The human gut resistome

Abstract

In recent decades, the emergence and spread of antibiotic resistance among bacterial pathogens has become a major threat to public health. Bacteria can acquire antibiotic resistance genes by the mobilization and transfer of resistance genes from a donor strain. The human gut contains a densely populated microbial ecosystem, termed the gut microbiota, which offers ample opportunities for the horizontal transfer of genetic material, including antibiotic resistance genes. Recent technological advances allow microbiota-wide studies into the diversity and dynamics of the antibiotic resistance genes that are harboured by the gut microbiota ('the gut resistome'). Genes conferring resistance to antibiotics are ubiquitously present among the gut microbiota of humans and most resistance genes are harboured by strictly anaerobic gut commensals. The horizontal transfer of genetic material, including antibiotic resistance genes, through conjugation and transduction is a frequent event in the gut microbiota, but mostly involves non-pathogenic gut commensals as these dominate the microbiota of healthy individuals. Resistance gene transfer from commensals to gut-dwelling opportunistic pathogens appears to be a relatively rare event but may contribute to the emergence of multi-drug resistant strains, as is illustrated by the vancomycin resistance determinants that are shared by anaerobic gut commensals and the nosocomial pathogen Enterococcus faecium.

Keywords: Enterococcus faecium; antibiotic resistance; gut commensals; gut microbiota; metagenomics.

Figure 1.

Methods for the analysis of the human gut resistome. Starting from a faecal sample, the resistome can be sampled by culture, through targeted detection of resistance genes (by polymerase chain reaction (PCR) or microarray hybridization), by metagenomic sequencing and by functional metagenomics. Further details of these methods are discussed in the text.

Figure 2.

Resistome dynamics of a hospitalized patient. Metagenomic sequencing was performed on DNA that was isolated from faecal samples of a patient that was hospitalized in an ICU (days 4, 14 and 16). After ICU discharge at day 17, further faecal samples were collected during hospitalization in a medium-care ward (day 28) and 270 days after hospital discharge (day 313). The relative abundance of each resistance gene is indicated. Letter codes indicate resistance gene families (B, β-lactams; A, aminoglycosides; M, macrolides; T, tetracyclines; G, glycopeptides; S, sulfonamides; C, chloramphenicols; Tr, trimethoprim). Adapted from [32] with permission from Oxford University Press.

Figure 3.

A schematic overview of the pathways for horizontal gene transfer in the human gut. Anaerobic commensal bacteria (green) form an important reservoir of antibiotic resistance genes. Horizontal gene transfer owing to conjugation (illustrated by plasmid transfer) and bacteriophage-mediated transduction appears to be a common event, particularly between closely related bacteria. Gut-dwelling opportunistic pathogens (red), such as the Enterobacteriaceae and the Enterococcaceae, can also acquire resistance genes from the gut microbiota, but this is likely to occur at lower rates, which may be due to their small population size compared with the anaerobic gut commensals. The relative contribution of the different mechanisms for horizontal gene transfer of antibiotic resistance genes from gut commensals to opportunistic pathogens remains to be determined, but gene transfer may be more common between bacteria from the same phylum (like the Firmicutes) than between bacteria from different phyla. The role of the host, as illustrated by the epithelial cells (not drawn to scale), in mediating gut conditions that may positively or negatively affect horizontal gene transfer has only recently been recognized and also deserves further study.