs) of antibiotics on aquatic environments is not yet fully understood. Here, we explore these effects by employing a replicated microcosm system fed with river water where biofilm communities were continuously exposed over an eight-week period to sub-MIC exposure (1/10, 1/50, and 1/100 MIC) to a mix of common antibiotics (ciprofloxacin, streptomycin, and oxytetracycline). Biofilms were examined using a structure-function approach entailing microscopy and metagenomic techniques, revealing details on the microbiome, resistome, virulome, and functional prediction. A comparison of three commonly used microbiome and resistome databases was also performed. Differences in biofilm architecture were observed between sub-MIC antibiotic treatments, with an overall reduction of extracellular polymeric substances and autotroph (algal and cyanobacteria) and protozoan biomass, particularly at the 1/10 sub-MIC condition. While metagenomic analyses demonstrated that microbial diversity was lowest at the sub-MIC 1/10 antibiotic treatment, resistome diversity was highest at sub-MIC 1/50. This study also notes the importance of benchmarking analysis tools and careful selection of reference databases, given the disparity in detected antimicrobial resistance genes (ARGs) identity and abundance across methods. Ultimately, the most detected ARGs in sub-MICs exposed biofilms were those that conferred resistance to aminoglycosides, tetracyclines, β-lactams, sulfonamides, and trimethoprim. Co-occurrence of microbiome and resistome features consistently showed a relationship between Proteobacteria genera and aminoglycoside ARGs. Our results support the hypothesis that constant exposure to sub-MICs antibiotics facilitate the transmission and promote prevalence of antibiotic resistance in riverine biofilms communities, and additionally shift overall microbial community metabolic function.Keywords:
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Despite increasing concerns over inappropriate use of antibiotics in medicine and food production, population-level resistance transfer into the human gut microbiota has not been demonstrated beyond individual case studies. To determine the “antibiotic resistance potential” for entire microbial communities, we employ metagenomic data and quantify the totality of known resistance genes in each community (its resistome) for 68 classes and subclasses of antibiotics. In 252 fecal metagenomes from three countries, we show that the most abundant resistance determinants are those for antibiotics also used in animals and for antibiotics that have been available longer. Resistance genes are also more abundant in samples from Spain, Italy, and France than from Denmark, the United States, or Japan. Where comparable country-level data on antibiotic use in both humans and animals are available, differences in these statistics match the observed resistance potential differences. The results are robust over time as the antibiotic resistance determinants of individuals persist in the human gut flora for at least a year.
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The routine therapeutic use of antibiotics has caused resistance genes to be disseminated across microbial populations. In particular, bacterial strains having antibiotic resistance genes are frequently observed in the human microbiome. Moreover, multidrug-resistant pathogens are now widely spread, threatening public health. Such genes are transferred and spread among bacteria even in different environments. Advances in high throughput sequencing technology and computational algorithms have accelerated investigation into antibiotic resistance genes of bacteria. Such studies have revealed that the antibiotic resistance genes are located close to the mobility-associated genes, which promotes their dissemination. An increasing level of information on genomic sequences of resistome should expedite research on drug-resistance in our body and environment, thereby contributing to the development of public health policy. In this review, the high prevalence of antibiotic resistance genes and their exchange in the human and environmental microbiome is discussed with respect to the genomic contents. The relationships among diverse resistomes, related bacterial species, and the antibiotics are reviewed. In addition, recent advances in bioinformatics approaches to investigate such relationships are discussed.
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Abstract Antibiotics at low concentration can promote processes such as biofilm formation, virulence and antibiotic resistance. This can be of high relevance in microbial communities like the oral microbiome, where commensals and pathogens share a common habitat and where the abundance of antibiotic resistance genes surpasses the abundance in the gut. Here, we used an ex vivo model of human oral biofilms to investigate the impact of ampicillin on biofilm viability. Further, the ecological impact on the microbiome and resistomes was investigated using shotgun metagenomics. The results showed that low concentrations promoted significant shifts in microbial taxonomic profile and could enhance biofilm viability by up to 1 to 2-log. For the resistome, low concentrations had no significant impact on antibiotic resistance gene (ARG) diversity, while ARG abundance decreased by up to 84%. A positive correlation was observed between reduced microbial diversity and reduced ARG abundance. The WHO priority pathogens Streptococcus pneumoniae and Staphylococcus aureus were identified in some of the samples, but their abundance was not significantly altered by ampicillin. Yet, most of the antibiotic resistance genes that increased in abundance in the ampicillin group were associated with streptococci, including Streptococcus mitis , a well-known potential donor of ARGs to S. pneumoniae . To our knowledge, this is the first report on antibiotic effects on oral microbial communities using an ex-vivo human microbiome model combining biofilms and shotgun metagenomics. Overall, the results highlight the potential of using the model to further our understanding of ecological and evolutionary forces driving antimicrobial resistance in oral microbiomes.
