Biology subjects

Magnan, M.

Publications and source records attributed to Magnan, M..

12 recordsLinked to original sources

bioRxiv2026

High-resolution lineage tracking maps the multi-phase evolution and adaptive potential of biofilms

Although biofilms represent the dominant bacterial lifestyle and are major contributors to recalcitrant, treatment-resistant infections, their evolutionary dynamics at the individual lineage resolution remain poorly understood. We combine DNA barcoding-mediated lineage tracking and spatial sampling of > 100,000 lineages of Escherichia coli to characterize sequential phases of biofilm evolution quantitatively. Severe founder effects during surface colonization initially reduce the effective population size by nearly three orders of magnitude, establishing significant spatial segregation. This structure is subsequently eroded by a previously underappreciated secondary migration phase, during which cells released upon perturbation recolonize biofilms with a rate 103-fold higher than naive planktonic cells. Adaptive evolution subsequently drives specialization through mutations targeting these distinct stages of the biofilm life cycle. Under severe antibiotic bottlenecks, active secondary migration continuously resuscitates local lineage diversity, enabling the parallel emergence of resistance across hundreds of independent lineages. Once locally established, migration drives a rapid spatial spread of resistant mutants. Together, these findings reveal how spatial segregation and secondary migration shape biofilm dynamics, coupling short-term ecological resilience with long-term adaptive potential.

microbiology↗

bioRxiv2026

Collective protection drives human gut microbiota response to amoxicillin treatment.

The gut microbiota is central to human health, contributing to nutrient processing, metabolite production and protection against pathogens. Yet it is also an unintended target of antibiotic treatments, particularly after oral administration. Antibiotic exposure can therefore disrupt community structure, leading to dysbiosis and promoting the selection of resistant bacteria. Although studies in patients and animal models have shown that these effects vary markedly between individuals, host-related factors have made it difficult to isolate the specific contribution of the microbiota itself. Here, we used a controlled in vitro gut model (MBRA) to examine how 16 human gut microbiotas from the NutriNet-Sante cohort respond to the widely prescribed {beta}-lactam amoxicillin (AMX). By combining dense temporal sampling, 16S amplicon sequencing and mass spectrometry, we observed highly heterogeneous response trajectories, ranging from near-stable communities to strong but reversible disruptions. These differences were not only reflected in the final magnitude of perturbation, but also in the timing, pace and recovery of microbiota change during treatment. Initial community composition partly structured these responses, as Lachnospiraceae/Bacteroidaceae ratio strongly correlated with perturbation. Dynamic quantification of AMX further showed that microbiotas differed in their capacity to deplete the drug over time, thereby altering the duration of exposure above critical concentration thresholds. Supplementation with clavulanic acid that inhibits {beta}-lactamases confirmed that this process was largely mediated by {beta}-lactamase activity. Finally, microbiotas displaying rapid AMX depletion showed reduced selection of resistant Enterobacteriaceae. Together, our results indicate that both initial community composition and the temporal dynamics of antibiotic inactivation jointly determine microbiota resilience and resistance selection.

microbiology↗

bioRxiv2025

High-Throughput Conjugation Reveals Strain Specific Recombination Patterns Enabling Precise Trait Mapping in Escherichia coli

Genetic exchange is a cornerstone of evolutionary biology and genomics, driving adaptation and enabling the identification of genetic determinants underlying phenotypic traits. In Escherichia coli, horizontal gene transfer via conjugation and transduction not only promotes diversification and adaptation but has also been instrumental in mapping genetic traits. However, the dynamics and variability of bacterial recombination remain poorly understood, particularly concerning the patterns of recombined DNA fragments. To elucidate these patterns and simultaneously develop a tool for trait mapping, we designed a high-throughput conjugation method to generate recombinant libraries. Recombination profiles were inferred through whole-genome sequencing of individual clones and populations after selection of a marker from the donor strain in the recipient. This analysis revealed an extraordinary range of recombined fragment sizes, spanning less than ten kilobases to over a megabase--a pattern that varied across the three tested strains. Mathematical modelling indicated that this diversity in recombined fragment size enables precise identification of selected loci following genetic crosses. Consistently, population sequencing pinpointed a selected marker at kilobase-scale accuracy, offering a robust tool for identifying subtle genetic determinants that could include point mutations in core genes. These findings challenge the conventional view that conjugation always transfers large fragments, suggesting that even short recombined segments, traditionally attributed to transduction, may originate from conjugation.

