Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial

Abstract

We conducted an open-label crossover trial to test whether proton pump inhibitors (PPIs) affect the gastrointestinal microbiome to facilitate Clostridium difficile infection (CDI). Twelve healthy volunteers each donated 2 baseline fecal samples, 4 weeks apart (at weeks 0 and 4). They then took PPIs for 4 weeks (40 mg omeprazole, twice daily) and fecal samples were collected at week 8. Six individuals took the PPIs for an additional 4 weeks (from week 8 to 12) and fecal samples were collected from all subjects at week 12. Samples were analyzed by 16S ribosomal RNA gene sequencing. We found no significant within-individual difference in microbiome diversity when we compared changes during baseline vs changes on PPIs. There were, however, significant changes during PPI use in taxa associated with CDI (increased Enterococcaceae and Streptococcaceae, decreased Clostridiales) and taxa associated with gastrointestinal bacterial overgrowth (increased Micrococcaceae and Staphylococcaceae). In a functional analysis, there were no changes in bile acids on PPIs, but there was an increase in genes involved in bacterial invasion. These alterations could provide a mechanism by which PPIs predispose to CDI. ClinicalTrials.gov ID NCT01901276.

Keywords: Acid Suppression; Clostridium difficile Infection; Gastroesophageal Reflux Disease; Pharmacology.

Figure 1. Changes in fecal microbiotal diversity and specific taxa throughout the study

(A) There was no significant change in overall diversity after 4 weeks of PPIs compared to 4 weeks at baseline. (B) Four weeks of PPIs induced within-individual changes in the relative abundance of prespecified taxa associated with CDI and with upper gastrointestinal bacterial overgrowth. Lines connect individuals.

Figure 2. Principal coordinate analyses

Weighted (A) and unweighted (B) UniFrac analyses from immediately before and after 4 weeks of PPIs. Circles represent samples from before PPIs (green) or after PPIs (red); the corresponding subject’s number is adjacent to each circle.