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Prolonged Use of a Proton Pump Inhibitor Reduces Microbial Diversity: Implications for Clostridium Difficile Susceptibility

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Prolonged Use of a Proton Pump Inhibitor Reduces Microbial Diversity: Implications for Clostridium Difficile Susceptibility

Charlie T Seto et al. Microbiome.

Abstract

Background: The role of the gut microbiome in arresting pathogen colonization and growth is important for protection against Clostridium difficile infection (CDI). Observational studies associate proton pump inhibitor (PPI) use and CDI incidence. We hypothesized that PPI use affected the distal gut microbiome over time, an effect that would be best explored by time-longitudinal study of healthy subjects on PPI in comparison to treatment-naïve CDI subjects. This study enrolled nine healthy human subjects and five subjects with treatment-naïve CDI. After random assignment to a low (20 mg/day) or high (2× 20 mg/day) dose group, fecal samples were collected from the nine healthy subjects before, during, and after 28 days of PPI use. This was done in conjunction with pre-treatment fecal collection from CDI subjects. High-throughput sequencing (16S rRNA) was performed on time-longitudinal samples to assess changes to the healthy gut microbiome associated with prolonged PPI usage. The healthy samples were then compared to the CDI subjects to explore changes over time to the gut microbiome associated with PPI use and potentially related to CDI.

Results: We report that PPI usage at low and high dosages, administered for 28 days, resulted in decreases to observed operational taxonomic unit (OTU) counts after both 1 week and 1 month. This decrease resulted in observed OTU levels that were similar to those found in treatment-naïve CDI patients, which was partly reversible after a 1 month recovery period. We did not detect a dose-dependent difference in OTU levels nor did we detect significant changes in taxa previously reported to be affected by PPI treatment.

Conclusion: While our observation of diminishing observed OTU counts during PPI therapy is a preliminary finding in a small cohort, our hypothesis that PPIs disrupt the healthy human gut microbiome is supported in this group. We conclude that decreases in observed species counts were reversible after cessation of PPI usage within 1 month. This finding may be a potential explanation for the association between prolonged PPI usage and CDI incidence.

Keywords: Clostridium difficile; Gut microbiome; Proton pump inhibitor.

Figures

Figure 1
Figure 1
Observed OTU counts on proton pump inhibitors. Plot depicts patient observed-OTU counts at start of treatment, 1 week into treatment, and at the end of the 1-month program, followed by final collection 1 month after ceasing PPI usage. Five first-incidence C. difficile patients had stool isolated and sequenced to represent the C. difficile cohort. Black horizontal bars represent within-group means. All statistical tests using matched-pair healthy volunteers used Wilcoxon signed rank; statistical tests between healthy volunteer groups (*p <0.05, **p <0.005) and C. difficile group used Wilcoxon rank sum (§p <0.05, §§p <0.01).
Figure 2
Figure 2
No overlap of on-PPI and CDI subjects. NMDS plots show no taxonomic overlap between short- and long-term PPI users and subjects with C. difficile infection, with strong overlap between all subjects and all time points.
Figure 3
Figure 3
KEGG Pathway disruptions on PPI. Plot depicts relative enrichment of KEGG pathway “Glycine, Serine, Threonine Metabolism” at start of treatment, one week into treatment, and at the end of the one-month program. The difference in relative abundance of the pathway for the duration of treatment did not vary significantly, with significant difference in means between subjects with C. difficile and other time points except the one-month group (§ p <0.05; §§ p <0.005).
Figure 4
Figure 4
Beta diversity of samples. Beta diversity via unweighted UniFrac of samples from healthy volunteers and C. difficile patients was calculated for all samples against all samples to generate a distance matrix. Samples were then clustered by Euclidean distance. CDI patients (4/5) formed a cluster distinct from the healthy volunteers and cluster by patient more than time point.

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