Enterococci enhance Clostridioides difficile pathogenesis

Alexander B. Smith, Matthew L. Jenior, Orlaith Keenan, Jessica L. Hart, Jonathan Specker, Arwa Abbas, Paula C. Rangel, Chao Di, Jamal Green, Katelyn A. Bustin, Jennifer A. Gaddy, Maribeth R. Nicholson, Clare Laut, Brendan J. Kelly, Megan L. Matthews, Daniel R. Evans, Daria Van Tyne, Emma E. Furth, Jason A. Papin, Frederic D. Bushman, Jessi Erlichman, Robert N. Baldassano, Michael A. Silverman, Gary M. Dunny, Boone M. Prentice, Eric P. Skaar and Joseph P. Zackular ()
Additional contact information
Alexander B. Smith: Division of Protective Immunity, Children’s Hospital of Philadelphia
Matthew L. Jenior: University of Virginia
Orlaith Keenan: Division of Protective Immunity, Children’s Hospital of Philadelphia
Jessica L. Hart: Division of Protective Immunity, Children’s Hospital of Philadelphia
Jonathan Specker: University of Florida
Arwa Abbas: Division of Protective Immunity, Children’s Hospital of Philadelphia
Paula C. Rangel: Division of Protective Immunity, Children’s Hospital of Philadelphia
Chao Di: Children’s Hospital of Philadelphia
Jamal Green: University of Pennsylvania
Katelyn A. Bustin: University of Pennsylvania
Jennifer A. Gaddy: Vanderbilt University School of Medicine
Maribeth R. Nicholson: Vanderbilt University School of Medicine
Clare Laut: Vanderbilt University School of Medicine
Brendan J. Kelly: University of Pennsylvania
Megan L. Matthews: University of Pennsylvania
Daniel R. Evans: University of Pittsburgh
Daria Van Tyne: University of Pittsburgh
Emma E. Furth: University of Pennsylvania
Jason A. Papin: University of Virginia
Frederic D. Bushman: University of Pennsylvania
Jessi Erlichman: Children’s Hospital of Philadelphia
Robert N. Baldassano: University of Pennsylvania
Michael A. Silverman: University of Pennsylvania
Gary M. Dunny: University of Minnesota Medical School
Boone M. Prentice: University of Florida
Eric P. Skaar: Vanderbilt University School of Medicine
Joseph P. Zackular: Division of Protective Immunity, Children’s Hospital of Philadelphia

Nature, 2022, vol. 611, issue 7937, 780-786

Abstract: Abstract Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract1. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens2. Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut—the enterococci—enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.

Date: 2022
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DOI: 10.1038/s41586-022-05438-x

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