Interspecies Interactions in Gut Affect C difficile’s Antibiotic Susceptibility

A new report suggests that microbial interactions within the gut may help determine the susceptibility of pathogens like Clostridioides difficile to antibiotic treatment.

The findings pave the way for new strategies to leverage antibiotics by tailoring prescriptions to individual patients. The study was published in the journal PLOS Biology.

Co-authors Susan Hromada, PhD, and Ophelia S. Venturelli, PhD, both of the University of Wisconsin-Madison, wrote that C difficile’s growth and persistence in the human gastrointestinal tract is greatly impacted by a person’s gut microbiota.

“The key role of colonization resistance is illustrated by the increased risk of C difficile infection after treatment with antibiotics that decimate the microbiota and by the efficacy of fecal microbiota transplants from healthy human donors in eliminating recurrent C difficile infections,” they wrote.

However, while the interactions between the microbiota and C difficile have been thoroughly studied, much less is known about how the microbiota affects the antibiotic susceptibility of C difficile, they said.

“Similar to other pathogens, C difficile antibiotic susceptibility has been studied using in vitro experiments of monoculture growth,” they wrote. “However, monoculture experiments do not consider how interactions with resident community members can modify the antibiotic susceptibility of a pathogen.”

Hromada and Venturelli used a diverse human gut community to examine how microbial interactions affected C difficile’s susceptibility to 2 common clinically relevant antibiotics, vancomycin and metronidazole.

The authors identified 2 types of microbial interactions that they said can affect C difficile’s antibiotic susceptibility. One class of interactions, which they said occurs only rarely, increases C difficile’s ability to grow even amid high concentrations of antibiotics. The other class of interactions—the more common type—results in C difficile’s growth at low concentrations of antibiotics.

Among their findings, they showed that the prevalent gut species Desulfovibrio piger significantly increases the minimum inhibitory concentration (MIC) of metronidazole for C difficile.

“Our data suggest D. piger’s impact on the environment induces a metal starvation transcriptional response in C difficile, leading to down-regulation of enzymes required to reduce metronidazole to its active form,” they wrote.

Hromada and Venturelli also found that competition between C difficile and other species that are more sensitive to a given antibiotic can lead to an increase in the growth of C difficile at low antibiotic concentrations, when C difficile “wins” the competition with the other species (a phenomenon known as “competitive release”).

The investigators said these findings could have implications for clinical care of patients. For instance, they said knowledge of how microbial interactions alter antibiotic susceptibility of pathogens like C difficile could enable physicians to “tailor” antibiotic treatments.

“This understanding could inform new microbiome interventions that selectively eradicate human pathogens while minimizing disruption of healthy gut microbiota and minimize the acquisition of antibiotic resistance,” they said.

Hromada and Venturelli said their findings suggest it might be difficult to identify interactions that sensitize C difficile to antibiotics, but they said the research also sheds light on other strategies.

“Therefore, future ecologically informed therapeutic strategies could exploit the strong biotic competition of C difficile by diverse human gut species that are resistant to the antibiotics as opposed to interactions that sensitize C difficile to antibiotics,” they said.