Clostridioides difficileoften called It’s hard Where C difference., is a bacterium that causes serious intestinal diseases and, as its name suggests, can be difficult to study and treat. About 1 in 6 patients infected with It’s hard will be reinfected within two months. Yet scientists have not understood why It’s hard the infection is more difficult to treat in some patients than in others. The human gut is filled with trillions of microbes, and these microbes influence the virulence of various pathogens, but until now scientists had little understanding of how It’s hard 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 that Enterococcus – an antibiotic-resistant opportunistic pathogen – acts in concert with It’s hardremodeling and improving the metabolic environment in the gut so that It’s hard can flourish.
When we talk about bacterial infections we often think of the pathogen itself, but the “bystanders” in the gut can have a huge impact on the course of infection. This study reveals that the coincidence of two pathogenic organisms – Enterococcus and It’s hard – is more than a coincidence; they really take advantage of each other. Understanding this relationship, as well as other factors that contribute to clinical outcomes of It’s hard infection, is key to tackling this urgent public health challenge.”
Joseph P. Zackular, PhD, senior author, researcher, and assistant professor of pathology and laboratory medicine at Children’s Hospital of Philadelphia
Previous studies have shown that adults infected with It’s hard also have high levels of Enterococcus in their gut and that resistant to vancomycin Enterococcus (ERV) frequently co-infects patients with It’s hard. However, the effect of Enterococcus on the susceptibility to It’s hard infection and clinical outcomes have not been established.
To better define the association between Enterococcus and It’s hard during the infection, the researchers analyzed stool samples from 54 pediatric patients infected with It’s hard. 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 enterococci and It’s hard burdens.
Having confirmed that enterococci are very abundant in the intestines of children with It’s hard infection and that this is positively correlated with It’s hard burden, the researchers then validated the mechanism of interaction of these two pathogens. Use both in vitro and Direct experimental models, they found that enterococci increased It’s hardvirulence by increasing its production of toxins.
Then, using data ranging from transcriptomics to metabolomics, i.e. the study of RNA transcripts and metabolites linked to these pathogens, the researchers discovered that enterococci reshape the intestinal environment, effectively reshaping the home It’s hard the pathogen penetrates and makes it more conducive to the proliferation of the pathogen. They found that enterococci use arginine, an amino acid, as an energy source, and in doing so, the pathogen exports ornithine, another amino acid. Further analysis showed that enterococci modulate arginine and ornithine levels in the gut during It’s hard infection and that arginine depletion plays a central role in It’s hard virulence.
Finally, the researchers investigated whether their laboratory findings correlated with findings in human patients. Analyze the microbiome of children with It’s hard infection 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 between It’s hard fillers and ornithine, supporting a key role for this amino acid in It’s hard infection.
“Together, these data suggest that enterococci and It’s hard interact during It’s hard infection through metabolic crosstalk 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 – as a way to alter the pathogenesis of It’s hard.”
This work was done in collaboration with researchers from the University of Pennsylvania, University of Florida, Vanderbilt University School of Medicine, University of Virginia, University of Pittsburgh, and from the University of Minnesota School of Medicine.
Philadelphia Children’s Hospital
Smith, AB, et al. (2022) Enterococci enhance the pathogenesis of Clostridioides difficile. Nature. doi.org/10.1038/s41586-022-05438-x.
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