microbiology↗

bioRxiv2024

Genomic evidence of Escherichia coli gut population diversity translocation in leukemia patients

Escherichia coli, a commensal species of the human gut, is an opportunistic pathogen which can reach extra-intestinal compartments, including the bloodstream and the bladder, among others. In non-immunosuppressed patients, purifying or neutral evolution of E. coli populations has been reported in the gut. Conversely, it has been suggested that when migrating to extra-intestinal compartments, E. coli genomes undergo diversifying selection as supported by strong evidence for adaptation. The level of genomic polymorphism and the size of the populations translocating from gut to extra-intestinal compartments is largely unknown. To gain insights in the pathophysiology of these translocations, we investigated the level of polymorphism and the evolutionary forces acting on the genomes of 77 E. coli isolated from various compartments in three immunosuppressed patients. Each patient had a unique strain which was a mutator in one case. In all instances, we observed that translocation encompasses the majority of the genomic diversity present in the gut. The same signature of selection, whether purifying or diversifying, and as anticipated, neutral for mutator isolates, was observed in both the gut and bloodstream. Additionally, we found a limited number of non-specific mutations among compartments for non-mutator isolates. In all cases, urine isolates were dominated by neutral selection. These findings indicate that substantial proportions of populations are undergoing translocation and that they present a complex compartment-specific pattern of selection at the patient level. ImportanceIt has been suggested that intra and extra-intestinal compartments differentially constrain the evolution of E. coli strains. Whether host particular conditions, such as immunosuppression, could affect the strain evolutionary trajectories remain understudied. We found that, in immunosuppressed patients, large fractions of E. coli gut populations are translocating with variable modifications of the signature of selection for commensal and pathogenic isolates according to the compartment and/or the patient. Such multiple site sampling should be performed in large cohorts of patients to get a better understanding of E. coli extra-intestinal diseases.

microbiology↗

bioRxiv2024

Lessons from twenty years of the life of commensal Escherichia coli populations in a human gut

Escherichia coli is an increasingly antibiotic-resistant opportunistic pathogen. Few data are available on its ecological and evolutionary dynamics in its primary commensal niche, the vertebrate gut. Using Illumina and/or Nanopore technologies, we sequenced whole genomes of 210 E. coli isolates from 22 stools sampled during a 20-year period from a healthy man (ED) living in Paris, France. All phylogroups, except C, were represented, with a predominance of B2 (34.3%), followed by A and F (19% each) phylogroups. Thirty-five clones were identified based on their haplogroup and pairwise genomic single nucleotide polymorphism distance and classified in three phenotypes according to their abundance and residence time: 25 sub-dominant/transient (52 isolates), five dominant/transient (48 isolates) and five dominant/resident (110 isolates). Four over five dominant/resident clones belonged to B2 and closely related F phylogroups, whereas sub-dominant/transient clones belonged mainly to B1, A and D phylogroups. The long residence times of B2 clones seemed to be counterbalanced by lower colonization abilities. Clones with larger within-host frequency persisted for longer in the host. By comparing ED strain genomes to a collection of commensal E. coli genomes from 359 French individuals, we identified ED-specific genomic properties including a set of genes involved in a metabolic pathway (mhp cluster) and a very rare antiviral defense island. The E. coli colonization within the gut microbiota was shaped by both the intrinsic properties of the strain lineages, in particular longer residence of phylogroup B2, and the environmental constraints such as diet or phages.

