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1. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases

Author

d’Humières, Camille, Delavy, Margot, Alla, Laurie, Ichou, Farid, Gauliard, Emilie, Ghozlane, Amine, Levenez, Florence, Galleron, Nathalie, Quinquis, Benoit, Pons, Nicolas, Mullaert, Jimmy, Bridier-Nahmias, Antoine, Condamine, Bénédicte, Touchon, Marie, Rainteau, Dominique, Lamazière, Antonin, Lesnik, Philippe, Ponnaiah, Maharajah, Lhomme, Marie, Sertour, Natacha, Devente, Savannah, Docquier, Jean-Denis, Bougnoux, Marie-Elisabeth, Tenaillon, Olivier, Magnan, Mélanie, Ruppé, Etienne, Grall, Nathalie, Duval, Xavier, Ehrlich, Dusko, Mentré, France, Denamur, Erick, Rocha, Eduardo P. C., Le Chatelier, Emmanuelle, and Burdet, Charles

Published
2024
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3. Unveiling Candida albicans intestinal carriage in healthy volunteers: the role of micro- and mycobiota, diet, host genetics and immune response

Author

Delavy, Margot, primary, Sertour, Natacha, additional, Patin, Etienne, additional, Le Chatelier, Emmanuelle, additional, Cole, Nathaniel, additional, Dubois, Florian, additional, Xie, Zixuan, additional, Saint-André, Violaine, additional, Manichanh, Chaysavanh, additional, Walker, Alan W., additional, Quintana-Murci, Lluis, additional, Duffy, Darragh, additional, d’Enfert, Christophe, additional, Bougnoux, Marie-Elisabeth, additional, and Consortium, Milieu Intérieur, additional

Published
2023
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4. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases.

Author

d'Humières, Camille, Delavy, Margot, Alla, Laurie, Ichou, Farid, Gauliard, Emilie, Ghozlane, Amine, Levenez, Florence, Galleron, Nathalie, Quinquis, Benoit, Pons, Nicolas, Mullaert, Jimmy, Bridier-Nahmias, Antoine, Condamine, Bénédicte, Touchon, Marie, Rainteau, Dominique, Lamazière, Antonin, Lesnik, Philippe, Ponnaiah, Maharajah, Lhomme, Marie, and Sertour, Natacha

Subjects
GUT microbiome, VOLUNTEERS, DRUG resistance in bacteria, MICROBIAL metabolites, HUMAN microbiota, VOLUNTEER service, CEFOTAXIME, LACTAMS
Abstract

Background: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. Results: While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. Conclusions: In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. 64G36U-BwhYzB4Dx7Xcq3U Video Abstract [ABSTRACT FROM AUTHOR]

Published
2024
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5. Perturbation and resilience of the gut microbiome up to three months after β-lactams exposure in healthy volunteers suggest an important role of endogenous β-lactamases

Author

d'Humières, Camille, primary, Delavy, Margot, additional, Alla, Laurie, additional, Ichou, Farid, additional, gauliard, Emilie, additional, Ghozlane, Amine, additional, Levenez, Florence, additional, Galleron, Nathalie, additional, Quinquis, Benoit, additional, Pons, Nicolas, additional, Mullaert, Jimmy, additional, Bridier-Nahmias, Antoine, additional, Condamine, Bénédicte, additional, Touchon, Marie, additional, Rainteau, Dominique, additional, Lamazière, Antonin, additional, Lesnik, Philippe, additional, Ponnaiah, Maharajah, additional, Lhomme, Marie, additional, Sertour, Natacha, additional, Devente, Savannah, additional, Docquier, Jean-Denis, additional, Bougnoux, Marie-Elisabeth, additional, Tenaillon, Olivier, additional, Magnan, Mélanie, additional, Ruppe, Etienne, additional, Grall, Nathalie, additional, Duval, Xavier, additional, Ehrlich, Dusko, additional, Mentre, France, additional, Denamur, erick, additional, Rocha, Eduardo P C, additional, Chatelier, Emmanuelle Le, additional, and Burdet, Charles, additional

Published
2023
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6. A Clinical Study Provides the First Direct Evidence That Interindividual Variations in Fecal β-Lactamase Activity Affect the Gut Mycobiota Dynamics in Response to β-Lactam Antibiotics

