1. In vivo commensal control of Clostridioides difficile virulence
- Author
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Mario L. Arrieta-Ortiz, Johann Peltier, Andrew B. Onderdonk, Selva Rupa Christinal Immanuel, Narjol Gonzalez-Escalona, Nicholas DiBenedetto, Richard Lavin, Nitin S. Baliga, Marc W. Allard, Maria Hoffman, Abraham L. Sonenshein, Yan Luo, Christopher K Cummins, Brintha P. Girinathan, Lynn Bry, Bruno Dupuy, Jay N. Worley, Mary L. Delaney, Georg K. Gerber, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), National Center for Biotechnology Information (NCBI), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institute for Systems Biology [Seattle] (ISB), U.S. Food and Drug Administration (FDA), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), Tufts University School of Medicine [Boston], This work was supported by the BWH Precision Medicine Institute, R01AI153605 from the National Institute of Allergy and Infectious Diseases (NIAID) and P30DK034854 from the National Institute of Diabetes, Digestive and Kidney Diseases to L.B., R01AI128215, R01AI141953, and U19AI135976 from NIAID and IIBR-2042948 from the National Science Foundation to N.S.B., B.P.G. was supported by T32 HL007627, and the work of J.N.W. was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. J.P. received support from the Institut Pasteur (Bourse ROUX). This work was conducted by authors from the FDA working as official U.S. Government employees and for which no additional external funding was utilized.
- Subjects
MESH: Clostridioides difficile ,MESH: Amino Acids ,colitis ,Systems biology ,MESH: Clostridium Infections ,[SDV]Life Sciences [q-bio] ,gnotobiotic mouse ,Clostridium sardiniense ,Virulence ,MESH: Butyrates ,Biology ,MESH: Virulence ,medicine.disease_cause ,Microbiology ,MESH: Clostridiales ,MESH: Fermentation ,Clostridia ,MESH: Gene Expression Profiling ,conventional mouse ,In vivo ,Virology ,MESH: Germ-Free Life ,MESH: Severity of Illness Index ,medicine ,Paraclostridium bifermentans ,MESH: Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Colitis ,Pathogen ,MESH: Mice ,MESH: Gene Regulatory Networks ,MESH: Gene Expression Regulation, Bacterial ,metatranscriptomics ,MESH: Symbiosis ,Toxin ,Host (biology) ,Clostridioides difficile ,MESH: Clostridium ,MESH: Arginine ,MESH: Cecum ,biology.organism_classification ,medicine.disease ,metabolomics ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,MESH: Systems Biology ,Parasitology ,carbon source enrichment analysis ,anaerobe metabolism - Abstract
International audience; Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.
- Published
- 2021
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