microbiology↗

bioRxiv2024

Escherichia coli extra-intestinal population translocation in leukemia patients

Escherichia coli, a commensal species of the human gut, is an opportunistic pathogen which can reach extra-intestinal compartments, including the bloodstream and the bladder, among others. In non-immunosuppressed patients, purifying or neutral evolution of E. coli populations has been reported in the gut. Conversely, it has been suggested that when migrating to extra-intestinal compartments, E. coli genomes undergo diversifying selection as supported by strong evidence for adaptation. The level of genomic polymorphism and the size of the populations translocating from the gut to extra-intestinal compartments is largely unknown. To gain insights in the pathophysiology of these translocations, we investigated the level of polymorphism and the evolutionary forces acting on the genomes of 77 E. coli isolated from various compartments in three immunosuppressed patients. We detected a unique strain for each patient across the blood, the urine and the gut. In one case, all isolates recovered were mutators i.e. isolates with a very high mutation rate. In all instances, we observed that translocation encompasses the majority of the genomic diversity present in the gut. The same signature of selection, whether purifying or diversifying, and as anticipated, neutral for mutator isolates, was observed in both the gut and bloodstream. Additionally, we found a limited number of non-specific mutations among compartments for non-mutator isolates. In all cases, urine isolates were dominated by neutral selection. These findings indicate that substantial proportions of populations are undergoing translocation and that they present a complex compartment-specific pattern of selection at the patient level. ImportanceIt has been suggested that intra and extra-intestinal compartments differentially constrain the evolution of E. coli strains. Whether host particular conditions, such as immunosuppression, could affect the strain evolutionary trajectories remain understudied. We found that, in immunosuppressed patients, large fractions of E. coli gut populations are translocating with variable modifications of the signature of selection for commensal and pathogenic isolates according to the compartment and/or the patient. Such multiple site sampling should be performed in large cohorts of patients to get a better understanding of E. coli extra-intestinal diseases.

microbiology↗

bioRxiv2023

Epigenetic control of myogenic identity of human muscle stem cells in Duchenne Muscular Dystrophy

In Duchenne Muscular Dystrophy (DMD), the absence of the subsarcolemmal dystrophin protein leads to repeated myofiber damages inducing cycles of muscle regeneration that is driven by muscle stem cells (MuSCs). With time, MuSC regenerative capacities are overwhelmed, leading to fibrosis and muscle atrophy. Whether MuSCs from DMD muscle have intrinsic defects that limit regenerative potential or are disrupted by their degenerative/regenerative environment is unclear. We investigated cell behavior and gene expression in human using MuSCs derived from DMD or healthy muscles. We found that proliferation, differentiation and fusion were not altered in DMD-MuSCs, but with time, they lost their myogenic identity twice as fast as healthy MuSCs. The rapid drift towards a fibroblast-like cell identity was observed at the clonal level, and resulted from the altered expression of epigenetic enzymes required to maintain the myogenic cell fate. Indeed, the re-expression of CBX3, SMC3, H2AFV and H3F3B prevented the MuSC identity drift. Amongst the epigenetic changes, a closing of chromatin at the gene encoding the transcription factor MEF2B caused a down-regulation of its expression and a loss of the myogenic fate. Thus, MEF2B is a key mediator of the myogenic identity in human MuSCs, that is altered in DMD pathology.

genomics↗

bioRxiv2023

Dissemination of IncI plasmid encoding blaCTX-M-1 is not hampered by its fitness cost in the pig's gut.

Multiresistance plasmids belonging to the IncI incompatibility group have become one of the most pervasive plasmid types in extended-spectrum beta-lactamase producing Escherichia coli of animal origin. The extent of the burden imposed on the bacterial cell by these plasmids seems to contribute to the emergence of "epidemic" plasmids. However, in vivo data in the natural environment of the strain are scarce. Here, we investigated the cost of a blaCTX-M-1-IncI1 epidemic plasmid in a commensal E. coli animal strain, UB12-RC, before and after oral inoculation of fifteen 6-to 8-week-old specific pathogen-free pigs. Growth rate in rich medium was determined on (i) UB12-RC and derivatives, with or without plasmid, in vivo and/or in vitro evolved, and (ii) strains that acquired the plasmid in the gut during the experiment. Although blaCTX-M-1-IncI1 plasmid imposed no measurable burden on the recipient strain after conjugation and during the longitudinal carriage in the pigs gut, we observed a significant difference in the bacterial growth rate between IncI1 plasmid-carrying and plasmid-free isolates collected during in vivo carriage. Only a few mutations on the chromosome of the UB12-RC derivatives were detected by whole-genome sequencing. RNA-Seq analysis of a selected set of these strains showed that transcriptional responses to the blaCTX-M-1-IncI1 acquisition were limited, affecting metabolism, stress response, and motility functions. Our data suggest that the effect of IncI plasmid on host cells is limited, fitness cost being insufficient to act as a barrier to IncI plasmid spread among natural population of E. coli in the gut niche.

