Resident microbial communities inhibit growth and antibiotic-resistance evolution of Escherichia coli in human gut microbiome samples

Abstract

Countering the rise of antibiotic-resistant pathogens requires improved understanding of how resistance emerges and spreads in individual species, which are often embedded in complex microbial communities such as the human gut microbiome. Interactions with other microorganisms in such communities might suppress growth and resistance evolution of individual species (e.g., via resource competition) but could also potentially accelerate resistance evolution via horizontal transfer of resistance genes. It remains unclear how these different effects balance out, partly because it is difficult to observe them directly. Here, we used a gut microcosm approach to quantify the effect of three human gut microbiome communities on growth and resistance evolution of a focal strain of Escherichia coli. We found the resident microbial communities not only suppressed growth and colonisation by focal E. coli but also prevented it from evolving antibiotic resistance upon exposure to a beta-lactam antibiotic. With samples from all three human donors, our focal E. coli strain only evolved antibiotic resistance in the absence of the resident microbial community, even though we found resistance genes, including a highly effective resistance plasmid, in resident microbial communities. We identified physical constraints on plasmid transfer that can explain why our focal strain failed to acquire some of these beneficial resistance genes, and we found some chromosomal resistance mutations were only beneficial in the absence of the resident microbiota. This suggests, depending on in situ gene transfer dynamics, interactions with resident microbiota can inhibit antibiotic-resistance evolution of individual species.

Human-associated microbiota suppress invading bacteria even under disruption by antibiotics

“…In conclusion, on the one hand, these results are entirely consistent with prevailing wisdom that healthy gut communities can suppress invading strains and thereby reduce the likelihood of resistance emerging [8,9,17]. On the other hand, the absence of a significant effect of broad, or even narrow, spectrum antibiotics on the degree of competitive suppression of our focal strain is much more surprising.…”

“…Finally, the drop in Shannon diversity indicates, unsurprisingly, microcosms are a novel environment relative to the source environment. Despite this, key taxa in each community were stable over the course of the experiment, and previously over a longer timescale in the same set-up [9], demonstrating these conditions sustain diverse human-associated communities over relevant timescales.…”

“…Several studies have shown that antibiotics can leave gut communities vulnerable to colonisation by other pathogens [5][6][7], and, most recently, resistance evolution in invading strains can be facilitated by the absence of community suppression [8,9].…”

Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance

“…Obtaining a better understanding of community evolution and ecological variability will be important for predicting dynamics of therapeutic phages in patients, especially since these complex environments will contain other community members that can impact evolutionary outcomes (23,24). Such future interdisciplinary work may include incorporating evolutionary factors and environmental heterogeneity into computational models of phage infection, tracking phage population sizes in infection models and clinical trials, and including both pharmacokinetic/pharmacodynamic and phage dosing (rather than relying on a single initial inoculum).…”

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

“…A comparison of short-read NGS and long-read, third-generation sequencing of samples from patients treated for C. difficile infection revealed similarities in community compositions at the phylum and family levels, but the long-read approach further allowed for species-level characterization, permitting a better understanding of the microbial ecology of this disease. Thus, as sequencing technologies continue to improve, new species-level insights can be gained in the study of complex and clinically-relevant microbial communities, as well as the relationships between gut microbiota and infectious diseases, to evaluate the effects of probiotics supplementation [101][102][103][104][105].…”