Author

Delavy, Margot, Burdet, Charles, Sertour, Natacha, Devente, Savannah, Docquier, Jean-Denis, Grall, Nathalie, Volant, Stevenn, Ghozlane, Amine, Duval, Xavier, Mentré, France, D’enfert, Christophe, Bougnoux, Marie-Elisabeth, Study Group, Predires, Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Siena = University of Siena (UNISI), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], This work was supported by grants from Agence Nationale de la Recherche (FunComPath ANR-14-IFEC-0004 and PrediRes ANR-16-CE15-0022), the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases [ANR10-LABX-62-IBEID]), the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action, Innovative Training Network (FunHoMic, Grant No. 812969) and Assistance Publique – Hôpitaux de Paris (CEREMI CRC13-179)., For the PrediRes study group: Charles Burdet (INSERM, Université de Paris APHP-Bichat Hospital), Erick Denamur (INSERM, Université de Paris), Xavier Duval (INSERM, Université de Paris, APHP-Bichat Hospital), Dusko Ehrlich (INRA Metagenopolis), France Mentré (INSERM, Université de Paris, APHP-Bichat Hospital), Eduardo P. C. Rocha (Institut Pasteur), Laurie Alla (INRA Metagenopolis), Emmanuelle Lechatelier (INRA Metagenopolis), Florence Levenez (INRA Metagenopolis), Nicolas Pons (INRA Metagenopolis), Benoît Quinquis (INRA Metagenopolis), Khadija Bourabha (INSERM), Antoine Bridier Nahmias (INSERM, Université de Paris), Olivier Clermont (INSERM, Université de Paris), Mélanie Magnan (INSERM, Université de Paris), Olivier Tenaillon (INSERM, Université de Paris), Camille d’Humières (INSERM, Université de Paris, APHP-Bichat Hospital, Institut Pasteur), Amandine Perrin (Institut Pasteur), Marie Touchon (Institut Pasteur), Dominique Rainteau (INSERM, Université Pierre et Marie Curie, APHP – Saint Antoine Hospital), Farid Ichou (ICAN), Philippe Lesnik (ICAN), Jimmy Mullaert (INSERM, Université de Paris, APHP – Bichat Hospital), Thu Thuy Nguyen (INSERM)., ANR-14-IFEC-0004,FunComPath,From fungal commensalism to pathogenicity:dissection of the colonization-to-infection shift of Candida albicans(2014), ANR-16-CE15-0022,PREDIRES,PREDIction de l'émergence de la RESistance bactérienne dans le microbiote intestinal humain lors d'un traitement antibiotique(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 812969,H2020-MSCA-ITN-2018,FunHoMic(2019)

Subjects
beta-lactamases, healthy individuals, Virology, [SDV]Life Sciences [q-bio], Candida albicans, gut mycobiota, Microbiology, antibiotics
Abstract

International audience; Antibiotics disturb the intestinal bacterial microbiota, leading to gut dysbiosis and an increased risk for the overgrowth of opportunistic pathogens. It is not fully understood to what extent antibiotics affect the fungal fraction of the intestinal microbiota, the mycobiota. There is no report of the direct role of antibiotics in the overgrowth in healthy humans of the opportunistic pathogenic yeast Candida albicans. Here, we have explored the gut mycobiota of 22 healthy subjects before, during, and up to 6 months after a 3-day regimen of third-generation cephalosporins (3GCs). Using ITS1-targeted metagenomics, we highlighted the strong intra- and interindividual diversity of the healthy gut mycobiota. With a specific quantitative approach, we showed that C. albicans prevalence was much higher than previously reported, with all subjects but one being carriers of C. albicans, although with highly variable burdens. 3GCs significantly altered the mycobiota composition and the fungal load was increased both at short and long term. Both C. albicans relative and absolute abundances were increased but 3GCs did not reduce intersubject variability. Variations in C. albicans burden in response to 3GC treatment could be partly explained by changes in the levels of endogenous fecal β-lactamase activity, with subjects characterized by a high increase of β-lactamase activity displaying a lower increase of C. albicans levels. A same antibiotic treatment might thus affect differentially the gut mycobiota and C. albicans carriage, depending on the treated subject, suggesting a need to adjust the current risk factors for C. albicans overgrowth after a β-lactam treatment.IMPORTANCE Fungal infections are redoubtable healthcare-associated complications in immunocompromised patients. Particularly, the commensal intestinal yeast Candida albicans causes invasive infections in intensive care patients and is, therefore, associated with high mortality. These infections are preceded by an intestinal expansion of C. albicans before its translocation into the bloodstream. Antibiotics are a well-known risk factor for C. albicans overgrowth but the impact of antibiotic-induced dysbiosis on the human gut mycobiota—the fungal microbiota—and the understanding of the mechanisms involved in C. albicans overgrowth in humans are very limited. Our study shows that antibiotics increase the fungal proportion in the gut and disturb the fungal composition, especially C. albicans, in a subject-dependent manner. Indeed, variations across subjects in C. albicans burden in response to β-lactam treatment could be partly explained by changes in the levels of endogenous fecal β-lactamase activity. This highlighted a potential new key factor for C. albicans overgrowth. Thus, the significance of our research is in providing a better understanding of the factors behind C. albicans intestinal overgrowth, which might lead to new means to prevent life-threatening secondary infections.

