Antibiotics and the gut microbiota

Abstract

Antibiotics have been a cornerstone of innovation in the fields of public health, agriculture, and medicine. However, recent studies have shed new light on the collateral damage they impart on the indigenous host-associated communities. These drugs have been found to alter the taxonomic, genomic, and functional capacity of the human gut microbiota, with effects that are rapid and sometimes persistent. Broad-spectrum antibiotics reduce bacterial diversity while expanding and collapsing membership of specific indigenous taxa. Furthermore, antibiotic treatment selects for resistant bacteria, increases opportunities for horizontal gene transfer, and enables intrusion of pathogenic organisms through depletion of occupied natural niches, with profound implications for the emergence of resistance. Because these pervasive alterations can be viewed as an uncoupling of mutualistic host-microbe relationships, it is valuable to reconsider antimicrobial therapies in the context of an ecological framework. Understanding the biology of competitive exclusion, interspecies protection, and gene flow of adaptive functions in the gut environment may inform the design of new strategies that treat infections while preserving the ecology of our beneficial constituents.

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Figure 2. Mechanisms for the acquisition of resistance genes.

Bacteria exchange genetic information with one another using horizontal routes of conjugation, phage transduction, and natural transformation. In conjugation (i), donor and recipient cells are physically connected through the formation of a transient bridge (pilus), and DNA copied from one cell flows to the next. Cells can transfer plasmid DNA, integrative conjugative elements (chromosomally encoded gene clusters with autonomous conjugation machinery), or chromosomal DNA through high frequency of recombination mediated by F plasmids. Phages or bacterial viruses serve as vehicles for bacterial gene transfer (ii) by transducing DNA from one host cell to another. During lysis, phages can inadvertently package bacterial DNA, either randomly incorporating pieces of the bacterial genome into phage particles (generalized transduction) or taking up bacterial DNA positioned near the phage integration site (specialized transduction). Upon lysogenic infection of a new host, genetic material can be maintained in the genome by homologous recombination or site-specific integration. In the process of natural transformation (iii), certain bacterial species can take up free DNA from the environment using membrane protein complexes. While some species exhibit competence during phases of their life cycle, others respond to extracellular cues to initiate DNA uptake.

Figure 1. Microbial community-wide effects of antibiotics on the human gut microbiota.

Antibiotic treatment alters the population structure of the indigenous microbiota, reducing bacterial diversity and redistributing member composition in both transient and persistent effects. Changes to the highly co-evolved microbial community architecture lead to changes in resource availability and species-species interactions, opening niches available for pathogenic intrusion and leading to the loss of colonization resistance. Antibiotics also select for antibiotic-resistant community members, enriching the presence of resistance genes in the microbiome. Treatment with antibiotics promotes the transfer of genetic information among bacteria by increasing conjugation, phage transduction, and plasmid mobility, primarily through the activation of cellular stress responses.