Biology subjects

Burdet, C.

Publications and source records attributed to Burdet, C..

5 recordsLinked to original sources

bioRxiv2025

Third-generation cephalosporin antibiotics induce phage bursts in the human gut microbiome.

The use of antibiotics disrupts the gut microbiota, potentially leading to long-term health issues and the spread of resistance. To investigate the impact of antibiotics on phage populations, we followed 22 healthy individuals two weeks before and up to six months after a three-day course of 3rd-generation cephalosporins. The populations of phages very rarely encoded antibiotic resistance genes and were mostly temperate including many phage-plasmids. Gut phages remained individual-specific even after microbiome perturbation by antibiotics. Yet, we found a 20% decline in phage diversity the day after treatment, alongside blooms of a few (mostly virulent) phages. We suggest that these temporary dominant phages contribute to the recovery of gut bacterial diversity through kill-the-winner dynamics. This is supported by the finding that several phages targeted Parabacteroides distasonis, a bacterium thriving after cephalosporin treatment, and which only proliferated when these phages were absent.Our findings suggest that phages play a crucial role in the gut microbiotas response to antibiotics by contributing to the restoration of microbial balance and diversity. HighlightsO_LIIn healthy individuals, cephalosporin antibiotics cause an approx. 20% decline in gut phage richness that is restored after 30 days C_LIO_LIHuman gut phage communities are specific of each individual, which is retained post-antibiotic treatment C_LIO_LIAntibiotic perturbation causes an increase in the number of dominant virulent phages supporting kill-the-winner dynamics as mechanisms for shaping bacterial diversity C_LIO_LIDominance of Parabacteroides distasonis (after cephalosporin treatment) is likely disrupted through its specific phages C_LI eTOCAntibiotic-induced disruption of the gut microbiome leads to a transient loss of microbiome diversity (bacterial and viral) and causes blooms of bacteria and their viruses. Our analysis suggests that these viruses prey on dominant bacteria, prevent their dominance, and contribute to the recovery of microbiome balance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/636470v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@98c366org.highwire.dtl.DTLVardef@1446921org.highwire.dtl.DTLVardef@51f941org.highwire.dtl.DTLVardef@1c328ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans

Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostics, prevention and treatment is still lacking. We used a collection of 1282 BSI and commensal E. coli isolates collected in France over a 17-year period (2000-2017) and we compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity increased steadily from 23% in 1980 to 46% in 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity.

microbiology↗

bioRxiv2019

Unexpected activity of oral fosfomycin against resistant strains of Escherichia coli in murine pyelonephritis.

Fosfomycin-tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of Escherichia coli (fosfomycin MICs: 1 g/ml to 256 g/ml). Urine pH was 4.5 before infection and 5.5-6.0 during infection. Animals were treated for 24h with fosfomycin (100 mg/kg subcutaneously every 4 hours) and CFU were enumerated in kidneys 24h after the last fosfomycin injection. Peak (20.5 g/ml at 1h) and trough (3.5 g/ml at 4h) levels in plasma were comparable to those obtained in human after an oral dose of 3 grams. Fosfomycin treatment significantly reduced bacterial loads in kidneys (3.65 log10CFU/g [min-max=1.83-7.03] and 1.88 log10CFU/g [1.78-5.74] in start-of-treatment control mice and treated mice, respectively, P < 10-6). However, this effect was not found to differ across the 6 study strains (P = 0.71) and between the 3 susceptible and the 3 resistant strains (P=0.09). Three phenomena may contribute to explain this unexpected in vivo activity: i) in mice, fosfomycin kidney/plasma concentrations ratio increased from 1 to 7.8 (95% CI, 5.2; 10.4) within 24 hours; in vitro, when pH decreased to 5: (ii) fosfomycin MICs for the 3 resistant strains (64-256 g/ml) decreased into the susceptible range (16-32 g/ml) and: iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favour fosfomycin activity in pyelonephritis, even against resistant strains.

microbiology↗

bioRxiv2018

Antibiotic-induced dysbiosis predicts mortality in an animal model of Clostridium difficile infection

BackgroundAntibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality.\n\nMethodsWe administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D1) to D5, and challenged them with a C. difficile toxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals.\n\nResultsIncreasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p<10-5 for the change of Shannon index in moxifloxacin-treated animals and p<10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively.\n\nConclusionsAltogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.

microbiology↗

bioRxiv2017

Protection of the human gut microbiome from antibiotics

BackgroundAntibiotics are life-saving drugs but severely affect the gut microbiome with short term consequences including diarrhoea, Clostridium difficile infections and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers.\n\nMethodsWe performed a randomized controlled trial (ClinicalTrials.gov NCT02176005) in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in two parallel groups, with or without DAV132 co-administration. Two control goups of 8 volunteers each receiving DAV132 alone, or a non-active substitute, were added.\n\nResultsThe co-administration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex-vivo.\n\nConclusionsDAV132 was highly effective to protect the gut microbiome of moxifloxacin - treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments.

clinical trials↗