microbiology↗

bioRxiv2022

Faecal carriage of ESBL-producing Escherichia coli in a remote region of Niger

ObjectiveWhole genome sequencing (WGS) of extended-spectrum {beta}-lactamase-producing Escherichia coli (ESBL-E. coli) in developing countries is lacking. Here we describe the population structure and molecular characteristics of ESBL-E. coli faecal isolates in rural Southern Niger. MethodsStools of 383 healthy participants were collected among which 92.4% were ESBL-E. coli carriers; 90 of these ESBL-E. coli containing stools (109 ESBL-E. coli isolates) were further analysed by WGS, using short- and long-reads. ResultsMost isolates belonged to the commensalism-adapted phylogroup A (83.5%), with high clonal diversity. The blaCTX-M-15 gene was the major ESBL determinant (98.1%), chromosome-integrated in approximately 50% of cases, in multiple integration sites. When plasmid-borne, blaCTX-M-15 was found in IncF (57.4%) and IncY plasmids (26.2%). Closely related plasmids were found in different genetic backgrounds. Genomic environment analysis of blaCTX-M-15 in closely related strains argued for mobilisation between plasmids or from plasmid to chromosome. ConclusionsMassive prevalence of community faecal carriage of CTX-M-15-producing E. coli was observed in a rural region of Niger due to the spread of highly diverse A phylogroup commensalism-adapted clones, with frequent chromosomal integration of blaCTX-M-15. Plasmid spread was also observed. These data suggest a risk of sustainable implementation of ESBL in community faecal carriage.

microbiology↗

bioRxiv2022

The evolution of fitness effects during long-term adaptation in bacteria

The distribution of fitness effects of new mutations is central to predicting adaptive evolution, but observing how it changes as organisms adapt is challenging. Here we use saturated, genome-wide insertion libraries to quantify how the fitness effects of new mutations changed in two E. coli populations that adapted to a constant environment for 15,000 generations. The proportions of neutral and deleterious mutations remained constant, despite large fitness gains. In contrast, the beneficial fraction declined rapidly, approximating an exponential distribution, with strong epistasis profoundly changing the genetic identity of adaptive mutations. Despite this volatility, many important targets of selection were predictable from the ancestral distribution. This predictability occurs because genetic target size contributed to the fixation of beneficial mutations as much as or more than their effect sizes. Overall, our results demonstrate that short-term adaptation can be idiosyncratic but empirically predictable, and that long-term dynamics can be described by simple statistical principles. One-Sentence SummaryCouce et al. demonstrate that short-term bacterial adaptation is predictable at the scale of individual genes, while long-term adaptation is predictable at a global scale.

evolutionary biology↗

bioRxiv2020

Relationship between the composition of the digestive microbiota and the concentrations of opportunistic pathogens in intensive care patients.

ObjectiveInfections caused by multidrug-resistant Gram-negative bacilli (MDR-GNB) are a major issue in intensive care. The intestinal and oropharyngeal microbiota being the reservoir of MDR-GNB. Our main objective was to assess the link between the composition of the intestinal and tracheal microbiota and colonization by MDR-GNB. MethodsWe performed a 2-month prospective, monocentric cohort study in the medical intensive care unit of our hospital. Patients ventilated >3 days and spontaneously passing faeces were included. A faecal sample and an endotracheal aspiration (EA) were collected twice a week. MDR-GNB but also Enterococcus faecium and yeasts (as potential dysbiosis surrogate markers) were detected by culture methods. The composition of the intestinal and tracheal microbiota was assessed by 16S profiling. ResultsWe collected 62 couples of faeces and EA from 31 patients, including 18 faeces and 9 EA positive for MDR-GNB. We did not observe a link between the diversity and the richness of the intestinal microbiota and the MDR-GNB intestinal relative abundance (RA). Conversely, we observed a negative link between the intestinal diversity and richness and the RA of Enterococcus spp. (p<0.001). ConclusionThe intestinal MDR-GNB RA was not associated to the diversity nor the richness of the intestinal microbiota, but that of Enterococcus spp. was.

microbiology↗

bioRxiv2018

The molecular basis of genetic interaction diversity in a metabolic pathway

Our ability to predict the impact of mutations on traits relevant for disease and evolution remains severely limited by the dependence of their effects on the genetic background and environment. Even when molecular interactions between genes are known, it is unclear how these translate to organism-level interactions between alleles. We therefore characterized the interplay of genetic and environmental dependencies in determining fitness by quantifying ~4,000 fitness interactions between expression variants of two metabolic genes, in different environments. We detect a remarkable variety of environment-dependent interactions, and demonstrate they can be quantitatively explained by a mechanistic model accounting for catabolic flux, metabolite toxicity and expression costs. Complex fitness interactions between mutations can therefore be predicted simply from their simultaneous impact on a few connected molecular phenotypes.

genetics↗