Published
2022
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7. S10.3c Clinical studies provide new insights on the association between the microbiota and host resistance to Candida albicans intestinal colonization

Author

Delavy, Margot, primary, Burdet, Charles, additional, Sertour, Natacha, additional, Chatelier, Emmanuelle Le, additional, Doquier, Jean-Denis, additional, Volant, Stevenn, additional, Ghozlane, Amine, additional, Grall, Nathalie, additional, Duval, Xavier, additional, Mentré, France, additional, Duffy, Darragh, additional, D'Enfert, Christophe, additional, and Bougnoux, Marie-Elisabeth, additional

Published
2022
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8. FunHoMic: A Marie Skłodowska-Curie Innovative Training Network for the study of the Fungus-Host-Microbiota interplay

Author

Cole, Nathaniel, primary, Marsaux, Benoît, additional, Rosati, Diletta, additional, Delavy, Margot, additional, Kosmala, Daria, additional, Xie, Zixuan, additional, Kaune, Ann-Kristin, additional, Valentine, Marisa, additional, Chakraborty, Sayoni, additional, Kaur, Manjyot, additional, Alaban, Leovigildo Rey, additional, Morelli, Moran, additional, Fróis-Martins, Ricardo, additional, Walker, Alan, additional, Van den Abbeele, Pieter, additional, Netea, Mihai, additional, Bougnoux, Marie-Elisabeth, additional, Manichanh, Chaysavanh, additional, Munro, Carol, additional, Hube, Bernhard, additional, Jacobsen, Ilse, additional, Roget, Karine, additional, Thomas, Vincent, additional, Queiroz, Karla, additional, Leibundgut-Landmann, Salomé, additional, Brown, Alistair, additional, and d'Enfert, Christophe, additional

Published
2021
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9. The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

Author

d'Enfert, Christophe, Kaune, Ann-Kristin, Alaban, Leovigildo-Rey, Chakraborty, Sayoni, Cole, Nathaniel, Delavy, Margot, Kosmala, Daria, Marsaux, Benoît, Fróis-Martins, Ricardo, Morelli, Moran, Rosati, Diletta, Valentine, Marisa, Xie, Zixuan, Emritloll, Yoan, Warn, Peter A, Bequet, Frédéric, Bougnoux, Marie-Elisabeth, Bornes, Stephanie, Gresnigt, Mark S, Hube, Bernhard, Jacobsen, Ilse D, Legrand, Mélanie, LeibundGut-Landmann, Salomé, Manichanh, Chaysavanh, Munro, Carol A, Netea, Mihai G, Queiroz, Karla, Roget, Karine, Thomas, Vincent, Thoral, Claudia, et al, University of Zurich, and d'Enfert, Christophe

Subjects
patient variability, fungus, 2700 General Medicine, 10263 Institute of Experimental Immunology, Microbiology, Infectious Diseases, host, microbiota, microbiota variability, 570 Life sciences, biology, fungal variability, microbiota interactions, Candida infections, mycobiota, antifungal immunity, 10244 Institute of Virology, Candida
Published
2021
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10. The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives

Author

d'Enfert, Christophe; https://orcid.org/0000-0002-6235-3886, Kaune, Ann-Kristin, Alaban, Leovigildo-Rey, Chakraborty, Sayoni, Cole, Nathaniel, Delavy, Margot, Kosmala, Daria, Marsaux, Benoît, Fróis-Martins, Ricardo, Morelli, Moran, Rosati, Diletta; https://orcid.org/0000-0003-2992-2503, Valentine, Marisa, Xie, Zixuan, Emritloll, Yoan, Warn, Peter A, Bequet, Frédéric, Bougnoux, Marie-Elisabeth, Bornes, Stephanie, Gresnigt, Mark S, Hube, Bernhard, Jacobsen, Ilse D, Legrand, Mélanie, LeibundGut-Landmann, Salomé; https://orcid.org/0000-0002-5724-4837, Manichanh, Chaysavanh, Munro, Carol A, Netea, Mihai G, Queiroz, Karla, Roget, Karine, Thomas, Vincent, Thoral, Claudia, et al, d'Enfert, Christophe; https://orcid.org/0000-0002-6235-3886, Kaune, Ann-Kristin, Alaban, Leovigildo-Rey, Chakraborty, Sayoni, Cole, Nathaniel, Delavy, Margot, Kosmala, Daria, Marsaux, Benoît, Fróis-Martins, Ricardo, Morelli, Moran, Rosati, Diletta; https://orcid.org/0000-0003-2992-2503, Valentine, Marisa, Xie, Zixuan, Emritloll, Yoan, Warn, Peter A, Bequet, Frédéric, Bougnoux, Marie-Elisabeth, Bornes, Stephanie, Gresnigt, Mark S, Hube, Bernhard, Jacobsen, Ilse D, Legrand, Mélanie, LeibundGut-Landmann, Salomé; https://orcid.org/0000-0002-5724-4837, Manichanh, Chaysavanh, Munro, Carol A, Netea, Mihai G, Queiroz, Karla, Roget, Karine, Thomas, Vincent, Thoral, Claudia, and et al

Abstract

Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients.

