https://orcid.org/0000-0003-1797-3426
Figures & data
Table 1. Summary of clinical data for 282 patients enrolled in this study.
Figure 1. Comparison of gut microbiomes between non-CRE and CRE groups.
(a) The Shannon diversity index and composition of phyla in the gut microbiomes were compared between non-CRE and CRE groups. Phyla with a relative abundance < 1% in each group were combined into the “others”. (b) The compositions of dominant species (>1% in each group) were compared between non-CRE and CRE groups. Species with a relative abundance < 1% in each group were combined into the “others”. (c) Species significantly contributing to the gut microbiomes of CRE and non-CRE groups were identified (P < .05). The x-axis indicates significance of ADONIS (PERMANOVA) coefficients. (d) The difference in gut microbiomes between non-CRE and CRE groups were analyzed via a nonmetric multidimensional scaling (NMDS) plot based on the Bray-Curtis distance (P = .001). The factors that correlated with the difference in gut microbiomes were determined using the EnvFit model. CRE, carbapenem-resistant Enterobacteriaceae; PPI, proton pump inhibitor; PERMANOVA, permutational multivariate analysis. ***P < .001, **P < .01, *P < .05.
Figure 2. Alterations of the gut microbiome according to PPI treatment.
(a) Compositions of gut microbiomes according to PPI treatment were compared at the species level. (b) The Shannon diversity and inter-variation of the gut microbiome according to PPI treatment were compared. (c) Contributions of 29 species to the gut microbiome according to PPI treatment in non-CRE and CRE groups. The analyzed 29 species were selected as the significant contributors to the microbiomes of non-CRE and CRE groups (as in ). The x-axis indicates the significance of ADONIS (PERMANOVA) coefficients. (d) The number of carbapenem resistance-related genes in the metagenome assembled genomes (MAGs) of Klebsiella pneumoniae was compared between PPI-treated CRE and PPI-treated non-CRE groups. CRE, carbapenem-resistant Enterobacteriaceae; PPI, proton pump inhibitor; PNT, PPI-not-treated; PT, PPI-treated; PERMANOVA, permutational multivariate analysis. ***P < .001, **P < .01, *P < .05.
Table 2. Comparison of the odds ratio (OR) for the concomitant use of proton pump inhibitors (PPIs) and specific antibiotic classes associated with carbapenem-resistant Enterobacteriaceae (CRE) colonization in the gut microbiome analyzed 98 patients based on multivariable analysis.
Figure 3. Comparison of normalized counts of carbapenemase genes and carbapenem resistance-related efflux pump genes among groups.
(a) Normalized read counts of carbapenemase genes were compared between non-CRE and CRE groups according to PPI treatment. Five major carbapenemase genes were selected for the comparison: IMP, imipenemase; KPC, K. pneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; VIM, verona integron metallo β-lactamase. (b) Distribution of carbapenem resistance-related efflux pump genes. The carbapenem resistance-associated efflux pump genes were retrieved from the CARD database. CRE, carbapenem-resistant Enterobacteriaceae; PPI, proton pump inhibitor; PNT, PPI-not-treated; PT, PPI-treated, CARD, comprehensive antibiotic resistance database; ABC, ATP-binding cassette; GBP, general bacterial porin; MFS, major facilitator superfamily; OMP, outer membrane porin; RND, resistance-nodulation-cell division; SMR, small multi-drug resistance. ***P < .001, **P < .01, *P < .05.
Figure 4. Predicted MGE transfer between bacterial species in CRE-PNT and CRE_PT groups compared using a circular phylogenetic tree based on MAGs.
The unweighted pair group method with arithmetic mean (UPGMA) phylogenetic tree was generated with 94 MAGs in the CRE_PNT group and 305 MAGs in the CRE_PT group. Colors in the outer circle indicate the phyla. Line colors in the inner circle indicate the MGE category. Number of transfer events in each category and number of transfer MGE categories between different phyla were compared. MGE, mobile genetic element; MAG, metagenome assembled genome; PT, proton pump inhibitor (PPI) treated; PNT, PPI-not-treated; IE, integration/excision; STD, stability/transfer/defense; RRR, replication/recombination/repair.
Figure 5. Transfer of carbapenem resistance genes (CRGs) between species in the gut microbiome of CRE carriers according to PPI treatment.
The transfer of CRGs between species was determined based on 100% nucleotide identify and query coverage > 98% for the paired genes. Colors in the outer circle indicate species, colors in the inner circle indicate PPI treatment, and lines in the circle indicate the processes of transfer. A red line indicates that transfer can occur via a plasmid harboring the tnp gene, a blue line indicates that transfer can occur via a plasmid not harboring the tnp gene, and a gray line indicates that transfer can occur through an unknown mechanism. CRE, carbapenem-resistant Enterobacteriaceae; PPI, proton pump inhibitor.
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