C. difficile bacterium strengthens by cooperating with Enterococcus, other gut microbes

The bacterium Clostridioides difficile tends to “cooperate” with microorganisms in the gastrointestinal tract, such as the pathogen Enterococcus, which can help the bacterium thrive, according to a study published in Nature.

“I personally have always been fascinated by C. difficile as a pathogen,” Joseph P. Zackular, PhD, study author and assistant professor of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania, told Healio. “It’s obviously a really big public health concern, causes a lot of disease in children and adults, and it’s a big problem in elderly patients, so it’s a big challenge.”

Zackular cited his background in microbial ecology as a driving factor behind his interest in how C. difficile reacts in different intestinal tracts.

“I’ve always been interested in microbial communities and how they interact with each other,” Zackular, who is also co-director of the Children’s Hospital of Philadelphia microbial archive and cryo-collection in the PennCHOP Microbiome Program, said.

“Everyone's microbiome is very different. ... We don’t understand why someone might get severe disease and maybe die, and someone else might get more mild disease,” Zackular said. “We postulated that it could be the context of the ecosystem by which C. diff is invading that might play a role during infection, and that’s what drove us to dive into this question.”

In their study, Zackular and colleagues examined stool samples from 54 pediatric patients with C. difficile infections.

“We looked for organisms using microbiome analyses that would be associated with this infection,” Zackular said. “And one of the things that we found was this opportunistic, pathogenic group of bacteria, the Enterococcus genus was associated with C. diff infection, and this had been shown previously in the literature. Using microbiome analysis from patients, we found this really strong signature of the Enterococcus and we wanted to know, does this matter?”

After examining this in a laboratory setting, the researchers found that Enterococcus was increasing the amount of toxin that C. difficile was producing, and conducted metabolic modeling to found how the two organisms communicated.

“What we found with all of these analyses is that Enterococcus is reshaping C. diff metabolism, and providing amino acids to C. diff, and also restricting other metabolic cues that allow C. diff to be more pathogenic, but also be more fit,” Zackular said. “It provides C. diff with nutrients, but also starved it of other signals that feed it to be both fit and pathogenic.”

Zackular said they were surprised at the ability of Enterococcus to “remodel the gut during infection.”

“You kind of take it for granted that the [gut’s] ecosystem is always the same, but what we’re finding is that domination by this opportunistic pathogen kind of totally remodeled that environment, and that can be sensed by the pathogen and really kind of tunes its behavior and its pathogenesis,” Zackular said.

“These are two pathogens that are cooperating in the gut, and that's incredibly fascinating,” he added. “It brings out a whole new way of thinking about C. difficile.”

References:

CHOP-led study shows that antibiotic-resistant microbes in the gut make C. difficile more infectious. https://www.eurekalert.org/news-releases/971337? . Published Nov. 16, 2022. Accessed Nov. 17, 2022.

Smith AB, et al. Nature. 2022;doi:10.1038/s41586-022-05438-x.