Proton pump inhibitors increase the risk of carbapenem-resistant Enterobacteriaceae colonization by facilitating the transfer of antibiotic resistance genes among bacteria in the gut microbiome

ABSTRACT

Carbapenem-resistant Enterobacteriaceae (CRE) pose a global health threat; however, there is still limited understanding of the risk factors and underlying mechanisms of CRE colonization in the gut microbiome. We conducted a matched case-control study involving 282 intensive care unit patients to analyze influencing covariates on CRE colonization. Subsequently, their effects on the gut microbiome were analyzed in a subset of 98 patients (47 CRE carriers and 51 non-CRE carriers) using whole metagenome sequences. The concomitant use of proton pump inhibitors (PPIs) and antibiotics was a significant risk factor for CRE colonization. The gut microbiome differed according to PPI administration, even within the CRE and non-CRE groups. Moreover, the transfer of mobile genetic elements (MGEs) harboring carbapenem resistance genes (CRGs) between bacteria was higher in the PPI-treated group than in the PPI-not-treated group among CRE carriers. The concomitant use of PPIs and antibiotics significantly alters the gut microbiome and increases the risk of CRE colonization by facilitating the transfer of CRGs among bacteria of the gut microbiome. Based on these findings, improved stewardship of PPIs as well as antibiotics can provide strategies to reduce the risk of CRE colonization, thereby potentially improving patient prognosis.

KEYWORDS:

• Carbapenem-resistant enterobacteriaceae
• proton pump inhibitors
• gut microbiome
• antibiotic resistance gene
• metagenome-assembled genome

Acknowledgments

We thank research nurse Soyoung Park for contributions to collecting clinical data and stool specimens.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

S.S.L. and B.-S.K. obtained funds and managed the study. I.L., J.-W.L., H.-J.W., K.T.S. and S.S.L. performed experiments and collected data. I.L. and B.-S.K. performed sequencing analyzes. I.L., S.S.L. and B.-S.K. performed bioinformatics and statistical analyzes. S.S.L. and B.-S.K. supervised statistical analyzes. I.L., S.S.L. and B.-S.K. drafted the manuscript, and all authors provided substantial revisions and approved the final manuscript.

Availability of data

The sequencing data obtained from this study are available in the EMBL SRA database under the study number PRJEB57404 (http://www.ebi.ac.uk/ena/data/view/PRJEB57404) and the sample numbers ERS14237031 to ERS14237128.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2341635

Additional information

Funding

This research was supported by the Basic Science Research Program [2019R1I1A3A01060465, 2020R1A6A1A03043026, and 2021R1A6A1A03044501] through the National Research Foundation of Korea (NRF) funded by the Ministry of Education; and the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science and ICT [2021M3A9I4023974]; and the Korea National Institute of Infectious Diseases, Korea National Institute of Health [2023-ER2107-00].