Resistome expansion in disease-associated human gut microbiomes

Fredriksen, Simen; de Warle, Stef; van Baarlen, Peter; Boekhorst, Jos; Wells, Jerry M.

doi:10.1186/s40168-023-01610-1

Cited by 26 publications

(10 citation statements)

References 91 publications

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“…We found a trend for case piglets having a higher abundance of ARGs than control piglets, despite case-control pairs having received equal antimicrobial treatment. A similar effect of disease-associated resistome expansion can be observed in the human gut microbiome [35]. In the present study, ARGs conferring resistance to doxycycline and tetracycline had the strongest case-association, and ARGs conferring resistance to other antimicrobials used against S. suis also trended towards being more abundant in case piglets.…”

Section: Discussionsupporting

confidence: 82%

Streptococcus suis infection on European farms is associated with an altered tonsil microbiome and resistome

Fredriksen

Neila‐Ibáñez

Hennig-Pauka

et al. 2022

Preprint

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Introduction Streptoccocus suis is a Gram-positive opportunistic pathogen causing systemic disease in piglets around weaning age. Outbreaks of S. suis disease are controlled by metaphylactic use of antibiotics, leading to high levels of antimicrobial resistance in S. suis isolates. This is an issue for both animal and human health due to the zoonotic disease potential of S. suis. The mechanisms facilitating invasive disease are not known but may involve host and environmental factors. The palatine tonsils are considered a portal of entry for pathogenic strains to cause systemic disease. We hypothesised that tonsil colonization by pathogenic and commensal bacteria may impact on disease risk via colonization resistance and co-infections. We conducted a case-control study on 9 European farms, comparing the tonsil microbiome of piglets with S. suis systemic disease with asymptomatic controls. We also compared these to piglets on control farms and piglets reared naturally in a forest. Results We found a small but significant difference in the tonsil microbiota composition of case and control piglets. Case-control associations varied between amplicon sequence variants (ASVs) and metagenome assembled genomes (MAGs) within the same species. Variants of putatively commensal taxa including Rothia nasimurium were reduced in abundance in case piglets compared to asymptomatic controls. Case piglets had higher relative abundance of Fusobacterium gastrosuis, Bacteroides heparinolyticus, and uncultured Prevotella and Alloprevotella species. There was, however, no higher abundance of S. suis itself at the species-level or of clinical strain marker genes in case piglets. Piglets sampled prospectively weeks prior to developing clinical signs had reduced microbiota alpha diversity. Despite case-control pairs receiving equal antimicrobial treatment, case piglets had higher abundance of antimicrobial resistance genes (ARGs) conferring resistance to antimicrobial classes used to treat S. suis. Conclusions The tonsillar microbiota of S. suis case piglets had increased abundance of taxa not previously linked to S. suis disease. This coincided with increased ARG abundance in case piglets, possibly due to adaptation of the disease-associated microbiota to frequent antimicrobial treatment.

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Section: Discussionsupporting

confidence: 82%

Streptococcus suis infection on European farms is associated with an altered tonsil microbiome and resistome

Fredriksen

Neila‐Ibáñez

Hennig-Pauka

et al. 2022

Preprint

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“…Our patient cohort consists of mostly elderly people with significant comorbidity and disturbance of the gut microbiota by multiple courses of antibiotic treatment for recurrent C. difficile infections. This has been described to alter the gut resistome [ 61 ]. Contrastingly, the gut of healthy individuals harbours mainly anaerobic commensal bacteria, which frequently carry aminoglycoside and tetracycline resistance genes [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Long-term beneficial effect of faecal microbiota transplantation on colonisation of multidrug-resistant bacteria and resistome abundance in patients with recurrent Clostridioides difficile infection

Nooij,

Vendrik,

Zwittink

et al. 2024

Genome Med

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Background Multidrug-resistant (MDR) bacteria are a growing global threat, especially in healthcare facilities. Faecal microbiota transplantation (FMT) is an effective prevention strategy for recurrences of Clostridioides difficile infections and can also be useful for other microbiota-related diseases. Methods We study the effect of FMT in patients with multiple recurrent C. difficile infections on colonisation with MDR bacteria and antibiotic resistance genes (ARG) on the short (3 weeks) and long term (1–3 years), combining culture methods and faecal metagenomics. Results Based on MDR culture (n = 87 patients), we notice a decrease of 11.5% in the colonisation rate of MDR bacteria after FMT (20/87 before FMT = 23%, 10/87 3 weeks after FMT). Metagenomic sequencing of patient stool samples (n = 63) shows a reduction in relative abundances of ARGs in faeces, while the number of different resistance genes in patients remained higher compared to stools of their corresponding healthy donors (n = 11). Furthermore, plasmid predictions in metagenomic data indicate that patients harboured increased levels of resistance plasmids, which appear unaffected by FMT. In the long term (n = 22 patients), the recipients’ resistomes are still donor-like, suggesting the effect of FMT may last for years. Conclusions Taken together, we hypothesise that FMT restores the gut microbiota to a composition that is closer to the composition of healthy donors, and potential pathogens are either lost or decreased to very low abundances. This process, however, does not end in the days following FMT. It may take months for the gut microbiome to re-establish a balanced state. Even though a reservoir of resistance genes remains, a notable part of which on plasmids, FMT decreases the total load of resistance genes.

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“…4A and B ). Antibiotic exposure in patients with CF has been associated with increased intestinal carriage of antibiotic-resistant bacteria compared to healthy controls which are a poor prognostic factor ( 83 – 85 ). Following ELX/TEZ/IVA, patients in our cohort required far fewer antibiotics ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

Reasoner,

Bernard,

Waalkes

et al. 2024

mBio

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The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores the function of the pathogenic mutated CF transmembrane conductance regulator (CFTR) channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in body mass index and percent predicted forced expiratory volume in one second, and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus , the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA. IMPORTANCE Cystic fibrosis (CF) is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Recently approved treatments for CF, CF transmembrane conductance regulator (CFTR) modulators, are anticipated to substantially improve the care of people with CF and extend their lifespans. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease.

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Resistome expansion in disease-associated human gut microbiomes

Cited by 26 publications

References 91 publications

Streptococcus suis infection on European farms is associated with an altered tonsil microbiome and resistome

Streptococcus suis infection on European farms is associated with an altered tonsil microbiome and resistome

Long-term beneficial effect of faecal microbiota transplantation on colonisation of multidrug-resistant bacteria and resistome abundance in patients with recurrent Clostridioides difficile infection

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

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