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

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 diffidie. But whether PEG impacts CDI susceptibility and clearance is unclear. To examine how PEG impacts susceptibility, we treated C57BU6 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 clindamycintreated, 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.

Automated summary

This study found that the osmotic laxative PEG affects susceptibility and clearance of C. difficile in mice. Mice treated with PEG for a longer period remained colonized for up to 30 days postchallenge, while those treated for a shorter period cleared the infection within 7 days. The findings suggest that PEG disrupts colonization resistance to C. difficile in mice.