Clostridioides difficileoften referred to as C. difficile or C.diff, is a bacterium that causes severe intestinal disease and, as the name suggests, can be difficult to study and treat. About 1 in 6 patients infected with C. difficile they will be reinfected within two months. Yet scientists have not figured out why C. difficilethe infection is more difficult to treat in some patients than in others. The human gut is filled with trillions of microbes, and these microbes affect the virulence of various pathogens, but until now, scientists had little understanding of how C. difficile cooperates with the rich collection of microorganisms in the gastrointestinal tract.
In a new study in Natureresearchers at Children’s Hospital of Philadelphia (CHOP) found this out Enterococcus – an antibiotic-resistant opportunistic pathogen – collaborates with C. difficilereshaping and improving the metabolic environment in the gut so that C. difficile can thrive.
“When we talk about bacterial infections, we often think only of the pathogen itself, but ‘bystanders’ in the gut can have a huge impact on the course of the 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 — Enterococcus And C. difficile — is more than a coincidence; they really take advantage of each other. Understand this relationship, as well as other factors that contribute to clinical outcomes C. difficile infection, is essential to combat this urgent public health challenge.”
Previous studies have shown that adults infected with C. difficile they also have high levels of Enterococcus in their gut and are resistant to vancomycin Enterococcus (VRE) frequently co-infects patients with C. difficile. However, the effect of Enterococcus on the susceptibility to C. difficile infection and clinical outcomes have not been established.
To further define the association between Enterococcus And C. difficile During the infection, the researchers analyzed stool samples from 54 pediatric patients infected with C. difficile. Consistent with studies in adults, the researchers found that the stools of these patients had high levels of Enterococcusas well as a positive correlation between enterococcus and C. difficile burdens.
Having confirmed that enterococci are very abundant in the intestines of children with a C. difficile infection and that this correlates positively with C. difficile burden, the researchers then validated the mechanism of how these two pathogens work together. Using both in vitro And live experimental models, found that enterococci increase C. difficilevirulence by increasing its toxin production.
Then, using data ranging from transcriptomics to metabolomics—the study of RNA transcripts and metabolites related to these pathogens—the researchers found that enterococci shape the intestinal environment, effectively reshaping the home. C. difficile the pathogen enters and makes it more conducive for the growth of the pathogen. They found that enterococci use arginine, an amino acid, for energy and that in doing so, the pathogen exports ornithine, another amino acid. Further analyzes showed that enterococci modulate the levels of arginine and ornithine in the intestine during C. difficile infection and that arginine depletion plays a central role C. difficile virulence.
Finally, the researchers explored whether their findings in the lab correlated with findings in human patients. Analyze the microbiome of children with C. difficile infection and inflammatory bowel disease (IBD), found that these children had high levels of fermentable amino acids, including ornithine. They also observed a positive correlation between C. difficile loads and ornithine, claiming a key role for this amino acid in C. difficile infection.
“Collectively, these data suggest that enterococci e C. difficile interact during C. difficile infection through metabolic cross-talk to support increased colonization, pathogenesis and persistence in the gut,” said Dr. Zackular. “Future research should explore targeting enterococcal metabolism – and the resulting amino acid landscape in the gut.” ‘gut – as a way to alter the pathogenesis of C. difficile.”
This work was done in collaboration with researchers from the University of Pennsylvania, the University of Florida, Vanderbilt University School of Medicine, the University of Virginia, the University of Pittsburgh and the University of Minnesota Medical School.
Smith et al. “The enterococci improve Clostridioides difficile pathogenesis”, Nature, online November 16, 2022, DOI: 10.1038/s41586-022-05438-x.