Sinani, H. | bioRxiv Science

bioRxiv2022

The gut bacterial community potentiates Clostridioides difficile infection severity

The severity of Clostridioides difficile infections (CDI) has increased over the last few decades. Patient age, white blood cell count, creatinine levels as well as C. difficile ribotype and toxin genes have been associated with disease severity. However, it is unclear whether there is an association between members of the gut microbiota and disease severity. The gut microbiota is known to interact with C. difficile during infection. Perturbations to the gut microbiota are necessary for C. difficile to colonize the gut. The gut microbiota can inhibit C. difficile colonization through bile acid metabolism, nutrient consumption and bacteriocin production. Here we sought to demonstrate that members of the gut bacterial communities can also contribute to disease severity. We derived diverse gut communities by colonizing germ-free mice with different human fecal communities. The mice were then infected with a single C. difficile ribotype 027 clinical isolate which resulted in moribundity and histopathologic differences. The variation in severity was associated with the human fecal community that the mice received. Generally, bacterial populations with pathogenic potential, such as Escherichia, Helicobacter, and Klebsiella, were associated with more severe outcomes. Bacterial groups associated with fiber degradation, bile acid metabolism and lantibiotic production, such as Anaerostipes and Coprobacillus, were associated with less severe outcomes. These data indicate that, in addition to the host and C. difficile, populations of gut bacteria can influence CDI disease severity. ImportanceClostridioides difficile colonization can be asymptomatic or develop into an infection, ranging in severity from mild diarrhea to toxic megacolon, sepsis, and death. Models that predict severity and guide treatment decisions are based on clinical factors and C. difficile characteristics. Although the gut microbiome plays a role in protecting against CDI, its effect on CDI disease severity is unclear and has not been incorporated into disease severity models. We demonstrated that variation in the microbiome of mice colonized with human feces yielded a range of disease outcomes. These results revealed groups of bacteria associated with both severe and mild C. difficile infection outcomes. Gut bacterial community data from patients with CDI could improve our ability to identify patients at risk of developing more severe disease and improve interventions which target C. difficile and the gut bacteria to reduce host damage.

microbiology↗

bioRxiv2020

Clearance of Clostridioides difficile colonization is associated with antibiotic-specific bacterial changes

The gut bacterial community prevents many pathogens from colonizing the intestine. Previous studies have associated specific bacteria with clearing Clostridioides difficile colonization across different community perturbations. However, those bacteria alone have been unable to clear C. difficile colonization. To elucidate the changes necessary to clear colonization, we compared differences in bacterial abundance between communities able and unable to clear C. difficile colonization. We treated mice with titrated doses of antibiotics prior to C. difficile challenge which resulted in no colonization, colonization and clearance, or persistent colonization. Previously, we observed that clindamycin-treated mice were susceptible to colonization but spontaneously cleared C. difficile. Therefore, we investigated whether other antibiotics would show the same result. We found reduced doses of cefoperazone and streptomycin permitted colonization and clearance of C. difficile. Mice that cleared colonization had antibiotic-specific community changes and predicted interactions with C. difficile. Clindamycin treatment led to a bloom in populations related to Enterobacteriaceae. Clearance of C. difficile was concurrent with the reduction of those blooming populations and the restoration of community members related to the Porphyromonadaceae and Bacteroides. Cefoperazone created a susceptible community characterized by a drastic reduction in the community diversity, interactions, and a sustained increase in abundance of many facultative anaerobes. Lastly, clearance in streptomycin-treated mice was associated with the recovery of multiple members of the Porphyromonadaceae, with little overlap in the specific Porphyromonadaceae observed in the clindamycin treatment. Further elucidation of how C. difficile colonization is cleared from different gut bacterial communities will improve C. difficile infection treatments. ImportanceThe community of microorganisms, known as the microbiota, in our intestines prevents pathogens, such as C. difficile, from establishing themselves and causing infection. This is known as colonization resistance. However, when a person takes antibiotics, their gut microbiota is disturbed. This disruption allows C. difficile to colonize. C. difficile infections (CDI) are primarily treated with antibiotics, which frequently leads to recurrent infections because the microbiota have not yet returned to a resistant state. The infection cycle often ends when the fecal microbiota from a presumed resistant person are transplanted into the susceptible person. Although this treatment is highly effective, we do not understand the mechanism of resistance. We hope to improve the treatment of CDI through elucidating how the bacterial community eliminates C. difficile colonization. We found C. difficile was able to colonize susceptible mice but was spontaneously eliminated in an antibiotic-treatment specific manner. These data indicate each community had different requirements for clearing colonization. Understanding how different communities clear colonization will reveal targets to improve CDI treatments.

microbiology↗