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Commensalism
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Abstract Background The resistome, the collection of antibiotic resistance genes (ARGs) in a microbiome, is increasingly recognised as relevant to the development of clinically relevant antibiotic resistance. Many metagenomic studies have reported resistome differences between groups, often in connection with disease and/or antibiotic treatment. However, the consistency of resistome associations with antibiotic- and non-antibiotic–treated diseases has not been established. In this study, we re-analysed human gut microbiome data from 26 case-control studies to assess the link between disease and the resistome. Results The human gut resistome is highly variable between individuals both within and between studies, but may also vary significantly between case and control groups even in the absence of large taxonomic differences. We found that for diseases commonly treated with antibiotics, namely cystic fibrosis and diarrhoea, patient microbiomes had significantly elevated ARG abundances compared to controls. Disease-associated resistome expansion was found even when ARG abundance was high in controls, suggesting ongoing and additive ARG acquisition in disease-associated strains. We also found a trend for increased ARG abundance in cases from some studies on diseases that are not treated with antibiotics, such as colorectal cancer. Conclusions Diseases commonly treated with antibiotics are associated with expanded gut resistomes, suggesting that historical exposure to antibiotics has exerted considerable selective pressure for ARG acquisition in disease-associated strains.
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The development of the intestinal microbiome in the neonate starts, mainly, at birth, when the infant receives its founding microbial inoculum from the mother. This microbiome contains genes conferring resistance to antibiotics since these are found in some of the microorganisms present in the intestine. Similarly to microbiota composition, the possession of antibiotic resistance genes is affected by different perinatal factors. Moreover, antibiotics are the most used drugs in early life, and the use of antibiotics in pediatrics covers a wide variety of possibilities and treatment options. The disruption in the early microbiota caused by antibiotics may be of great relevance, not just because it may limit colonization by beneficial microorganisms and increase that of potential pathogens, but also because it may increase the levels of antibiotic resistance genes. The increase in antibiotic-resistant microorganisms is one of the major public health threats that humanity has to face and, therefore, understanding the factors that determine the development of the resistome in early life is of relevance. Recent advancements in sequencing technologies have enabled the study of the microbiota and the resistome at unprecedent levels. These aspects are discussed in this review as well as some potential interventions aimed at reducing the possession of resistance genes.
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Colonisation resistance
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Anthropogenic environments have been implicated in enrichment and exchange of antibiotic resistance genes and bacteria. Here we study the impact of confined and controlled swine farm environments on temporal changes in the gut microbiome and resistome of veterinary students with occupational exposure for 3 months. By analyzing 16S rRNA and whole metagenome shotgun sequencing data in tandem with culture-based methods, we show that farm exposure shapes the gut microbiome of students, resulting in enrichment of potentially pathogenic taxa and antimicrobial resistance genes. Comparison of students' gut microbiomes and resistomes to farm workers' and environmental samples revealed extensive sharing of resistance genes and bacteria following exposure and after three months of their visit. Notably, antibiotic resistance genes were found in similar genetic contexts in student samples and farm environmental samples. Dynamic Bayesian network modeling predicted that the observed changes partially reverse over a 4-6 month period. Our results indicate that acute changes in a human's living environment can persistently shape their gut microbiota and antibiotic resistome.
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Abstract The exposure of the human gut to antibiotics can have a great impact on human health. Antibiotics pertain to the preservation of human health and are useful tools for fighting bacterial infections. They can be used for curing infections and can play a critical role in immunocompromised or chronic patients, or in fighting childhood severe malnutrition. Yet, the genomic and phylogenetic diversity of the human gut changes under antibiotic exposure. Antibiotics can also have severe side effects on human gut health, due to the spreading of potential antibiotic resistance genetic traits and to their correlation with virulence of some bacterial pathogens. They can shape, and even disrupt, the composition and functioning diversity of the human gut microbiome. Traditionally bacterial antibiotic resistances have been evaluated at clone or population level. However, the understanding of these two apparently disparate perspectives as both friends and foes may come from the study of microbiomes as a whole and from the evaluation of both positive and negative effects of antibiotics on microbial community dynamics and diversity. In this review we present some metagenomic tools and databases that enable the studying of antibiotic resistance in human gut metagenomes, promoting the development of personalized medicine strategies, new antimicrobial therapy protocols and patient follow‐up.
