Highlighted publications

Three or four of each year's publications are highlighted below.

Year 2018

Fecal microbiota transplantation reverses antibiotic and chemotherapy-induced gut dysbiosis in mice

Le Bastard, Q., Ward, T., Sidiropoulos, D., Hillmann, B.M., Chun, C.L., Sadowsky, M.J., Knights, D., Montassier, E., 2018. Sci Rep 8, 6219.

This study showed that fecal microbiota transplantation (FMT) reversed ampicillin- and 5-Fluorouracil-induced gut dysbiosis in a mouse model. Antibiotic and chemotherapy administration caused significant alteration in species distribution, including a decrease in the relative proportions of Clostridium scindens and Faecalibacterium prausnitzii, and an increase of various pathogens, including Acinetobacter baumannii, Enterococcus faecium, Staphylococcus aureus and Clostridium difficile. FMT reversed the disruption of the intestinal microbiota, and increased Faecalibacterium prausnitzii.

Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications
Le Bastard, Q., Al-Ghalith, G.A., Gregoire, M., Chapelet, G., Javaudin, F., Dailly, E., Batard, E., Knights, D., Montassier, E.
Aliment Pharmacol Ther 2018;47:332–345.

In addition to antibacterial agents, numerous drugs alter the intestinal microbiota. Among those drugs are heavily used proton pump inhibitors, metformin, statins, nonsteroidal anti-inflammatory drugs, antipsychotics and antidepressants.

Tetracycline use in the community may promote decreased susceptibility to quinolones in Escherichia coli isolates.
Batard, E., Vibet, M.-A., Thibaut, S., Corvec, S., Pivette, J., Lepelletier, D., Caillon, J., Montassier, E. Eur J Clin Microbiol Infect Dis 2018; 37: 271–276.

Exposure of a population to a given antibiotic may promote resistance to other antibacterial agents, in bacteria that were not targeted by this antibiotic. In this study, we report that tetracyclines promote resistance to quinolones in Escherichia coli, in the ambulatory setting. Of note, tetracyclines are prescribed to treat cutaneous diseases ( e.g. acne) and sexually transmitted diseases, not to treat E. coli infections.
Year 2017
Heisel, T., Montassier, E., Johnson, A., Al-Ghalith, G., Lin, Y.-W., Wei, L.-N., Knights, D., Gale, C.A., 2017. High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut. mSphere 2. https://doi.org/10.1128/mSphere.00351-17

This collaborative study between Minneapolis and Nantes showed that mice fed with a high-fat diet had significantly different abundances of both bacterial and fungal taxa, in comparison with mice fed with a standard diet. Predicted microbiome functional modules related to metabolism were less abundant in high-fat-diet-fed mice.

Birgand, G., Hayatgheib, N., Bemer, P., Guilloteau, V., Legeay, C., Perron, S., Chapelet, G., Corvec, S., Bourigault, C., Batard, E., Lepelletier, D., 2017. Multi-drug-resistant Enterobacteriacae carriage in highly exposed nursing homes:  prevalence in western France. J Hosp Infect 97, 258–259. https://doi.org/10.1016/j.jhin.2017.07.032

This article reports the prevalence of fecal carriage of extended-spectrum beta lactamase (ESBL) producing and carbapenemase producing Enterobacteriaceae in residents of nursing home in western France. We identified no carriage of carbapenemase producing Enterobacteriaceae, and the prevalence of ESBL-producing Enterobacteriaceae (ESBL-E) was 6.4%. We have recently completed the comparative study of the fecal microbiome of ESBL-E carriers and non-carriers.

Batard, E., Vibet, M.-A., Lemarchand, C., Navas, D., Lepelletier, D., Potel, G., Montassier, E., EDANTIBIOTICS Study Group, 2017. Use of broad-spectrum antibiotics in French EDs: different trends for third-generation cephalosporins and fluoroquinolones. Eur J Emerg Med 24, 189–195. https://doi.org/10.1097/MEJ.0000000000000331

Exposure of patients to 3rd generation cephalosporins (3GCs) is a major driver of the extension of 3GC resistance. This multicentric study (11 academic centres) alerts to the increasing use of 3GCs in French Emergency Departments between 2009 and 2012. This increase was associated with a decreased use of fluoroquinolones. These results suggest that decreasing the use of 3GCs, without increasing fluoroquinolone use, should be aimed at through antibiotic stewardship programs in the Emergency Department.
Year 2016

Montassier, E., Al-Ghalith, G.A., Ward, T., Corvec, S., Gastinne, T., Potel, G., Moreau, P., de la Cochetiere, M.F., Batard, E., Knights, D., 2016. Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Med 8, 49. 

