An Osmotic Laxative Renders Mice Susceptible to Prolonged Clostridioides difficile Colonization and Hinders Clearance

Tomkovich

Henry

et al. 2022

Preprint

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Fecal communities transplanted into individuals can eliminate recurrent Clostridioides difficile infection (CDI) with high efficacy. However, this treatment is only used once CDI becomes resistant to antibiotics or has recurred multiple times. We sought to investigate whether a fecal community transplant (FCT) pre-treatment could be used to prevent CDI altogether. We treated male C57BL/6 mice with either clindamycin, cefoperazone, or streptomycin, and then inoculated them with the microbial community from untreated mice before challenging with C. difficile. We measured colonization and sequenced the V4 region of the 16S rRNA gene to understand the dynamics of the murine fecal community in response to the FCT and C. difficile challenge. Clindamycin-treated mice became colonized with C. difficile but cleared it naturally and did not benefit from the FCT. Cefoperazone-treated mice became colonized by C. difficile, but the FCT enabled clearance of C. difficile. In streptomycin-treated mice, the FCT was able to prevent C. difficile from colonizing. Then we diluted the FCT and repeated the experiments. Cefoperazone-treated mice no longer cleared C. difficile. However, streptomycin-treated mice colonized with 1:102 dilutions resisted C. difficile colonization. Streptomycin-treated mice that received a FCT diluted 1:103, C. difficile colonized but later was cleared. In streptomycin-treated mice, inhibition of C. difficile was associated with increased relative abundance of a group of bacteria related to Porphyromonadaceae and Lachnospiraceae. These data demonstrate that C. difficile colonization resistance can be restored to a susceptible community with a FCT as long as it complements the missing populations.ImportanceAntibiotic use, ubiquitous with the healthcare environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection. While this relationship between the gut bacteria and CDI is well established, there are no therapies to treat a perturbed gut community to prevent CDI. This study explored the potential of restoring colonization resistance to antibiotic-induced susceptible gut communities. We described the effect gut bacteria community variation has on the effectiveness of a fecal community transplant for inhibiting CDI. These data demonstrated that communities susceptible to CDI can be supplemented with fecal communities but the effectiveness depended on the structure of the community following the perturbation. Thus, a simplified bacterial community may be able to recover colonization resistance to patients treated with antibiotics.

Section: Discussionsupporting

confidence: 93%

Simplified fecal community transplant restores Clostridioides difficile colonization resistance to antibiotic perturbed murine communities

Tomkovich

Henry

et al. 2022

Preprint

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“…Since we titrated the FCT dilutions, we could compare the bacterial communities of the mice that gained the ability to clear C. difficile to the mice receiving the next dilution which could not to elucidate the minimal relative abundance differences. In agreement with previous studies, OTUs related to Lachnospiraceae , Porphyromonadaceae , and Ruminococcaceae increased with the clearance of C. difficile in the streptomycin-treated mice ( 14 , 17 – 21 ). These data agree with our previous hypothesis that a reduced fecal community would be able to promote clearance of C. difficile only in streptomycin-treated mice.…”

Section: Discussionsupporting

confidence: 93%

“…It may be possible to restore colonization resistance to clindamycin or cefoperazone if the antibiotic treatment, recovery period, and FCT treatment were modified to allow the FCT to have an effect. Other methods could be used to make the mice susceptible to CDI and then tested for the effectiveness of the FCT treatment ( 18 , 33 ). Further modification and characterization of the fecal communities could reduce the necessary community members and metabolites to promote colonization resistance.…”

Section: Discussionmentioning

confidence: 99%

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Diluted Fecal Community Transplant Restores Clostridioides difficile Colonization Resistance to Antibiotic-Perturbed Murine Communities

Tomkovich

Henry

et al. 2022

mBio

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Antibiotic use, ubiquitous with the health care environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection.

“…The groups of bacteria that were associated with either a higher histopathologic score or moribundity are members of the indigenous gut community that also have been associated with disease, often referred to as opportunistic pathogens. Some of the populations of Bacteroides , Enterococcus , and Klebsiella that are associated with worse outcomes have been shown to have pathogenic potential, expand after antibiotic use, and are commonly detected in CDI cases ( 66 – 69 ). In addition to these populations, Eggerthella , Prevotellaceae , and Helicobacter , which are associated with worse outcomes, have also been associated with intestinal inflammation ( 70 – 72 ).…”

Section: Discussionmentioning

confidence: 99%

The Gut Bacterial Community Potentiates Clostridioides difficile Infection Severity

Schubert

Flynn

et al. 2022

mBio

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