Antibiotic-resistant microbes in the gut make C. difficile more infectious

In a new study inNature, researchers at Children's Hospital of Philadelphia (CHOP) have found thatEnterococcus-- an antibiotic-resistant, opportunistic pathogen -- works together withC. difficile, reshaping and enhancing the metabolic environment in the gut so thatC. difficilecan thrive.

“当我们谈论细菌感染,我们经常just think of the pathogen itself, but the 'bystanders' in the gut can have a huge impact on the course of infection," said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at Children's Hospital of Philadelphia. "This study reveals that the coincidence of two pathogenic organisms --EnterococcusandC. difficile-- is more than a coincidence; they truly take advantage of each other. Understanding this relationship, as well as other factors that contribute to clinical outcomes ofC. difficileinfection, is essential for combating this urgent public health challenge."

Prior studies have shown that adults infected withC. difficilealso have high levels ofEnterococcusin their gut and that vancomycin-resistantEnterococcus(VRE) frequently co-infects patients withC. difficile. However, the effect ofEnterococcuson susceptibility toC. difficileinfection and clinical outcomes has not been established.

To further define the association betweenEnterococcusandC. difficileduring infection, the researchers analyzed stool samples from 54 pediatric patients infected withC. difficile. Consistent with studies in adults, the researchers found the stool of these patients had high levels ofEnterococcus, as well as a positive correlation between enterococcal andC. difficileburdens.

Having confirmation that enterococci are highly abundant in the gut of children with aC. difficile感染和积极,这与withC. difficileburden, the researchers then validated the mechanism of how these two pathogens work together. Using bothin vitroandin vivoexperimental models, they found that enterococci increaseC. difficilevirulence by enhancing its production of toxins.

Then, using data ranging from transcriptomics to metabolomics -- that is, the study of the RNA transcripts and metabolites related to these pathogens -- the researchers found that enterococcireshape the gut environment, effectively remodeling the house theC. difficilepathogen walks into and making it more conducive for the pathogen to thrive. They found that enterococci use arginine, an amino acid, for energy and that in the process of doing so, the pathogen exports ornithine, another amino acid. Further analysis showed that enterococci modulate levels of arginine and ornithine in the gut duringC. difficileinfection and that arginine depletion plays a central role inC. difficilevirulence.

Finally, the researchers explored whether their findings in the lab correlated with findings in human patients. Analyzing the microbiome of children withC. difficileinfection and inflammatory bowel disease (IBD), they found that these children had high levels of fermentable amino acids, including ornithine. They also observed a positive correlation betweenC. difficileburdens and ornithine, supporting a key role for this amino acid inC. difficileinfection.

"Collectively, these data suggest that enterococci andC. difficileinteract duringC. difficileinfection through metabolic cross-talk to support increased colonization, pathogenesis and persistence in the gut," Dr. Zackular said. "Future research should explore targeting enterococcal metabolism -- and the resulting amino acid landscape in the gut -- as a way of altering the pathogenesis ofC. difficile”。

This work was done in collaboration with researchers at the University of Pennsylvania, University of Florida, Vanderbilt University School of Medicine, University of Virginia, University of Pittsburgh, and University of Minnesota Medical School.

Smith et al. "Enterococci enhanceClostridioides difficilepathogenesis," Nature, online November 16, 2022, DOI: 10.1038/s41586-022-05438-x.