This is the first study where we used microbiome data to predict a subsequent clinical event. Here, we showed that patients who developed subsequent blood stream infections (BSI) exhibited decreased overall diversity and decreased abundance of taxa including Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella. Using machine-learning methods, we developed a BSI risk index capable of predicting BSI incidence with a sensitivity of 90 % at a specificity of 90 % based only on the pretreatment fecal microbiome.

Chapelet, G., Corvec, S., Montassier, E., Herbreteau, G., Berrut, G., Batard, E., de Decker, L., 2016. Rapid detection of amoxicillin-susceptible Escherichia coli in fresh uncultured urine: a new tool to limit the use of broad-spectrum empirical therapy of community-acquired pyelonephritis. Int. J. Antimicrob. Agents 47, 486–489.

Fluoroquinolones and 3rd-generation cephalosporins are particularly prone to promote resistance in Enterobacteriaceae. They are often used as an empiciral treatment of community-onset pyelonephritis. When urine culture and antimicrobial susceptibility test is available, it is recommended to de-escalate the empirical treatment to amoxicillin, if the isolate proves to be susceptible to amoxicillin. However, the patient is exposed to 3GC or fluoroquinolone during this 2- or 3-day empirical phase of treatment. This exposure may be avoided, provided that clinicians have a rapid test to establish that a patient with a pyelonephritis is infected by an amoxicillin-susceptible isolate. The test's result should be available within 4 hours. In this study, we designed, developed and evaluated a real-time PCR that identified amoxicillin-susceptible Escherichia coli from fresh, uncultured urines. The lab processing duration was 3h.

Al-Ghalith, G.A., Montassier, E., Ward, H.N., Knights, D., 2016. NINJA-OPS: Fast Accurate Marker Gene Alignment Using Concatenated Ribosomes. PLoS Comput. Biol. 12, e1004658. https://doi.org/10.1371/journal.pcbi.1004658

The analysis of microbiome is resource-consuming. One of this resource is time of bio-informatical analysis. The Dan Knights Lab, with whom Emmanuel Montassier started to collaborate during a post-doc internship, has developed the NINJA-OPS tool to march microbial marker genes with existing databases.

Year 2015

Chemotherapy-driven Dysbiosis in the Intestinal Microbiome

Montassier E, Gastinne T, Vangay P, Al-Ghalith GA, Bruley des Varannes S, Massart S, Moreau P, Potel G, De La Cochetiere MF, Batard E, Knights D. Aliment Pharmacol Ther 2015;42:515-528.

Data have been collected in France during Emmanuel Montassier's PhD scholarship. Bioinformatics and statistical analyses have been deepened during his post-doctoral stay in Dan Knights Lab at the University of Minnesota Minneapolis. Although this study does not focus on antibiotics and bacterial resistance, it shows that the lab now masters powerful tools to study the role of intestinal microbiota in bacterial resistance (including network analysis and the computational prediction of the metagenome functional composition) . Other exciting results from this cohort are currently submitted for publication.

Systematic analysis of the relationship between antibiotic use and extended-spectrum beta-lactamase resistance in Enterobacteriaceae in a French hospital: a time series analysis.

Vibet MA, Roux J, Montassier E, Corvec S, Juvin ME, Ngohou C, Lepelletier D, Batard E. Eur J Clin Microbiol Infect Dis 2015; DOI 10.1007/s10096-015-2437-3

Combining data from the Microbiology lab, Pharmacy and Hospital Information System, we explored the relationship between antibiotic use and ESBL mediated resistance in nosocomial isolates of Enterobacteriaceae. As we suspected it from a previous litterature analysis, we did not find amoxicilin or amoxicillin-clavulanate to be linked with ESBL incidence, although 3rd and 4th generation cephalosporins and fluoroquinolones were. These results encourage us to compare the ecological effects of penicillins, cephalosporins and fluoroquinolones on the intestinal microbiota. Furthermore, our systematic analysis showed that ESBL resistance was linked to tetracycline use. This result is in line with a previous study where we found tetracyclines to be more used in hospitals with the highest rates of fluoroquinolone resistant Escherichia coli. Further works will be conducted on the impact of tetracycline use on cephalosporin and fluoroquinolone resistance.

Challenges of controlling a large outbreak of OXA-48 carbapenemase-producing Klebsiella pneumoniae in a French university hospital.

Semin-Pelletier B, Cazet L, Bourigault C, Juvin ME, Boutoille D, Raffi F, Hourmant M, Blancho G, Agard C, Connault J, Corvec S, Caillon J, Batard E, Lepelletier D. J Hosp Infect 2015; 89(4): 248-53.