Published
2021

11. The impact of the Fungus-Host-Microbiota interplay uponCandida albicansinfections: current knowledge and new perspectives

Author

d'Enfert, Christophe, primary, Kaune, Ann-Kristin, additional, Alaban, Leovigildo-Rey, additional, Chakraborty, Sayoni, additional, Cole, Nathaniel, additional, Delavy, Margot, additional, Kosmala, Daria, additional, Marsaux, Benoît, additional, Fróis-Martins, Ricardo, additional, Morelli, Moran, additional, Rosati, Diletta, additional, Valentine, Marisa, additional, Xie, Zixuan, additional, Emritloll, Yoan, additional, Warn, Peter A, additional, Bequet, Frédéric, additional, Bougnoux, Marie-Elisabeth, additional, Bornes, Stephanie, additional, Gresnigt, Mark S, additional, Hube, Bernhard, additional, Jacobsen, Ilse D, additional, Legrand, Mélanie, additional, Leibundgut-Landmann, Salomé, additional, Manichanh, Chaysavanh, additional, Munro, Carol A, additional, Netea, Mihai G, additional, Queiroz, Karla, additional, Roget, Karine, additional, Thomas, Vincent, additional, Thoral, Claudia, additional, Van den Abbeele, Pieter, additional, Walker, Alan W, additional, and Brown, Alistair J P, additional

Published
2020
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14. Unveiling Candida albicansintestinal carriage in healthy volunteers: the role of micro- and mycobiota, diet, host genetics and immune response

Author

Delavy, Margot, Sertour, Natacha, Patin, Etienne, Le Chatelier, Emmanuelle, Cole, Nathaniel, Dubois, Florian, Xie, Zixuan, Saint-André, Violaine, Manichanh, Chaysavanh, Walker, Alan W., Quintana-Murci, Lluis, Duffy, Darragh, d’Enfert, Christophe, Bougnoux, Marie-Elisabeth, and Consortium, Milieu Intérieur

Abstract

ABSTRACTCandida albicansis a commensal yeast present in the gut of most healthy individuals but with highly variable concentrations. However, little is known about the host factors that influence colonization densities. We investigated how microbiota, host lifestyle factors, and genetics could shape C. albicansintestinal carriage in 695 healthy individuals from the Milieu Intérieur cohort. C. albicansintestinal carriage was detected in 82.9% of the subjects using quantitative PCR. Using linear mixed models and multiway-ANOVA, we explored C. albicansintestinal levels with regard to gut microbiota composition and lifestyle factors including diet. By analyzing shotgun metagenomics data and C. albicansqPCR data, we showed that Intestinimonas butyriciproducenswas the only gut microbiota species whose relative abundance was negatively correlated with C. albicansconcentration. Diet is also linked to C. albicansgrowth, with eating between meals and a low-sodium diet being associated with higher C. albicanslevels. Furthermore, by Genome-Wide Association Study, we identified 26 single nucleotide polymorphisms suggestively associated with C. albicanscolonization. In addition, we found that the intestinal levels of C. albicansmight influence the host immune response, specifically in response to fungal challenge. We analyzed the transcriptional levels of 546 immune genes and the concentration of 13 cytokines after whole blood stimulation with C. albicanscells and showed positive associations between the extent of C. albicansintestinal levels and NLRP3expression, as well as secreted IL-2 and CXCL5 concentrations. Taken together, these findings open the way for potential new interventional strategies to curb C. albicansintestinal overgrowth.

Published
2023
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15. The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives.

Author

d'Enfert C, Kaune AK, Alaban LR, Chakraborty S, Cole N, Delavy M, Kosmala D, Marsaux B, Fróis-Martins R, Morelli M, Rosati D, Valentine M, Xie Z, Emritloll Y, Warn PA, Bequet F, Bougnoux ME, Bornes S, Gresnigt MS, Hube B, Jacobsen ID, Legrand M, Leibundgut-Landmann S, Manichanh C, Munro CA, Netea MG, Queiroz K, Roget K, Thomas V, Thoral C, Van den Abbeele P, Walker AW, and Brown AJP

Subjects
Candida albicans immunology, Candida albicans pathogenicity, Humans, Candidiasis immunology, Candidiasis microbiology, Host Microbial Interactions physiology, Microbial Interactions physiology
Abstract

Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

Published
2021
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