Influence of proton pump inhibitor or rebamipide use on gut microbiota of rheumatoid arthritis patients

Objective: Patients with RA commonly use gastrointestinal (GI) protective drugs for treatment and prevention of drug-associated GI injuries. However, how these drugs affect the gut microbiota in RA patients remains unknown. The objective of this study was to examine the gut microbiota of RA patients according to use of GI protective drugs such as proton pump inhibitors (PPIs), histamine 2-receptor antagonists and rebamipide. Methods: Faecal samples were obtained from 15 healthy controls and 32 RA patients who were receiving PPI, histamine 2-receptor antagonist or rebamipide. Bacterial DNA was extracted from the faecal samples and 16S rRNA sequencing was performed. Microbial composition and function were analysed using Quantitative Insights Into Microbial Ecology and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. Results: RA patients exhibited reduced diversity and altered composition of the gut microbiota compared with healthy controls. The gut microbiota of RA patients receiving acid-suppressing drugs, particularly PPIs, was distinct from that of RA patients receiving rebamipide (PPI vs rebamipide, P = 0.005). Streptococcus was enriched in RA patients receiving PPI, while Clostridium bolteae was enriched in RA patients receiving rebamipide. The gut microbiota of PPI users was abundant with microbial functional pathway involved in the production of virulence factors. This featured microbial function was positively correlated with relative abundance of Streptococcus, the differentially abundant taxa of PPI users. Conclusion: The gut microbiota of RA patients receiving PPIs was distinguishable from that of those receiving rebamipide. The enriched virulent function in the gut microbiota of PPI users suggests that inappropriate PPI use may be harmful in RA patients.