Interaction of Microbes in the Gut May Impact Efficacy of C Diff Treatment

Interactions between species in the gut microbiota may impact the efficacy of antibiotic treatment of Clostridioides difficile, according to a study by investigators at the University of Wisconsin-Madison.

The study, published in PLOS Biology, examined how interspecies interactions in the gastrointestinal tract affect how C diff responds to vancomycin and metronidazole.

“Here, we show that bacteria that reside in our gastrointestinal tract can modify the efficacy of clinically relevant antibiotics used to treat C. difficile infections,” Ophelia Venturelli, assistant professor in the Departments of Biochemistry, Chemical & Biological Engineering, Bacteriology at the University of Wisconsin-Madison told Contagion. “This arises from the inhibition of bacteria that are more sensitive to the antibiotic than C difficile and also compete with C difficile. The presence of the antibiotic reduces the abundance of these competitors, which in turn leads to an enhancement of C difficile. In addition, a bacterium that resides in our gastrointestinal tract can also modify the environment to deplete metals, which in turn leads to a change in the internal state of C difficile. This altered internal state also renders C difficile tolerant to the antibiotic.”

The investigators built a computational model to analyze interspecies interactions. Using a broth dilution method, they determined the minimum inhibitory concentrations (MIC) for each species in a monoculture and in pairwise including C difficile.

Compared to the monospecies, the MIC of C difficile was unchanged in 15 pairwise communities and showed a 2-fold difference in five pairwise communities. In the presence of Desulfovibrio piger, metronidazole was less effective against C diff, with a 4-fold increase in metronidazole MIC, from 6 μg/mL to greater than or equal to 24 μg/mL.

“This was not specific to C difficile as other prevalent gut bacteria were also less susceptible to the action of metronidazole in the presence of D piger,” Venturelli said. “The proposed mechanism by which this occurs is novel. We think it is remarkable that microbial interactions can determine whether a human bacterial pathogen is tolerant or not to an antibiotic.”

Capturing the pairwise interactions between species and the effect of antibiotics with a simple computational model demonstrates that antibiotic disruption of interspecies interactions is generalizable across different contexts, she said.

“The efficacy of antibiotic treatments for bacterial pathogens can be shaped by interactions with resident microbiota. This may contribute to inter-individual variability in the response to and recovery from antibiotic treatments,” Venturelli said. “In the future, next-generation anti-pathogen therapies could be informed by an individual’s microbiota composition and their associated interaction networks. Also, knowledge of these interactions can guide the choice of antibiotics by prioritizing treatments whose effects are less prone to interaction-mediated changes in efficacy.”

Venturelli said her team will continue to research the effects of interspecies interactions, including in vivo studies to explore the metronidazole susceptibility ofC. difficile and patient response to antibiotics in the presence of certain bacteria.

“In addition, we can study the effects of interactions on susceptibility to antibiotics that are risk factors for C difficile infections such as clindamycin, cephalosporins, and fluoroquinolones,” she said. “Finally, we will explore ecologically-informed strategies to introduce key species before/during antibiotic treatment to enhance the efficacy of antibiotics.The design of these treatments will be informed by knowledge of the interaction networks and the ecological and molecular principles shaping bacterial growth in the presence of antibiotics.”