Girinathan, Brintha P.DiBenedetto, NicholasWorley, Jay N.Peltier, JohannArrieta-Ortiz, Mario L.Immanuel, Selva Rupa ChristinalLavin, RichardCummins, Christopher K.Hoffman, MariaLuo, YanGonzalez-Escalona, NarjolAllard, MarcGerber, Georg K.Sonenshein, Abraham L.Onderdonk, AndrewBaliga, Nitin S.Dupuy, BrunoDelaney, MaryBry, Lynn2026-07-312021-11-10Girinathan, B. P., DiBenedetto, N., Worley, J. N., Peltier, J., Arrieta-Ortiz, M. L., Immanuel, S. R. C., Lavin, R., Delaney, M. L., Cummins, C. K., Hoffman, M., Luo, Y., Gonzalez-Escalona, N., Allard, M., Onderdonk, A. B., Gerber, G. K., Sonenshein, A. L., Baliga, N. S., Dupuy, B., & Bry, L. (2021). In vivo commensal control of Clostridioides difficile virulence. Cell Host & Microbe, 29(11), 1693-1708.e7. https://doi.org/10.1016/j.chom.2021.09.0071931-31281934-606934637781https://dash.harvard.edu/handle/1/42746871An in-depth, systematic analysis leveraging in vivo metabolomic and meta-transcriptomic analyses to define how protective and disease-promoting commensal species modulate C. difficile's behaviors and host outcomes from infection. Findings identified complex metabolic and cellular interactions among C. difficile, host, protective commensal Paraclostridium bifermentans, and disease-promoting commensal Clostridium sardiniense.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.enClostridioides difficileClostridium sardinienseParaclostridium bifermentansanaerobe metabolismcarbon source enrichment analysiscolitisconventional mousegnotobiotic mousemetabolomicsmetatranscriptomicsArticle10.1016/j.chom.2021.09.007