Proton pump inhibitors affect the gut microbiome

Floris Imhann, Marc Jan Bonder, Arnau Vich Vila, Jingyuan Fu, Zlatan Mujagic, Lisa Vork, Ettje F Tigchelaar, Soesma A Jankipersadsing, Maria Carmen Cenit, Hermie J M Harmsen, Gerard Dijkstra, Lude Franke, Ramnik J Xavier, Daisy Jonkers, Cisca Wijmenga, Rinse K Weersma, Alexandra Zhernakova, Floris Imhann, Marc Jan Bonder, Arnau Vich Vila, Jingyuan Fu, Zlatan Mujagic, Lisa Vork, Ettje F Tigchelaar, Soesma A Jankipersadsing, Maria Carmen Cenit, Hermie J M Harmsen, Gerard Dijkstra, Lude Franke, Ramnik J Xavier, Daisy Jonkers, Cisca Wijmenga, Rinse K Weersma, Alexandra Zhernakova

Abstract

Background and aims: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome.

Methods: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis.

Results: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli.

Conclusions: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.

Keywords: ENTERIC INFECTIONS; INTESTINAL BACTERIA; PROTON PUMP INHIBITION.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
PPI-associated statistically significant differences in the gut microbiome. Meta-analysis of three independent cohorts comprising 1815 faecal samples, showing a cladogram (circular hierarchical tree) of 92 significantly increased or decreased bacterial taxa in the gut microbiome of PPI users compared with non-users (FDR

Figure 2

Significantly altered families in PPI…

Figure 2

Significantly altered families in PPI users consistent in three cohorts. Meta-analysis of three…

Figure 2
Significantly altered families in PPI users consistent in three cohorts. Meta-analysis of three independent cohorts comprising 1815 faecal samples. The heatmap shows 19 families significantly increased or decreased associated with PPI use in the gut microbiome for each cohort and for the meta-analysis (meta-analysis FDR

Figure 3

Principal coordinate analysis of 1815…

Figure 3

Principal coordinate analysis of 1815 gut microbiome samples and 116 oral microbiome samples.…

Figure 3
Principal coordinate analysis of 1815 gut microbiome samples and 116 oral microbiome samples. The gut microbiome of PPI users is significantly different from non-PPI users in the first coordinate (PCoA1: p=1.39×10−20, Wilcoxon test). For Principal Coordinate 1 there is a significant shift of the gut microbiome of PPI users towards the oral microbiome. PCoA, principal coordinate analysis; PPI, proton pump inhibitor.
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Figure 2
Figure 2
Significantly altered families in PPI users consistent in three cohorts. Meta-analysis of three independent cohorts comprising 1815 faecal samples. The heatmap shows 19 families significantly increased or decreased associated with PPI use in the gut microbiome for each cohort and for the meta-analysis (meta-analysis FDR

Figure 3

Principal coordinate analysis of 1815…

Figure 3

Principal coordinate analysis of 1815 gut microbiome samples and 116 oral microbiome samples.…

Figure 3
Principal coordinate analysis of 1815 gut microbiome samples and 116 oral microbiome samples. The gut microbiome of PPI users is significantly different from non-PPI users in the first coordinate (PCoA1: p=1.39×10−20, Wilcoxon test). For Principal Coordinate 1 there is a significant shift of the gut microbiome of PPI users towards the oral microbiome. PCoA, principal coordinate analysis; PPI, proton pump inhibitor.
Figure 3
Figure 3
Principal coordinate analysis of 1815 gut microbiome samples and 116 oral microbiome samples. The gut microbiome of PPI users is significantly different from non-PPI users in the first coordinate (PCoA1: p=1.39×10−20, Wilcoxon test). For Principal Coordinate 1 there is a significant shift of the gut microbiome of PPI users towards the oral microbiome. PCoA, principal coordinate analysis; PPI, proton pump inhibitor.

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