Clostridioides difficile, sometimes known as C. difficile or C. diff, is a bacteria that causes severe intestinal sickness and, as the name implies, can be difficult to study and treat.

Within two months, 1 in 6 C. difficile-infected patients will contract the disease again. However, researchers are still baffled as to why some individuals’ C. difficile infections are harder to treat than others.

There are billions of microbes in the human gut, and these microbes can affect the virulence of different infections. However, until recently, it was unclear how C. difficile interacted with the vast range of microbes in the digestive tract.

In a recent study published in Nature, scientists from Children’s Hospital of Philadelphia (CHOP) discovered that Enterococcus, an opportunistic pathogen that is antibiotic-resistant, collaborates with C. difficile to change and improve the metabolic environment in the gut so that C. difficile can flourish.

“When we talk about bacterial infections,” according to senior author Joseph P. Zackular, “we often just think of the pathogen itself, but the ‘bystanders’ in the gut can have a huge impact on the course of infection.

The findings show “that the coincidence of two pathogenic organisms – Enterococcus and C. difficile – is more than a coincidence; they truly take advantage of each other.”

“Understanding this relationship,” according to the autho, “as well as other factors that contribute to clinical outcomes of C. difficile infection, is essential for combating this urgent public health challenge.”

According to earlier research, people with C. difficile infections also have high amounts of enterococci in their guts and commonly co-infect patients with vancomycin-resistant enterococci (VRE). It is unknown how Enterococcus affects clinical outcomes and susceptibility to C. difficile infection.

The researchers examined stool samples from 54 young patients who had C. difficile infections to better understand the relationship between Enterococcus and C. difficile during infection. The researchers discovered substantial quantities of Enterococcus in the stool of these patients, as well as a positive association between enterococcal and C. difficile loads, which is consistent with findings in adults.

The researchers subsequently verified the mechanism of how these two infections cooperate after receiving confirmation that enterococci are significantly prevalent in the stomach of children with a C. difficile infection and that this positively correlates with C. difficile burden. They discovered that enterococci improve C. difficile virulence by increasing its production of toxins using both in vitro and in vivo experimental methods.

Then, using data ranging from transcriptomics to metabolomics – that is, the study of RNA transcripts and metabolites associated with these pathogens – the researchers discovered that enterococci reconstruct the gut surroundings, effectively remodeling the house the C. difficile pathogen enters and making it more conducive to the pathogen’s growth. They discovered that enterococci export ornithine, another amino acid, as a byproduct of using arginine, an amino acid, for energy. Further investigation revealed that arginine depletion is a key factor in C. difficile virulence and that enterococci adjust arginine and ornithine levels in the gut during C. difficile infection.

Finally, the researchers looked into the relationship between laboratory results and patient results. They discovered that children with C. difficile infection and inflammatory bowel disease (IBD) have significant quantities of fermentable amino acids, particularly ornithine, in their microbiomes. Additionally, they found a strong link between C. difficile burdens and ornithine, indicating that this amino acid plays a significant role in C. difficile infection.

Together, these findings show that “enterococci and C. difficile interact during C. difficile infection through metabolic cross-talk to support increased colonization, pathogenesis and persistence in the gut,” according to Dr. Zackular. “Future research should explore targeting enterococcal metabolism – and the resulting amino acid landscape in the gut – as a way of altering the pathogenesis of C. difficile.”

Source: 10.1038/s41586-022-05438-x

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