This paper describes the incomplete success and high costs of control measures in a large outbreak of Carbapenemase-producing Klebsiella pneumoniae in Centre Hospitalier Universitaire de Nantes. Further works are currently conducted to understand the dynamics of this outbreak. Personalised control measures that we explore in the MiHAR Lab may help us to be more efficient and cost-effective when we face the next epidemics.


Year 2014

Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications.

Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, Le Vacon F, de La Cochetiere MF. Aliment Pharmacol Ther 2014; 40(5): 409-21

This paper reviewed the role of chemotherapy-induced alterations of the intestinal microbiota in mucositis. Future works will have to describe the interaction between antineoplastic chemotherapy, intestinal microbiota, the host mucosa and intestinal carriage of resistant bacteria.

Prolonged hospital stay, an adverse effect of strict national policy for controlling the spread of highly resistant microorganisms.

Birgand G, Schwarzinger M, Perozziello A, Lolom I, Pelat C, Armand-Lefevre L, Buzzi JC, Andremont A, Yazdanpanah Y, Lucet JC. Infect Control Hosp Epidemiol 2014; 35(11): 1427-9.

Before joining the MiHAR Lab, Gabriel Birgand showed that infection control measures for controlling the spread of Highly Resistant Organisms (HRO, including Carbapanemase Producing Enterobacteriaceae and Glycopeptide Resistant Enterococci) resulted in a great and highly significant increase of Length of Stay (LOS), from 21days in HRO-negative patients to 45 days in HRO-positive patients. Current infection control measures are resource-consuming, and they have to be optimized. Personalised strategies, based on host characteristics, antibacterial therapy and intestinal microbiota composition may help to decrease the burden of infection control measures.

16S rRNA gene pyrosequencing reveals shift in patient faecal microbiota during high-dose chemotherapy as conditioning regimen for bone marrow transplantation.

Montassier E, Batard E, Massart S, Gastinne T, Carton T, Caillon J, Le Fresne S, Caroff N, Hardouin JB, Moreau P, Potel G, Le Vacon F, de La Cochetiere MF. Microb Ecol 2014; 67(3): 690-9

This is the first Lab publication where we used High-Throughput 454 DNA Pyrosequencing for analysis, and the QIIME tools for bioinformatics. Here, we detailed the alterations of the intestinal microbiota, in non-Hodgkin's lymphoma patients undergoing bone marrow transplantation conditioning treatment. Microbiota diversity was decreased, and more than 50 taxa varied significantly between the prechemotherapy and postchemotherapy samples.

Increasing use of third-generation cephalosporins for pneumonia in the emergency department: may some prescriptions be avoided?

Goffinet N, Lecadet N, Cousin M, Peron C, Hardouin JB, Batard E, Montassier E. Eur J Clin Microbiol Infect Dis 2014; 33(7): 1095-9

Third-generation cephalosporins, as well as fluoroquinolones, are particularly prone to select resistance in Enterobacteriaceae. In a previous work based on quantities of antibiotics that were delivered by the hospital pharmacy , we showed that the use of 3rd-generation cephalosporins dramatically increased in the Emergency Department between 2002 and 2012, from 9.7% of total antibiotic use to 22.6% (estimate per year,+1.2±0.2%) [Montassier E, Corvec S, Hardouin JB, Potel G, Batard E. Use of fluoroquinolones and third-generation cephalosporins in the emergency department: an 11-year survey. Eur J Emerg Med 2014; 21(6): 442-6]. In this study, by reviewing patient charts, we observed a similar increase in patients treated in the ED for a community-acquired pneumonia, from 13.9 % of patients in 2002 to 29.5 % in 2012. This increase was independent from illness severity, comorbidities and previous antibacterial therapy. Moreover, we estimated that the 3rd-generation cephalosporin was avoidable - i.e. could have been replaced by an antibiotic less prone to select bacterial resistance, like an aminopenicillin -  in 80 % of patients. Since this work, we completed this study with a multicentric investigation, where we found that the proportion of patients treated with a 3rd-generation cephalosporin or a fluoroquinolone was highly variable among EDs [Batard E, Lecadet N, Goffinet N, Hardouin JB, Group TCS, Lepelletier D, Potel G, Montassier E. High variability among Emergency Departments in 3rd-generation cephalosporins and fluoroquinolones use for community-acquired pneumonia. Infection 2015]. Taken together, these results show that 3rd-generation cephalosporins, as well as fluoroquinolones, are overused in ED patients treated for a community-acquired pneumonia, with potential increased risk of intestinal carriage and secondary infection of ESBL producing Enterobacteriaceae.