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Human Microbiome Project
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ABSTRACT The rising of multiresistant bacterial pathogens is currently one of the most critical threats to global health, demanding a better understanding of the origin and spread of antibiotic resistance. In this regard, the resistome hosted by the microbiota from natural and remote environments remains poorly explored. Moreover, little is known about the availability of antimicrobial resistance genes (ARGs) from these environments to be disseminated through horizontal transfer, potentially mediating the rise of novel resistance factors among clinically relevant pathogens. In this context, the North Antarctica soils are attractive ecosystems to study due to the presence of a microbiota naturally adapted to thrive in harsh conditions, including potential factors to resist natural toxic substances. In this work, we evaluated the antibiotic resistance of bacteria isolated from soils collected in humanized and non-intervened areas of North Antarctica. We identified resistance to a wide array of antibiotics, with isolates harboring up to 10 simultaneous resistances, mainly native Pseudomonas . Genomic analysis revealed the presence of a wide array of genes encoding efflux pumps but the lack of genes explaining some of the resistance phenotypes, suggesting novel uncharacterized mechanisms. Also, using 16S rRNA amplicon and shotgun metagenome sequencing, we explored the microbial diversity in the sampled soils and evaluated the presence of ARGs and their host microbiota. High microbial diversity was found in all the sites, with Proteobacteria, Bacteroidota, Acidobacteriota, and Verrucomicrobiota being the most abundant Phyla, while Candidatus Udaeobacter , RB41, Polaromonas , and Ferruginibacter the most abundant genera. We identified hundreds of genes potentially conferring resistance to more than 15 drug classes, both by short reads analyses and ARG detection among assembled contigs and MAGs obtained combining short and long-read sequence data. Polaromonas, Pseudomonas, Streptomyces, Variovorax, Bhurkolderia , and Gemmatimonas were the main host taxa of the identified ARGs. Part of these ARGs was found inside predicted plasmids, including a putative OXA-like beta-lactamase from Polaromonas harboring the key conserved residues of this kind of enzyme and a conserved predicted protein structure. All this evidence indicates that microbial communities from North Antarctica soil have a highly diverse natural resistome, part of it located inside mobile genetic elements, which would act as a source of novel ARGs.
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Horizontal Gene Transfer
Efflux
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Abstract: The human body habitats are home to an array of micro-organisms, and within these microbial ecosystems there is an exchange of genetic material, including antibiotic resistance genes. Recent metagenomic studies revealed that the human gut microbiota is a reservoir of antibiotic resistant genes (the gut resistome). However, little is known about the diversity and abundances of antibiotic resistance genes in other body habitats and how that compares to the gut resistome. By leveraging the most comprehensive human microbiome dataset of healthy adults generated by the human microbiome project, we characterize the human microbiome resistome from four body habitats including gut (stool), oral, anterior nares and vagina. The human resistome was profiled using a metagenomic shotgun sequencing alignment-based approach. By determining the resistome size per individual we found resistance genes distribute distinctly by body sites with certain body habitats being a better reservoirs then others. Furthermore, while resistance classes were incoming among body habitats (e.g. tetracyclin), the specific resistance genes per class were different (e.g. tetM in oral vs tetQ in gut). The profiles of resistance genes (in the body sites with universally present resistance genes) are more similar for the same subjects over time than between subjects at the same time of sampling. Finally, association analysis with sex, age and geography showed certain significant correlation for habitat specific resistance genes. These findings illustrate that the healthy human microbiota in general, beyond the gut microbiota, is a reservoir for antibiotic resistance genes. This reservoir may serve as a mobile resistance gene pool that facilitates the transmission of antibiotic resistance genes.
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Antibiotic resistance is considered one of the greatest threats to global public health. Resistance is often conferred by the presence of antibiotic resistance genes (ARGs), which are readily found in the oral microbiome. In-depth genetic analyses of the oral microbiome through metagenomic techniques reveal a broad distribution of ARGs (including novel ARGs) in individuals not recently exposed to antibiotics, including humans in isolated indigenous populations. This has resulted in a paradigm shift from focusing on the carriage of antibiotic resistance in pathogenic bacteria to a broader concept of an oral resistome, which includes all resistance genes in the microbiome. Metagenomics is beginning to demonstrate the role of the oral resistome and horizontal gene transfer within and between commensals in the absence of selective pressure, such as an antibiotic. At the chairside, metagenomic data reinforce our need to adhere to current antibiotic guidelines to minimize the spread of resistance, as such data reveal the extent of ARGs without exposure to antimicrobials and the ecologic changes created in the oral microbiome by even a single dose of antibiotics. The aim of this review is to discuss the role of metagenomics in the investigation of the oral resistome, including the transmission of antibiotic resistance in the oral microbiome. Future perspectives, including clinical implications of the findings from metagenomic investigations of oral ARGs, are also considered.
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Horizontal Gene Transfer
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