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

ABSTRACT: Antibiotics are a major risk factor for Clostridioides difficile infections (CDIs) because of their impact on the microbiota. However, nonantibiotic medications such as the ubiquitous osmotic laxative polyethylene glycol 3350 (PEG 3350) also alter the microbiota. Clinicians also hypothesize that PEG helps clear C. difficile. But whether PEG impacts CDI susceptibility and clearance is unclear. To examine how PEG impacts susceptibility, we treated C57BL/6 mice with 5-day and 1-day doses of 15% PEG in the drinking water and then challenged the mice with C. difficile 630. We used clindamycin-treated mice as a control because they consistently clear C. difficile within 10 days postchallenge. PEG treatment alone was sufficient to render mice susceptible, and 5-day PEG-treated mice remained colonized for up to 30 days postchallenge. In contrast, 1-day PEG-treated mice were transiently colonized, clearing C. difficile within 7 days postchallenge. To examine how PEG treatment impacts clearance, we administered a 1-day PEG treatment to clindamycin-treated, C. difficile-challenged mice. Administering PEG to mice after C. difficile challenge prolonged colonization up to 30 days postchallenge. When we trained a random forest model with community data from 5 days postchallenge, we were able to predict which mice would exhibit prolonged colonization (area under the receiver operating characteristic curve [AUROC] = 0.90). Examining the dynamics of these bacterial populations during the postchallenge period revealed patterns in the relative abundances of Bacteroides, Enterobacteriaceae, Porphyromonadaceae, Lachnospiraceae, and Akkermansia that were associated with prolonged C. difficile colonization in PEG-treated mice. Thus, the osmotic laxative PEG rendered mice susceptible to C. difficile colonization and hindered clearance. IMPORTANCE Diarrheal samples from patients taking laxatives are typically rejected for Clostridioides difficile testing. However, there are similarities between the bacterial communities from people with diarrhea and those with C. difficile infections (CDIs), including lower diversity than the communities from healthy patients. This observation led us to hypothesize that diarrhea may be an indicator of C. difficile susceptibility. We explored how osmotic laxatives disrupt the microbiota's colonization resistance to C. difficile by administering a laxative to mice either before or after C. difficile challenge. Our findings suggest that osmotic laxatives disrupt colonization resistance to C. difficile and prevent clearance among mice already colonized with C. difficile. Considering that most hospitals recommend not performing C. difficile testing on patients taking laxatives, and laxatives are prescribed prior to administering fecal microbiota transplants via colonoscopy to patients with recurrent CDIs, further studies are needed to evaluate if laxatives impact microbiota colonization resistance in humans.

SUBMITTER: Tomkovich S

PROVIDER: S-EPMC8550136 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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, resulting 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 that 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 drastic reductions in the community diversity and interactions and a sustained increase in the 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.IMPORTANCE The community of microorganisms, or microbiota, in our intestines prevents pathogens like C. difficile from colonizing and causing infection. However, antibiotics can disturb the gut microbiota, which allows C. difficile to colonize. C. difficile infections (CDI) are primarily treated with antibiotics, which frequently leads to recurrent infections because the microbiota has not yet returned to a resistant state. The recurrent infection cycle often ends when the fecal microbiota from a presumed resistant person is transplanted into the susceptible person. Although this treatment is highly effective, we do not understand the mechanism. We hope to improve the treatment of CDI through elucidating how the bacterial community eliminates CDI. We found that C. difficile colonized susceptible mice but was spontaneously eliminated in an antibiotic treatment-specific manner. These data indicate that each community had different requirements for clearing colonization. Understanding how different communities clear colonization will reveal targets to improve CDI treatments.

Project description:Diarrheal disease, a major cause of morbidity and mortality in dairy calves, is strongly associated with the health and composition of the gut microbiota. Clostridioides difficile is an opportunistic pathogen that proliferates and can produce enterotoxins when the host experiences gut dysbiosis. However, even asymptomatic colonization with C. difficile can be associated with differing degrees of microbiota disruption in a range of species, including people, swine, and dogs. Little is known about the interaction between C. difficile and the gut microbiota in dairy calves. In this study, we sought to define microbial features associated with C. difficile colonization in pre-weaned dairy calves less than 2 weeks of age. We characterized the fecal microbiota of 80 calves from 23 different farms using 16S rRNA sequencing and compared the microbiota of C. difficile-positive (n = 24) and C. difficile-negative calves (n = 56). Farm appeared to be the greatest source of variability in the gut microbiota. When controlling for calf age, diet, and farm location, there was no significant difference in Shannon alpha diversity (P = 0.50) or in weighted UniFrac beta diversity (P = 0.19) between C. difficile-positive and-negative calves. However, there was a significant difference in beta diversity as assessed using Bray-Curtiss diversity (P = 0.0077), and C. difficile-positive calves had significantly increased levels of Ruminococcus (gnavus group) (Adj. P = 0.052), Lachnoclostridium (Adj. P = 0.060), Butyricicoccus (Adj. P = 0.060), and Clostridium sensu stricto 2 compared to C. difficile-negative calves. Additionally, C. difficile-positive calves had fewer microbial co-occurrences than C. difficile-negative calves, indicating reduced bacterial synergies. Thus, while C. difficile colonization alone is not associated with dysbiosis and is therefore unlikely to result in an increased likelihood of diarrhea in dairy calves, it may be associated with a more disrupted microbiota.

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

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