The Proton Pump Inhibitor Omeprazole Does Not Promote Clostridioides difficile Colonization in a Murine Model.

Sarah Tomkovich,Nicholas A Lesniak,Yuan Li,Lucas Bishop,Patrick D Schloss,Madison J Fitzgerald,Patricia A Bradford

doi:10.1128/msphere.00693-19

Abstract

Proton pump inhibitor (PPI) use has been associated with microbiota alterations and susceptibility to Clostridioides difficile infections (CDIs) in humans. We assessed how PPI treatment alters the fecal microbiota and whether treatment promotes CDIs in a mouse model. Mice receiving a PPI treatment were gavaged with 40 mg of omeprazole per kg of body weight during a 7-day pretreatment phase, the day of C. difficile challenge, and the following 9 days. We found that mice treated with omeprazole were not colonized by C. difficile When omeprazole treatment was combined with a single clindamycin treatment, one cage of mice remained resistant to C. difficile colonization, while the other cage was colonized. Treating mice with only clindamycin followed by challenge resulted in C. difficile colonization. 16S rRNA gene sequencing analysis revealed that omeprazole had minimal impact on the structure of the murine microbiota throughout the 16 days of omeprazole exposure. These results suggest that omeprazole treatment alone is not sufficient to disrupt microbiota resistance to C. difficile infection in mice that are normally resistant in the absence of antibiotic treatment.IMPORTANCE Antibiotics are the primary risk factor for Clostridioides difficile infections (CDIs), but other factors may also increase a person's risk. In epidemiological studies, proton pump inhibitor (PPI) use has been associated with CDI incidence and recurrence. PPIs have also been associated with alterations in the human intestinal microbiota in observational and interventional studies. We evaluated the effects of the PPI omeprazole on the structure of the murine intestinal microbiota and its ability to disrupt colonization resistance to C. difficile We found omeprazole treatment had minimal impact on the murine fecal microbiota and did not promote C. difficile colonization. Further studies are needed to determine whether other factors contribute to the association between PPIs and CDIs seen in humans or whether aspects of murine physiology may limit its utility to test these types of hypotheses.

Highlights

Proton pump inhibitor (PPI) use has been associated with microbiota alterations and susceptibility to Clostridioides difficile infections (CDIs) in humans
We evaluated the impact of daily PPI treatment with omeprazole on the murine microbiome and susceptibility to C. difficile colonization in relation to clindamycin, an antibiotic that perturbs the microbiome enough to allow C. difficile to colonize but is mild enough that C. difficile is cleared within 10 days [11]
Our results suggest that omeprazole treatment had no effect on bacterial community resistance to C. difficile colonization in mice

Summary

Introduction

Proton pump inhibitor (PPI) use has been associated with microbiota alterations and susceptibility to Clostridioides difficile infections (CDIs) in humans. To test whether omeprazole treatment alters the microbiome and promotes susceptibility to CDIs, we gavaged mice with 40 mg of omeprazole per kg of body weight for 7 days before C. difficile challenge (Fig. 1A). These results demonstrated that the omeprazole treatment alone had minimal impact on the murine fecal bacterial community after 7 days of pretreatment.

Results

Conclusion